University of Edinburgh



THE ROLE OF 11?-HYDROXY STEROID DEHYDROGENASE TYPE 2 IN GLUCOCORTICOID PROGRAMMING OF AFFECTIVE AND COGNITIVE BEHAVIOURS Fraser J.G. Shearer1,2, Caitlin S. Wyrwoll3, Megan C. Holmes1,2*1 Centre for Cardiovascular Science, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK2 Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK3 School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, AustraliaShort Title: HSD2 and Programming of Adult Health*Corresponding AuthorProfessor Megan C. HolmesCentre for Cardiovascular ScienceQueen’s Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburgh, EH16 4TJ, UKTel: (+44) 131 242 6737E-mail: Megan.Holmes@ed.ac.ukKeywords: 11β-Hydroxysteroid Dehydrogenase, Placenta, Fetus, Brain, Glucocorticoids, BehaviourAbstractDevelopmental exposure to stress hormones, glucocorticoids, is central to the process of prenatal programming of later life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolising enzyme 11β-Hydroxysteroid Dehydrogenase type 2 (HSD2). HSD2 is highly expressed in two hubs during development: the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development is observed. However, brain-specific HSD2 removal (HSD2BKO), also generated adult phenotypes of depressive-like behaviour and memory deficit, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.Prenatal Glucocorticoids Programme Later Life HealthThe notion that the prenatal environment can affect the lifetime health of a fetus is well established though not entirely understood mechanistically. Since the initial observation that birthweight, a readily accessible proxy of prenatal health, positively correlated with cardiovascular health in adulthood, began a revolution in how we think about the origins of health outcomes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.311.6998.171","ISBN":"0007-0769 (Print)$\\$r0007-0769 (Linking)","ISSN":"0007-0769","PMID":"8461215","abstract":"The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease. Animal studies have shown that undernutrition before birth programmes persisting changes in a range of metabolic, physiological, and structural parameters. Studies in humans have shown that men and women whose birth weights were at the lower end of the normal range, who were thin or short at birth, or who were small in relation to placental size have increased rates of coronary heart disease. We are beginning to understand something of the mechanisms underlying these associations. The programming of blood pressure, insulin responses to glucose, cholesterol metabolism, blood coagulation, and hormonal settings are all areas of active research.","author":[{"dropping-particle":"","family":"Barker","given":"D J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"British Medical Journal","id":"ITEM-1","issued":{"date-parts":[["1995"]]},"page":"171-174","title":"Fetal origins of coronary heart disease","type":"article-journal","volume":"311"},"uris":[""]}],"mendeley":{"formattedCitation":"[1]","plainTextFormattedCitation":"[1]","previouslyFormattedCitation":"[1]"},"properties":{"noteIndex":0},"schema":""}[1] . In the decades since Barker first described this phenomenon, the repertoire of adult conditions linked to low birthweight and prenatal life has expanded to include a range of neuropsychiatric disorders. The prevalence and complex aetiology of neuropsychiatric disorders makes the possibility of a common root in the prenatal environment a tantalising treatment window. Low birthweight has been found to associate with an increased risk for affective and anxiety disorders ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/ppsych.2007.04.005","ISBN":"0010-440X","ISSN":"0010-440X","PMID":"17707257","abstract":"Numerous studies have demonstrated that low birth weight (LBW) is associated with the development of medical conditions, such as hypertension and diabetes, and psychiatric disorders, such as depression. One possible mechanism through which LBW might increase risk for both medical and psychiatric disorders is by altering the biologic systems (such as the hypothalamic-pituitary-adrenal [HPA] axis function) that govern emotion regulation and physical reactivity. In this study, we conducted secondary data analyses in a longitudinal study originally designed to understand the intergenerational transmission of major depressive disorder (MDD). We examined the risk for both medical and psychiatric illnesses known to be influenced by HPA axis dysregulation in the context of parental depression. The study had 2 primary objectives: (1) to examine whether LBW increases the risk of selected adult illness that may be influenced by the HPA axis and (2) to examine whether the increased risk of illness varies by parental depression status. We conducted longitudinal assessments of 244 offspring of depressed and nondepressed parents for more than 20 years. Psychopathology and medical illness were assessed by direct interview conducted by clinicians blind to risk status and previous diagnosis. We examined the effect of BW in 3 categories: less than 2.5 kg (LBW), 2.5-3.5 kg, and more than 3.5 kg (reference group). Offspring with LBW had a significantly increased risk of MDD, anxiety disorders, phobia, suicidal ideation, impaired functioning, allergies, and hypertension compared to those with BW exceeding 3.5 kg. The association between LBW and depression was stronger among children of depressed parents than among children of nondepressed parents, with an interaction term (BW and parental depression status) significant for MDD (P = .05), suggesting that parental depression may augment the impact of LBW on offspring depression:","author":[{"dropping-particle":"","family":"Nomura","given":"Yoko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wickramaratne","given":"Priya J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pilowsky","given":"Daniel J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newcorn","given":"Jeffrey H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruder-Costello","given":"Beth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davey","given":"Charles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fifer","given":"William P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brooks-Gunn","given":"Jeanne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weissman","given":"Myrna M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Comprehensive psychiatry","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2007"]]},"page":"470-8","title":"Low birth weight and risk of affective disorders and selected medical illness in offspring at high and low risk for depression.","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"[2]","plainTextFormattedCitation":"[2]","previouslyFormattedCitation":"[2]"},"properties":{"noteIndex":0},"schema":""}[2], behaviour and attention disorders ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1542/peds.2008-2816","ISBN":"1098-4275 (Electronic)\\r0031-4005 (Linking)","ISSN":"0031-4005","PMID":"19651588","abstract":"OBJECTIVE: Sequelae of academic underachievement, behavioral problems, and poor executive function (EF) have been extensively reported for very preterm (<or=33 weeks' gestation) and/or very low birth weight (VLBW) (<or=1500 g) children. Great variability in the published results, however, hinders the field in studying underlying dysfunctions and developing intervention strategies. We conducted a quantitative meta-analysis of studies published between 1998 and 2008 on academic achievement, behavioral functioning, and EF with the aim of providing aggregated measures of effect size for these outcome domains. METHODS: Suitable for inclusion were 14 studies on academic achievement, 9 studies on behavioral problems, and 12 studies on EF, which compared a total of 4125 very preterm and/or VLBW children with 3197 term-born controls. Combined effect sizes for the 3 outcome domains were calculated in terms of Cohen's d. Q-test statistics were performed to test homogeneity among the obtained effect sizes. Pearson's correlation coefficients were calculated to examine the impact of mean birth weight and mean gestational age, as well as the influence of mean age at assessment on the effect sizes for academic achievement, behavioral problems, and EF. RESULTS: Combined effect sizes show that very preterm and/or VLBW children score 0.60 SD lower on mathematics tests, 0.48 SD on reading tests, and 0.76 SD on spelling tests than term-born peers. Of all behavioral problems stacked, attention problems were most pronounced in very preterm and/or VLBW children, with teacher and parent ratings being 0.43 to 0.59 SD higher than for controls, respectively. Combined effect sizes for parent and teacher ratings of internalizing behavior problems were small (<0.28) and for externalizing behavior problems negligible (<0.09) and not significant. Combined effect sizes for EF revealed a decrement of 0.57 SD for verbal fluency, 0.36 SD for working memory, and 0.49 SD for cognitive flexibility in comparison to controls. Mean age at assessment was not correlated with the strength of the effect sizes. Mathematics and reading performance, parent ratings of internalizing problems, teacher ratings of externalizing behavior, and attention problems, showed strong and positive correlations with mean birth weight and mean gestational age (all r values > 0.51). CONCLUSIONS: Very preterm and/or VLBW children have moderate-to-severe deficits in academic achievement, attention problems, and internaliz…","author":[{"dropping-particle":"","family":"Aarnoudse-Moens","given":"C. S. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weisglas-Kuperus","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goudoever","given":"J. B.","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oosterlaan","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatrics","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2009"]]},"page":"717-728","title":"Meta-Analysis of Neurobehavioral Outcomes in Very Preterm and/or Very Low Birth Weight Children","type":"article-journal","volume":"124"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/apa.13094","ISBN":"1651-2227 (Electronic)\\r0803-5253 (Linking)","ISSN":"16512227","PMID":"26098907","abstract":"AIM: This Swedish study compared reading skills between seven-year-old children with a very low birthweight (VLBW) and controls with a normal birthweight, exploring associations between reading variables and cognition, parent-rated behaviour, perinatal factors and family factors.\\n\\nMETHODS: We studied 51 VLBW children, with no major neurodevelopmental impairments and attending their first year at a regular school, and compared them with the 51 sex- and age-matched controls. The test battery, carried out at 7.8?±?0.4?years of age, included reading skills, the Wechsler Intelligence Scale for Children - III and the Child Behaviour Checklist.\\n\\nRESULTS: Very low birthweight children with a mean birthweight of 1105?g (±291?g) and a gestational age of 28.8 (±2.2) weeks scored significantly lower in all reading subtests and cognition and demonstrated more behavioural problems than normal birthweight controls. We also found significant associations between poor vocabulary, combined with attention problems, and phonological awareness, rapid naming and spelling control. Perinatal factors had no association with reading function, and socio-economic factors had very few.\\n\\nCONCLUSION: Very low birthweight children demonstrated deficits in all reading domains and had poorer cognition and more behavioural problems at the age of seven, with reading ability related to vocabulary and attention.","author":[{"dropping-particle":"","family":"Leijon","given":"Ingemar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ingemansson","given":"Fredrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wadsby","given":"Marie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samuelsson","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Acta Paediatrica, International Journal of Paediatrics","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2016"]]},"page":"60-68","title":"Reading deficits in very low birthweight children are associated with vocabulary and attention issues at the age of seven","type":"article-journal","volume":"105"},"uris":[""]}],"mendeley":{"formattedCitation":"[3,4]","plainTextFormattedCitation":"[3,4]","previouslyFormattedCitation":"[3,4]"},"properties":{"noteIndex":0},"schema":""}[3,4], lower IQ ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/adc.85.3.189","ISBN":"1468-2044 (Electronic)","ISSN":"00039888","PMID":"11517097","abstract":"AIMS: To examine the relation between birth weight and cognitive function at age 11 years, and to examine whether this relation is independent of social class. METHODS: Retrospective cohort study based on birth records from 1921 and cognitive function measured while at school at age 11 in 1932. Subjects were 985 live singletons born in the Edinburgh Royal Maternity and Simpson Memorial Hospital in 1921. Moray House Test scores from the Scottish Mental Survey 1932 were traced on 449 of these children. RESULTS: Mean score on Moray House Test increased from 30.6 at a birth weight of <2500 g to 44.7 at 4001-4500 g, after correcting for gestational age, maternal age, parity, social class, and legitimacy of birth. Multiple regression showed that 15.6% of the variance in Moray House Test score is contributed by a combination of social class (6.6%), birth weight (3.8%), child's exact age (2.4%), maternal parity (2.0%), and illegitimacy (1.5%). Structural equation modelling confirmed the independent contribution from each of these variables in predicting cognitive ability. A model in which birth weight acted as a mediator of social class had poor fit statistics. CONCLUSION: In this 1921 birth cohort, social class and birth weight have independent effects on cognitive function at age 11. Future research will relate these childhood data to health and cognition in old age.","author":[{"dropping-particle":"","family":"Shenkin","given":"S D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Starr","given":"J M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pattie","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rush","given":"M a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Whalley","given":"L J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deary","given":"I J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of disease in childhood","id":"ITEM-1","issued":{"date-parts":[["2001"]]},"page":"189-196","title":"Birth weight and cognitive function at age 11 years: the Scottish Mental Survey 1932.","type":"article-journal","volume":"85"},"uris":[""]}],"mendeley":{"formattedCitation":"[5]","plainTextFormattedCitation":"[5]","previouslyFormattedCitation":"[5]"},"properties":{"noteIndex":0},"schema":""}[5], schizophrenia ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1017/S003329171200267X","ISBN":"1469-8978 (Electronic)\\r0033-2917 (Linking)","ISSN":"00332917","PMID":"23298736","abstract":"BACKGROUND: Accumulating evidence suggests that fetal growth restriction may increase risk of later schizophrenia but this issue has not been addressed directly in previous studies. We examined whether the degree of fetal growth restriction was linearly related to risk of schizophrenia, and also whether maternal pre-eclampsia, associated with both placental dysfunction and poor fetal growth, was related to risk of schizophrenia.\\n\\nMETHOD: A population-based cohort of single live births in the Medical Birth Registry of Norway (MBRN) between 1967 and 1982 was followed to adulthood (n=873 612). The outcome was schizophrenia (n=2207) registered in the National Insurance Scheme (NIS). The degree of growth restriction was assessed by computing sex-specific z scores (standard deviation units) of ‘ birth weight for gestational age’ and ‘ birth length for gestational age’. Analyses were adjusted for potential confounders. Maternal pre-eclampsia was recorded in the Medical Birth Registry by midwives or obstetricians using strictly defined criteria.\\n\\nRESULTS: The odds ratio (OR) for schizophrenia increased linearly with decreasing birth weight for gestational age z scores (p value for trend=0.005). Compared with the reference group (z scores 0.01–1.00), the adjusted OR [95% confidence interval (CI)] for the lowest z-score category (<x3.00) was 2.0 (95% CI 1.2–3.5). A similar pattern was observed for birth length for gestational age z scores. Forty-nine individuals with schizophrenia were identified among 15 622 births with pre-eclampsia. The adjusted OR for schizophrenia following maternal pre-eclampsia was 1.3 (95% CI 1.0–1.8).\\n\\nCONCLUSIONS: Associations of schizophrenia risk with degree of fetal growth restriction and pre-eclampsia suggest future research into schizophrenia etiology focusing on mechanisms that influence fetal growth, including placental function.","author":[{"dropping-particle":"","family":"Eide","given":"M. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moster","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Irgens","given":"L. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reichborn-Kjennerud","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stoltenberg","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Skj?rven","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Susser","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abel","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Psychological Medicine","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2013"]]},"page":"2057-2066","title":"Degree of fetal growth restriction associated with schizophrenia risk in a national cohort","type":"article-journal","volume":"43"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1192/bjp.165.3.357","ISSN":"0007-1250","PMID":"7994506","abstract":"BACKGROUND: Low birth weight has been postulated to be a risk factor for schizophrenia.\\n\\nMETHOD: Obstetric history, premorbid adjustment, and cognitive function during admission were assessed in 167 patients with DSM-III schizophrenia or affective psychosis.\\n\\nRESULTS: A birth weight of less than 2500 g was significantly more common in patients with schizophrenia than in those with affective psychosis. Schizophrenic patients as a group had significantly lower mean birth weight, a finding which was particularly marked after controlling for sociodemographic confounders. In schizophrenic men, lower birth weight was highly significantly correlated with poorer premorbid social and cognitive ability, and with impairment of adult cognitive function.\\n\\nCONCLUSIONS: Neurodevelopmental impairment may cause poor foetal growth, and schizophrenia in adult life.","author":[{"dropping-particle":"","family":"Rifkin","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewis","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Toone","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The British Journal of Psychiatry","id":"ITEM-2","issue":"November 2015","issued":{"date-parts":[["1994"]]},"page":"357-362","title":"Low birth weight and schizophrenia","type":"article-journal","volume":"165"},"uris":[""]}],"mendeley":{"formattedCitation":"[6,7]","plainTextFormattedCitation":"[6,7]","previouslyFormattedCitation":"[6,7]"},"properties":{"noteIndex":0},"schema":""}[6,7] and autism spectrum disorder ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2012.04.058","ISBN":"2122633255","ISSN":"00223476","PMID":"22677565","abstract":"Objective: To examine the relationship between birth weight, gestational age, small for gestational age (SGA), and 3 of the most common autism spectrum disorder (ASD) subtypes. Study design: In this population-based case-control study conducted in Finland, 4713 cases born between 1987 and 2005 with International Classification of Diseases-diagnoses of childhood autism, Asperger syndrome, or pervasive developmental disorder (PDD), were ascertained from the Finnish Hospital Discharge Register. Four controls, individually matched on sex, date of birth, and place of birth, were selected from the Finnish Medical Birth Register for each case. Conditional logistic regression models were used to assess whether birth weight and gestational age information predicted ASD after controlling for maternal age, parity, smoking during pregnancy, and psychiatric history, as well as for infant's major congenital anomalies. Results: Very low (<1500 g) and moderately low (<2500 g) birth weight, very low gestational age (less than 32 weeks), and SGA increased risk of childhood autism (adjusted OR 3.05, 95% CI 1.4-6.5; 1.57, 1.1-2.3; 2.51, 1.3-5.0; and 1.72, 1.1-2.6, respectively). Very low and moderately low birth weight, very low gestational age, and SGA were also associated with increase in PDD risk (OR 3.44, 95% CI 1.9-6.3; 1.81, 1.4-2.4; 2.46, 1.4-2.3; and 2.24, 1.7-3.0, respectively). No associations were found between the perinatal characteristics and Asperger syndrome. The increased risks persisted after controlling for selected potential confounders. Conclusions: The finding that low birth weight, prematurity, and SGA were related to childhood autism and PDD but not to Asperger syndrome suggests that prenatal factors related to these exposures may differ for these ASD subtypes, which may have preventive implications. Copyright ? 2012 Mosby Inc.","author":[{"dropping-particle":"","family":"Lampi","given":"Katja M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehtonen","given":"Liisa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tran","given":"Phuong Lien","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suominen","given":"Auli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehti","given":"Venla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Banerjee","given":"P. Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gissler","given":"Mika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brown","given":"Alan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sourander","given":"Andre","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatrics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2012"]]},"page":"830-836","publisher":"Mosby, Inc.","title":"Risk of autism spectrum disorders in low birth weight and small for gestational age infants","type":"article-journal","volume":"161"},"uris":[""]}],"mendeley":{"formattedCitation":"[8]","plainTextFormattedCitation":"[8]","previouslyFormattedCitation":"[8]"},"properties":{"noteIndex":0},"schema":""}[8]. Amongst the many factors that affect birthweight, stress hormones – glucocorticoids - have emerged as candidates for mediating the programming effects, through observations that maternal stress during pregnancy causes low birthweight and increases the risk of later-life neurological disorder ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/neuro.08.019.2009","ISBN":"ISSN 1662-5153","ISSN":"16625153","PMID":"19826624","abstract":"Numerous clinical studies associate an adverse prenatal environment with the development of cardio-metabolic disorders and neuroendocrine dysfunction, as well as an increased risk of psychiatric diseases in later life. Experimentally, prenatal exposure to stress or excess glucocorticoids in a variety of animal models can malprogram offspring physiology, resulting in a reduction in birth weight and subsequently increasing the likelihood of disorders of cardiovascular function, glucose homeostasis, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviours in adulthood. During fetal development, placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides a barrier to maternal glucocorticoids. Reduced placental 11beta-HSD2 in human pregnancy correlates with lower birth weight and higher blood pressure in later life. Similarly, in animal models, inhibition or knockout of placental 11beta-HSD2 lowers offspring birth weight, in part by reducing glucose delivery to the developing fetus in late gestation. Molecular mechanisms thought to underlie the programming effects of early life stress and glucocorticoids include epigenetic changes in target chromatin, notably affecting tissue-specific expression of the intracellular glucocorticoid receptor (GR). As such, excess glucocorticoids in early life can permanently alter tissue glucocorticoid signalling, effects which may have short-term adaptive benefits but increase the risk of later disease.","author":[{"dropping-particle":"","family":"Cottrell","given":"Elizabeth C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Behavioral Neuroscience","id":"ITEM-1","issue":"September","issued":{"date-parts":[["2009"]]},"page":"1-9","title":"Prenatal stress, glucocorticoids and the programming of adult disease","type":"article-journal","volume":"3"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1523/JNEUROSCI.4464-05.2006","ISSN":"0270-6474","author":[{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neuroscience","id":"ITEM-2","issue":"14","issued":{"date-parts":[["2006"]]},"page":"3840-3844","title":"The Mother or the Fetus? 11beta-Hydroxysteroid Dehydrogenase Type 2 Null Mice Provide Evidence for Direct Fetal Programming of Behavior by Endogenous Glucocorticoids","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"[9,10]","manualFormatting":"(Cottrell 2009; Holmes 2006)","plainTextFormattedCitation":"[9,10]","previouslyFormattedCitation":"[9,10]"},"properties":{"noteIndex":0},"schema":""}(Cottrell 2009; Holmes 2006). Animal models have further indicated that excess glucocorticoids in pregnancy have detrimental effects on neurodevelopment ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/sj.npp.1300892","ISBN":"0893-133X (Print)","ISSN":"0893-133X","PMID":"16160705","abstract":"Glucocorticoid administration to preterm infants is associated with neurodevelopmental disorders. We treated developing rats with dexamethasone (Dex) at 0.05, 0.2, or 0.8 mg/kg, doses below or spanning the range in clinical use, testing the effects of administration during three different stages: gestational days 17-19, postnatal days 1-3 or postnatal days 7-9. In adulthood, we assessed the impact on synaptic biomarkers for serotonin (5-hydroxytryptamine (5HT)) systems. Across all three regimens, Dex administration evoked upregulation of cerebrocortical 5HT1A and 5HT2 receptors and the presynaptic 5HT transporter, greatest for 5HT1A receptors. The effects were fully evident even at the lowest dose. In contrast, 5HT levels in the cerebral cortex and hippocampus showed disparate patterns of temporal sensitivity, with no change after gestational treatment, an increase with the early postnatal regimen, and a decrease with the later postnatal exposure. None of the changes in 5HT concentrations were offset by adaptive changes in the fractional 5HT turnover rate. Furthermore, the critical period of sensitivity seen for 5HT levels differed from that of dopamine even within the same brain region. These findings suggest that developmental exposure to Dex during the critical neurodevelopmental period corresponding to its use in preterm infants, elicits selective changes in 5HT and dopaminergic synaptic function over and above its effects on general aspects of neural cell development, below the threshold for somatic growth impairment, and even at doses below those used clinically. Accordingly, adverse neurobehavioral consequences may be inescapable in glucocorticoid therapy of preterm infants.","author":[{"dropping-particle":"","family":"Slotkin","given":"Theodore a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kreider","given":"Marisa L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tate","given":"Charlotte a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seidler","given":"Frederic J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2006"]]},"page":"904-11","title":"Critical prenatal and postnatal periods for persistent effects of dexamethasone on serotonergic and dopaminergic systems.","type":"article-journal","volume":"31"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0085671","ISBN":"1932-6203","ISSN":"19326203","PMID":"24465645","abstract":"Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.","author":[{"dropping-particle":"","family":"Noorlander","given":"Cornelle W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tijsseling","given":"Deodata","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hessel","given":"Ellen V S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vries","given":"Willem B.","non-dropping-particle":"De","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Derks","given":"Jan B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visser","given":"Gerard H a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graan","given":"Pierre N E","non-dropping-particle":"De","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2014"]]},"page":"1-7","title":"Antenatal glucocorticoid treatment affects hippocampal development in mice","type":"article-journal","volume":"9"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.cobeha.2015.08.001","ISSN":"23521546","abstract":"Synthetic glucocorticoids are frequently used antenatally in order to reduce morbidity and mortality in babies born preterm and have been used in the management of fetuses known to be at risk of congenital adrenal hyperplasia. Although such treatment has short term advantages, evidence suggests that it can affect health in later life. Several studies have reported negative consequences of prenatal exposure to the synthetic glucocorticoid dexamethasone on offspring behavior in humans and in animal models, in association with changes in brain structure, hypothalamic-pituitary-adrenal axis function, neurotransmitter pathways, gene transcription and epigenetic regulation. These studies also highlight the importance of timing and tissue/organ-specific and sex-specific effects of prenatal glucocorticoid exposure. Here we review the evidence from human and animal studies that links prenatal synthetic glucocorticoid exposure with an increased risk for neurodevelopmental disorders.","author":[{"dropping-particle":"","family":"Cartier","given":"Jessy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zeng","given":"Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drake","given":"Amanda J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Current Opinion in Behavioral Sciences","id":"ITEM-3","issued":{"date-parts":[["2016"]]},"page":"1-7","publisher":"Elsevier Ltd","title":"Glucocorticoids and the prenatal programming of neurodevelopmental disorders","type":"article-journal","volume":"7"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.3389/neuro.08.019.2009","ISBN":"ISSN 1662-5153","ISSN":"16625153","PMID":"19826624","abstract":"Numerous clinical studies associate an adverse prenatal environment with the development of cardio-metabolic disorders and neuroendocrine dysfunction, as well as an increased risk of psychiatric diseases in later life. Experimentally, prenatal exposure to stress or excess glucocorticoids in a variety of animal models can malprogram offspring physiology, resulting in a reduction in birth weight and subsequently increasing the likelihood of disorders of cardiovascular function, glucose homeostasis, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviours in adulthood. During fetal development, placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides a barrier to maternal glucocorticoids. Reduced placental 11beta-HSD2 in human pregnancy correlates with lower birth weight and higher blood pressure in later life. Similarly, in animal models, inhibition or knockout of placental 11beta-HSD2 lowers offspring birth weight, in part by reducing glucose delivery to the developing fetus in late gestation. Molecular mechanisms thought to underlie the programming effects of early life stress and glucocorticoids include epigenetic changes in target chromatin, notably affecting tissue-specific expression of the intracellular glucocorticoid receptor (GR). As such, excess glucocorticoids in early life can permanently alter tissue glucocorticoid signalling, effects which may have short-term adaptive benefits but increase the risk of later disease.","author":[{"dropping-particle":"","family":"Cottrell","given":"Elizabeth C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Behavioral Neuroscience","id":"ITEM-4","issue":"September","issued":{"date-parts":[["2009"]]},"page":"1-9","title":"Prenatal stress, glucocorticoids and the programming of adult disease","type":"article-journal","volume":"3"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.6084/m9.figshare.5285401","ISBN":"1111111111","ISSN":"1932-6203","PMID":"28945761","abstract":"Adverse experiences early in life impair cognitive function both in rodents and humans. In humans this increases the vulnerability to develop mental illnesses while in the rodent brain early life stress (ELS) abnormalities are associated with changes in synaptic plasticity, excit- ability and microstructure. Detailed information on the effects of ELS on rodent brain struc- tural integrity at large and connectivity within the brain is currently lacking; this information is highly relevant for understanding the mechanism by which early life stress predisposes to mental illnesses. Here, we exposed rats to 24 hours of maternal deprivation (MD) at postnatal day 3, a par- adigm known to increase corticosterone levels and thereby activate glucocorticoid receptors in the brain. Using structural magnetic resonance imaging we examined: i) volumetric changes and white/grey matter properties of the whole cerebrum and of specific brain areas; and ii) whether potential alterations could be normalized by blocking glucocorticoid receptors with mifepristone during the critical developmental window of early adolescence, i.e. between postnatal days 26 and 28. The results show thatMDcaused a volumetric reduction of the prefrontal cortex, particu- larly the ventromedial part, and the orbitofrontal cortex. Within the whole cerebrum, white (relative to grey) matter volume was decreased and region-specifically in prefrontal cortex and dorsomedial striatum following MD. A trend was found for the hippocampus. Grey matter fractions were not affected. Treatment with mifepristone did not normalize these changes. This study indicates that early life stress in rodents has long lasting consequences for the volume and structural integrity of the brain. However, changes were relatively modest and– unlike behavior- not mitigated by blockade of glucocorticoid receptors during a critical devel- opmental period.","author":[{"dropping-particle":"","family":"Dijkhuizen","given":"Rick M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sarabdjitsingh","given":"R Angela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Loi","given":"Manila","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Joe","given":"Marian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-5","issue":"9","issued":{"date-parts":[["2017"]]},"page":"1-14","title":"Early life stress-induced alterations in rat brain structures measured with high resolution MRI","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"[9,11–14]","plainTextFormattedCitation":"[9,11–14]","previouslyFormattedCitation":"[9,11–14]"},"properties":{"noteIndex":0},"schema":""}[9,11–14].During pregnancy, glucocorticoid levels increase trimester to trimester until serum levels are up to three times that of pre-pregnancy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/cen.13548","ISBN":"0000000154871","ISSN":"13652265","PMID":"27935037","abstract":"? 2018 The Authors. Objective: Hypothalamic-pituitary-adrenal axis (HPA) activity is decreased in obese pregnancy and associates with increased foetal size. Pulsatile release of glucocorticoid hormones regulates their action in target tissues. Glucocorticoids are essential for normal foetal growth, but little is known about glucocorticoid pulsatility in pregnancy. We aimed to investigate the ultradian rhythm of glucocorticoid secretion during obese and lean pregnancy and nonpregnancy. Design: Serum cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were measured by LC-MS/MS from samples obtained at 10-minute intervals between 08.00-11.00 hours and 16.00-19.00 hours, from 8 lean (BMI < 25 kg/m 2 ) and 7 obese (BMI > 35 kg/m 2 ) pregnant women between 16-24 weeks gestation and again at 30-36 weeks), and nonpregnant controls (lean n = 3, obese n = 4) during the luteal phase of their menstrual cycle. Interstitial fluid cortisol was measured by ELISA, from samples obtained using a portable microdialysis and automated collection device at 20-minute intervals over 24 hours. Results: Serum cortisol AUC, highest peak and lowest trough increased significantly with gestation in lean and obese pregnant compared with nonpregnant subjects. Pulsatility of cortisol was detected in interstitial fluid. In pregnant subjects, interstitial fluid pulse frequency was significantly lower with advancing gestation in obese, but not in lean. Conclusions: We demonstrate cortisol pulsatility in interstitial fluid. Pulse frequency is altered with increased gestation and BMI. This may be a novel mechanism to explain decreased HPA activity in obese pregnancy.","author":[{"dropping-particle":"","family":"Stirrat","given":"Laura I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Jamie J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stryjakowska","given":"Ksenia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Natalie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Homer","given":"Natalie Z.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andrew","given":"Ruth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Norman","given":"Jane E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lightman","given":"Stafford L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reynolds","given":"Rebecca M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Endocrinology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2018"]]},"page":"592-600","title":"Pulsatility of glucocorticoid hormones in pregnancy: Changes with gestation and obesity","type":"article-journal","volume":"88"},"uris":[""]}],"mendeley":{"formattedCitation":"[15]","plainTextFormattedCitation":"[15]","previouslyFormattedCitation":"[15]"},"properties":{"noteIndex":0},"schema":""}[15], in part to facilitate essential maternal adaptations. There is a complexity to this rise in circulating maternal glucocorticoids however, as circulating corticosterone binding globulin and its affinity for glucocorticoids also varies during pregnancy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000354702","ISBN":"1423-0194 (Electronic)\\r0028-3835 (Linking)","ISSN":"14230194","PMID":"23969897","abstract":"ther understanding of the changes in the HPA axis during pregnancy and the impact of these changes may ultimately allow early identification of those most at risk of future dis-ease.","author":[{"dropping-particle":"","family":"Duthie","given":"Leanne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reynolds","given":"Rebecca M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroendocrinology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013"]]},"page":"106-115","title":"Changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy and postpartum: Influences on maternal and fetal outcomes","type":"article-journal","volume":"98"},"uris":[""]}],"mendeley":{"formattedCitation":"[16]","plainTextFormattedCitation":"[16]","previouslyFormattedCitation":"[16]"},"properties":{"noteIndex":0},"schema":""}[16], thus regulating free glucocorticoid levels and action. Conversely, the fetus is maintained in a glucocorticoid environment 5-10 times lower than the maternal circulation until the last stages of gestation, at which point a surge in glucocorticoids aids the maturation of organs, by promoting cell differentiation and the arrest of proliferation in preparation for the ex utero environment ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1079/PNS19980017","ISBN":"1475-2719","ISSN":"0029-6651","PMID":"9571716","abstract":"See, stats, and : https : / / www . researchgate . net / publication / 51343710 Glucocorticoids after : Are -term of ? Article DOI : 10 . 1079 / PNS19980017 : PubMed CITATIONS 306 READS 197 3 , including : Some : Nutritional Developmental Abigail University 361 , 960 SEE All . The . All - text and , letting .","author":[{"dropping-particle":"","family":"Fowden","given":"Abigail L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Juan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forhead","given":"Alison J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the Nutrition Society","id":"ITEM-1","issue":"01","issued":{"date-parts":[["1998"]]},"page":"113-122","title":"Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance?","type":"article-journal","volume":"57"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/physrev.00020.2012","ISSN":"0031-9333","author":[{"dropping-particle":"","family":"Chapman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1139-1206","title":"11?-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action","type":"article-journal","volume":"93"},"uris":[""]}],"mendeley":{"formattedCitation":"[17,18]","plainTextFormattedCitation":"[17,18]","previouslyFormattedCitation":"[17,18]"},"properties":{"noteIndex":0},"schema":""}[17,18]. This is most notable in the case of the lungs, where the formation of surfactant is reliant on glucocorticoids. Consequently, babies likely to be born prematurely (at 24-37 weeks) are administered synthetic glucocorticoids (such as dexamethasone or betamethasone) to induce lung maturation early and increase survival ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1079/PNS19980017","ISBN":"1475-2719","ISSN":"0029-6651","PMID":"9571716","abstract":"See, stats, and : https : / / www . researchgate . net / publication / 51343710 Glucocorticoids after : Are -term of ? Article DOI : 10 . 1079 / PNS19980017 : PubMed CITATIONS 306 READS 197 3 , including : Some : Nutritional Developmental Abigail University 361 , 960 SEE All . The . All - text and , letting .","author":[{"dropping-particle":"","family":"Fowden","given":"Abigail L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Juan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forhead","given":"Alison J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the Nutrition Society","id":"ITEM-1","issue":"01","issued":{"date-parts":[["1998"]]},"page":"113-122","title":"Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance?","type":"article-journal","volume":"57"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/0002-9378(95)90210-4","ISBN":"0002-9378","ISSN":"00029378","PMID":"7631700","abstract":"The scientific basis for use of prenatal steroid therapy in preparing the human fetus for premature delivery is extensive and convincing. Studies in numerous animal species have documented precocious maturation of lung and other tissues after administration of glucocorticoids to the fetus, and ablation experiments indicate delayed organ maturation with a deficiency of endogenous corticosteroid. The timing of lung differentiation correlates well with the developmental increase in circulating corticosteroid, supporting the concepts that endogenous corticosteroids, interacting with other hormones, are important physiologic modulators of tissue maturation and that prenatal steroid therapy mimics the effect of endogenous glucocorticoids. In fetal lung the response to glucocorticoid involves induction of a limited number of proteins, including all the components of surfactant, as well as key lipogenic enzymes. These effects are mediated by glucocorticoid receptors, occur with physiologic concentrations of hormone, are primarily exerted at the level of gene activation, and are reversible on removal of hormone from cultured tissue. These various observations predict that a relatively brief exposure of the human fetus to glucocorticoid accelerates the normal developmental process in lung and other tissues and reduces disease resulting from developmental immaturity. Prenatal treatment with either betamethasone or dexamethasone at the recommended doses provides similar physiologic stress levels of glucocorticoid activity in fetal plasma sufficient to provide a near-maximal occupancy of receptors and induction of target proteins. Elevated glucocorticoid levels are maintained during the course of treatment and values return to normal by 2 days after the last dose. Treatment causes a transient suppression of maternal and fetal adrenal function; however, treated infants respond to newborn stress with a near-normal cortisol surge. However, there is little information, and reason for concern, regarding the safety of higher or repeated dose of prenatal steroid, and accordingly, routine retreatment of women who are not in active labor is not advised. The recommendation of the consensus panel that corticosteroid therapy is indicated for women at risk of premature delivery with few exceptions is thus well supported by evidence relating to glucocorticoid effects, mechanisms, and pharmacokinetics. ? 1995, All rights reserved.","author":[{"dropping-particle":"","family":"Ballard","given":"Philip L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ballard","given":"Roberta A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Obstetrics and Gynecology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["1995"]]},"page":"254-262","title":"Scientific basis and therapeutic regimens for use of antenatal glucocorticoids","type":"article-journal","volume":"173"},"uris":[""]}],"mendeley":{"formattedCitation":"[17,19]","plainTextFormattedCitation":"[17,19]","previouslyFormattedCitation":"[17,19]"},"properties":{"noteIndex":0},"schema":""}[17,19].Given the potent effects of glucocorticoids on fetal development, it is critical that fetal glucocorticoid exposure is tightly regulated. This regulation is achieved in part through the presence of 11β-Hydroxysteroid Dehydrogenase Type 2 (HSD2), an NAD-dependent enzyme which converts active, receptor binding, glucocorticoids to their inactive forms in the cytoplasm ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00020.2012","ISSN":"0031-9333","author":[{"dropping-particle":"","family":"Chapman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1139-1206","title":"11?-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action","type":"article-journal","volume":"93"},"uris":[""]}],"mendeley":{"formattedCitation":"[18]","plainTextFormattedCitation":"[18]","previouslyFormattedCitation":"[18]"},"properties":{"noteIndex":0},"schema":""}[18]. The sister glucocorticoid metabolising enzyme, 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1), is also expressed in the placenta. It converts inactive 11 keto derivatives to the active glucocorticoid, therefore raising active glucocorticoid levels [18]. HSD1 is expressed in the labyrinth zone of the rodent placenta in late gestation (rising as HSD2 levels fall), potentially increasing glucocorticoids reaching the fetus to induce terminal differentiation before parturition [18]. It is the protective barrier of HSD2 that will be investigated further in this review. Two Hubs of HSD2 Limit Fetal Exposure to GlucocorticoidsIn the adult organism, the role of HSD2 is primarily to protect mineralocorticoid responsive tissue from inappropriate binding of glucocorticoids to mineralocorticoid receptors (MR), for which they have a high affinity ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00020.2012","ISSN":"0031-9333","author":[{"dropping-particle":"","family":"Chapman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1139-1206","title":"11?-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action","type":"article-journal","volume":"93"},"uris":[""]}],"mendeley":{"formattedCitation":"[18]","plainTextFormattedCitation":"[18]","previouslyFormattedCitation":"[18]"},"properties":{"noteIndex":0},"schema":""}[18]. For example, HSD2 is highly expressed in the distal nephron of the kidney where MR activation by aldosterone is required for sodium reabsorption. However, during gestation, HSD2 is much more widely expressed in the fetus and placenta. Fetal expression of HSD2 is widespread but transient. In the mouse, HSD2 is expressed in the majority of fetal tissues until E13.5 when a rapid decline in expression is observed ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Brown","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"A C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Kotelevtsev","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullins","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"M H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1996"]]},"page":"794-797","title":"The Ontogeny of 11beta-Hydroxysteroid Dehydrogenase Type 2 and Mineralocorticoid Receptor Gene Expression Reveal Intricate Control of Glucocorticoid Action in Development","type":"article-journal","volume":"137"},"uris":[""]}],"mendeley":{"formattedCitation":"[20]","plainTextFormattedCitation":"[20]","previouslyFormattedCitation":"[20]"},"properties":{"noteIndex":0},"schema":""}[20]. Expression of HSD2 in the brain declines after mid-gestation but is maintained in discreet pockets into the third trimester after which it further declines, with early postnatal expression restricted to the thalamus and cerebellum in the rodent ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Brown","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"A C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Kotelevtsev","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullins","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"M H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1996"]]},"page":"794-797","title":"The Ontogeny of 11beta-Hydroxysteroid Dehydrogenase Type 2 and Mineralocorticoid Receptor Gene Expression Reveal Intricate Control of Glucocorticoid Action in Development","type":"article-journal","volume":"137"},"uris":[""]},{"id":"ITEM-2","itemData":{"ISBN":"0270-6474 (Print)\\r0270-6474 (Linking)","ISSN":"0270-6474","PMID":"9502816","abstract":"Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has recently been recognized that GC access to receptors is determined by the presence of tissue-specific 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD type 1 (11beta-HSD1) is a bidirectional enzyme in vitro that acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11beta-HSD type 2 (11beta-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivity in vivo. We have examined the ontogeny of 11beta-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11beta-HSD2 mRNA is highly expressed in all CNS regions during midgestation, but expression is dramatically reduced during the third trimester except in the thalamus and cerebellum; (2) 11beta-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11beta-HSD1 mRNA is absent from the CNS until the the third trimester, and activity is low or undectectable; and (4) GR mRNA is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11beta-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11beta-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.","author":[{"dropping-particle":"","family":"Diaz","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brown","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of neuroscience : the official journal of the Society for Neuroscience","id":"ITEM-2","issue":"7","issued":{"date-parts":[["1998"]]},"page":"2570-2580","title":"Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions.","type":"article-journal","volume":"18"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.neuroscience.2005.09.037","ISSN":"0306-4522","PMID":"16289840","abstract":"11beta-Hydroxysteroid dehydrogenase type 2 is a glucocorticoid metabolizing enzyme that catalyzes rapid inactivation of corticosterone and cortisol to inert 11-keto derivatives. As 11beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the developing brain, but not in the adult CNS, we hypothesized that it may represent a protective barrier to the deleterious actions of corticosteroids on proliferating cells. To test this hypothesis we have investigated the development and growth of the cerebellum in neonatal C57BL/6 mice and mice lacking 11beta-hydroxysteroid dehydrogenase type 2 (-/-). 11beta-Hydroxysteroid dehydrogenase type 2-/- mice had consistently lower body weight throughout the neonatal period, coupled with a smaller brain size although this was normalized when corrected for body weight. The cerebellar size was smaller in 11beta-hydroxysteroid dehydrogenase type 2-/- mice, due to decreases in size of both the molecular and internal granule layers. When exogenous corticosterone was administered to the pups between postnatal days 4 and 13, 11beta-hydroxysteroid dehydrogenase type 2(-/-) mice were more sensitive, showing further inhibition of cerebellar growth while the wildtype mice were not affected. Upon withdrawal of exogenous steroid, there was a rebound growth spurt so that at day 21 postnatally, the cerebellar size in 11beta-hydroxysteroid dehydrogenase type 2-/- mice was similar to untreated mice of the same genotype. Furthermore, 11beta-hydroxysteroid dehydrogenase type 2-/- mice had a delay in the attainment of neurodevelopmental landmarks such as negative geotaxis and eye opening. We therefore suggest that 11beta-hydroxysteroid dehydrogenase type 2 acts as to protect the developing nervous system from the deleterious consequences of glucocorticoid overexposure.","author":[{"dropping-particle":"","family":"Holmes","given":"M C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sangra","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"French","given":"K L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Whittle","given":"I R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paterson","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullins","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroscience","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2006"]]},"page":"865-73","title":"11beta-Hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids.","type":"article-journal","volume":"137"},"uris":[""]}],"mendeley":{"formattedCitation":"[20–22]","plainTextFormattedCitation":"[20–22]","previouslyFormattedCitation":"[20–22]"},"properties":{"noteIndex":0},"schema":""}[20–22]. In the placenta HSD2 is expressed in the syncytiotrophoblast where maternal and fetal circulations are in apposition ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISBN":"0169-328X (Print)\\r0169-328X (Linking)","ISSN":"0169-328X","PMID":"9795098","abstract":"11 Beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. The recently discovered type 2 isozyme (11 beta-HSD-2) is a high affinity, NAD-dependent, exclusive 11 beta-dehydrogenase, which rapidly inactivates glucocorticoids. Thus the enzyme generates aldosterone-selectivity for intrinsically non-selective mineralocorticoid receptors in vivo as well as excluding glucocorticoids from glucocorticoid receptors, the latter being particularly important during development. Aldosterone exerts selective central effects upon salt appetite and blood pressure whilst glucocorticoids have potent effects upon postnatal neurogenesis and brain remodelling. We examined 11 beta-HSD-2 expression during postnatal ontogeny and in adult rat brain. High 11 beta-HSD-2 mRNA expression was found specifically in the postnatal thalamus and the external granule cell layer of the cerebellum. Expression peaked at the end of the first postnatal week and declined rapidly thereafter. Postnatal brain showed considerable activity of high affinity 11 beta-HSD-2 which paralleled expression of 11 beta-HSD-2 messenger ribonucleic acid (mRNA). Adult brain showed high 11 beta-HSD-2 mRNA expression limited to the subcommissural organ, with lower expression in the ventromedial nucleus of the hypothalamus, amygdala, locus coeruleus and nucleus tractus solitarius. These discrete areas are compatible with proposed selective central actions of aldosterone on blood pressure (subcommissural organ, nucleus tractus solitarius) and salt appetite (ventromedial nucleus, amygdala). In contrast, early postnatal 11 beta-HSD-2 coincides with glucocorticoid receptor rather than mineralocorticoid receptor expression, and areas of expression are among the regions where glucocorticoids have been demonstrated to have profound effects upon neuronal division, growth and maturation.","author":[{"dropping-particle":"","family":"Robson","given":"a C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leckie","given":"C M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Brain research. Molecular brain research","id":"ITEM-1","issued":{"date-parts":[["1998"]]},"page":"1-10","title":"11 Beta-hydroxysteroid dehydrogenase type 2 in the postnatal and adult rat brain.","type":"article-journal","volume":"61"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/physrev.00020.2012","ISSN":"0031-9333","author":[{"dropping-particle":"","family":"Chapman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1139-1206","title":"11?-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action","type":"article-journal","volume":"93"},"uris":[""]},{"id":"ITEM-3","itemData":{"author":[{"dropping-particle":"","family":"Brown","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"A C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Kotelevtsev","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullins","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"M H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-3","issue":"2","issued":{"date-parts":[["1996"]]},"page":"794-797","title":"The Ontogeny of 11beta-Hydroxysteroid Dehydrogenase Type 2 and Mineralocorticoid Receptor Gene Expression Reveal Intricate Control of Glucocorticoid Action in Development","type":"article-journal","volume":"137"},"uris":[""]}],"mendeley":{"formattedCitation":"[18,20,23]","plainTextFormattedCitation":"[18,20,23]","previouslyFormattedCitation":"[18,20,23]"},"properties":{"noteIndex":0},"schema":""}[18,20,23]. Only the fetal side of the placenta expresses HSD2 and its expression declines along a similar timeline to fetal HSD2 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Brown","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"A C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Kotelevtsev","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullins","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"M H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["1996"]]},"page":"794-797","title":"The Ontogeny of 11beta-Hydroxysteroid Dehydrogenase Type 2 and Mineralocorticoid Receptor Gene Expression Reveal Intricate Control of Glucocorticoid Action in Development","type":"article-journal","volume":"137"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/physrev.00020.2012","ISSN":"0031-9333","author":[{"dropping-particle":"","family":"Chapman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1139-1206","title":"11?-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action","type":"article-journal","volume":"93"},"uris":[""]}],"mendeley":{"formattedCitation":"[18,20]","plainTextFormattedCitation":"[18,20]","previouslyFormattedCitation":"[18,20]"},"properties":{"noteIndex":0},"schema":""}[18,20]. In early-gestation placental HSD2 regulates fetal exposure to maternal glucocorticoids ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1096/fj.12-203489","ISBN":"1530-6860 (Electronic)\\r0892-6638 (Linking)","ISSN":"0892-6638","PMID":"22321728","abstract":"Fetal growth restriction associates with increased risk of adult cardiometabolic and neuropsychiatric disorders. Both maternal malnutrition [notably a low-protein (LP) diet] and stress/glucocorticoid exposure reduce fetal growth and cause persisting abnormalities (programming) in adult offspring. Deficiency of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which inactivates glucocorticoids, is reduced by an LP diet and has been proposed as a unifying mechanism. Here, we explored the importance of glucocorticoids and placental 11β-HSD2 in dietary programming. Pregnant mice were fed a control or isocaloric LP diet throughout gestation. The LP diet first elevated fetal glucocorticoid levels, then reduced placental growth, and finally decreased fetal weight near term by 17%. Whereas the LP diet reduced placental 11β-HSD2 activity near term by ～25%, consistent with previous reports, activity was increased between 20 and 40% at earlier ages, implying that glucocorticoid overexposure in LP fetuses occurs via 11β-HSD2-independent mechanisms. Consistent with this, heterozygous 11β-HSD2(+/-) crosses showed that although both LP and 11β-HSD2 deficiency reduced fetal growth, LP indeed acted independently of 11β-HSD2. Instead, the LP diet induced the fetal hypothalamic-pituitary-adrenal axis per se. Thus, maternal malnutrition and placental 11β-HSD2 deficiency act via distinct processes to retard fetal growth, both involving fetoplacental overexposure to glucocorticoids but from distinct sources.","author":[{"dropping-particle":"","family":"Cottrell","given":"E. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Livingstone","given":"D. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kenyon","given":"C. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J. R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The FASEB Journal","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2012"]]},"page":"1866-1874","title":"Reconciling the nutritional and glucocorticoid hypotheses of fetal programming","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"[24]","plainTextFormattedCitation":"[24]","previouslyFormattedCitation":"[24]"},"properties":{"noteIndex":0},"schema":""}[24]. Interestingly, when HSD2 is inhibited, cortisol does not freely perfuse across the placenta ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2017-02140","ISSN":"19457197","PMID":"29161409","abstract":"Context Fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life. Objective To develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesized placental 11-β-hydroxysteroid dehydrogenase-type 2 (11β-HSD2) would be the major rate-limiting step in maternal cortisol transfer to the fetus. Design We used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modeling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus. Participants Term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery. Intervention Maternal artery of the isolated perfused placenta was perfused with D4-cortisol. Main Outcome Measures D4-cortisol, D3-cortisone, and D3-cortisol were measured in maternal and fetal venous outflows. Results D4-cortisol, D3-cortisone, and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11-β-hydroxysteroid dehydrogenase (11β-HSD) activity was inhibited. At the highest inlet concentration, only 3.0% of the maternal cortisol was transferred to the fetal circulation, whereas 26.5% was metabolized and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, whereas 92.7% exited via the maternal vein. Conclusions Our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major \"barrier\" to cortisol transfer to the fetus.","author":[{"dropping-particle":"","family":"Stirrat","given":"Laura I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sengers","given":"Bram G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Norman","given":"Jane E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Homer","given":"Natalie Z.M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andrew","given":"Ruth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewis","given":"Rohan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reynolds","given":"Rebecca M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2018"]]},"page":"640-648","title":"Transfer and metabolism of cortisol by the isolated perfused human placenta","type":"article-journal","volume":"103"},"uris":[""]}],"mendeley":{"formattedCitation":"[25]","plainTextFormattedCitation":"[25]","previouslyFormattedCitation":"[25]"},"properties":{"noteIndex":0},"schema":""}[25], highlighting the likely contribution of transporters, potentially adenosine triphosphate binding cassette (ABC) transporters, in protecting the fetus from elevated cortisol ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/en.2006-0633","ISBN":"0013-7227 (Print)\\n0013-7227 (Linking)","ISSN":"00137227","PMID":"16873536","abstract":"Exposure of the fetus and placenta to maternal glucocorticoids is normally limited by the placental glucocorticoid barrier, which consists primarily of placental 11beta-hydroxy-steroid dehydrogenase type 2-mediated conversion of cortisol to the biologically inactive cortisone. Studies in the rodent brain show that P-glycoprotein (P-gp) is also an important physiological regulator of glucocorticoid access to the glucocorticoid receptor (GR) in target cells because it exports cortisol back into peripheral circulation against a concentration gradient. Whether P-gp of placental origin also has this capacity is unknown. Therefore, we used the human placental choriocarcinoma cell line BeWo and its daughter cell line, BeWoMDR, virally transduced with P-gp, to assess whether placental P-gp regulates access of glucocorticoids to the GR. Quantitative PCR showed that BeWoMDR cells express approximately 10-fold higher levels of P-gp mRNA than BeWo cells, and syncytialization increased P-gp mRNA by approximately 7-fold. Elevated P-gp expression in BeWoMDR cells reduced activation of the GR by dexamethasone and cortisol (10(-9) to 10(-6) M) to around 40% of that in BeWo cells. Inhibition of P-gp-mediated glucocorticoid efflux by cyclosporin A in BeWoMDR cells returned GR activation to levels similar to those in BeWo cells. Diffusion of dexamethasone across BeWoMDR monolayers occurred at a slower rate than that across BeWo monolayers, but this difference was eliminated by cyclosporin A. These data support the hypothesis that P-gp contributes to the placental glucocorticoid barrier. Thus, 11beta-hydroxysteroid dehydrogenase type 2 and P-gp may act in unison to reduce fetal and placental exposure to maternal glucocorticoids and thereby minimize their growth inhibitory actions.","author":[{"dropping-particle":"","family":"Mark","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waddell","given":"Brendan J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2006"]]},"page":"5147-5152","title":"P-glycoprotein restricts access of cortisol and dexamethasone to the glucocorticoid receptor in placental BeWo cells","type":"article-journal","volume":"147"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/ajpregu.2000.279.4.R1495","ISBN":"0363-6119 (Print)","ISSN":"0363-6119","PMID":"11004020","abstract":"The placenta serves, in part, as a barrier to exclude noxious substances from the fetus. In humans, a single-layered syncytium of polarized trophoblast cells and the fetal capillary endothelium separate the maternal and fetal circulations. P-glycoprotein is present in the syncytiotrophoblast throughout gestation, consistent with a protective role that limits exposure of the fetus to hydrophobic and cationic xenobiotics. We have examined whether members of the multidrug resistance protein (MRP) family are expressed in term placenta. After screening a placenta cDNA library, partial clones of MRP1, MRP2, and MRP3 were identified. Immunofluorescence and immunoblotting studies demonstrated that MRP2 was localized to the apical syncytiotrophoblast membrane. MRP1 and MRP3 were predominantly expressed in blood vessel endothelia with some evidence for expression in the apical syncytiotrophoblast. ATP-dependent transport of the anionic substrates dinitrophenyl-glutathione and estradiol-17-beta-glucuronide was also demonstrated in apical syncytiotrophoblast membranes. Given the cellular distribution of these transporters, we hypothesize that MRP isoforms serve to protect fetal blood from entry of organic anions and to promote the excretion of glutathione/glucuronide metabolites in the maternal circulation.","author":[{"dropping-particle":"V","family":"St-Pierre","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serrano","given":"M A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Macias","given":"R I R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dubs","given":"U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zu","given":"Ch-","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Expression","given":"J J G Marin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Regulatory","given":"Physiol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Comp","given":"Integrative","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"AJP Regulatory Integrative Comp Physiol","id":"ITEM-2","issued":{"date-parts":[["2000"]]},"page":"1495-1503","title":"Expression of members of the multidrug resistance protein family in human term placenta","type":"article-journal","volume":"279"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1111/jcmm.13646","ISSN":"15821838","PMID":"29691980","abstract":"The placental multidrug transporters, P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP, ABCG2) protect the foetus from exposure to maternally derived glucocorticoids, toxins and xenobiotics. During pregnancy, maternal glucocorticoid levels can be elevated by stress or exogenous administration. We hypothesized that glucocorticoids modulate the expression of ABCB1/P-gp and ABCG2/BCRP in the first trimester human placenta. Our objective was to examine whether dexamethasone (DEX) or cortisol modulate first trimester placental expression of multidrug transporters and determine whether cytotrophoblasts or the syncytiotrophoblast are/is responsible for mediating these effects. Three models were examined: (i) an ex-vivo model of placental villous explants (7-10 weeks), (ii) a model of isolated first trimester syncytiotrophoblast and cytotrophoblast cells and (iii) the BeWo immortalized trophoblast cell line model. These cells/tissues were treated with DEX or cortisol for 24 hour to 72 hour. In first trimester placental explants, DEX (48 hour) increased ABCB1 (P < .001) and ABCG2 (P < .05) mRNA levels, whereas cortisol (48 hour) only increased ABCB1 mRNA levels (P < .01). Dex-amethasone (P < .05) and cortisol (P < .01) increased BCRP but did not affect P-gp protein levels. Breast cancer resistance protein expression was primarily confined to syncytiotrophoblasts. BeWo cells, when syncytialized with forskolin, increased expression of BCRP protein, and this was further augmented by DEX (P < .05). Our data suggest that the protective barrier provided by BCRP increases as cytotro-phoblasts fuse to form the syncytiotrophoblast. Increase in glucocorticoid levels during the first trimester may reduce embryo/foetal exposure to clinically relevant BCRP substrates, because of an increase in placental BCRP. K E Y W O R D S BeWo, breast cancer related protein (BCRP), dexamethasone, first trimester placenta, glucocorticoids, P-glycoprotein (P-gp)This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.","author":[{"dropping-particle":"","family":"Lye","given":"Phetcharawan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bloise","given":"Enrrico","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nadeem","given":"Lubna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gibb","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lye","given":"Stephen J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matthews","given":"Stephen G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Cellular and Molecular Medicine","id":"ITEM-3","issue":"7","issued":{"date-parts":[["2018"]]},"page":"3652-3660","title":"Glucocorticoids modulate multidrug resistance transporters in the first trimester human placenta","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"[26–28]","plainTextFormattedCitation":"[26–28]","previouslyFormattedCitation":"[26–28]"},"properties":{"noteIndex":0},"schema":""}[26–28]. Furthermore, the regulatory activity of HSD2 is somewhat malleable. Elevated glucocorticoids, such as during stress, can increase the fetal exposure by overwhelming and down regulating HSD2 activity ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.psyneuen.2011.09.014","ISBN":"0306-4530","ISSN":"03064530","PMID":"22001010","abstract":"Background: Raised maternal anxiety during pregnancy is associated with increased risk of adverse neurodevelopmental outcomes for her child. The mechanisms underlying this are not known but animal studies suggest prenatal stress may alter the function of the placenta. Here we determined whether maternal prenatal anxiety was associated with a downregulation of placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme which metabolises cortisol. Methods: We recruited mothers the day before delivery by elective caesarean, and gave them the Spielberger Trait and State anxiety and Edinburgh Depression self-rating scales. Placentae were collected and aliquots stored for later analysis. Results: Prenatal Trait anxiety was negatively correlated with placental 11β-HSD2 mRNA expression (r= -0.40, p< 0.01, n= 56). Results were similar with male and female fetuses (r= -0.39, p= 0.04, n= 28; r= -0.40, p= 0.03, n= 28) respectively. Results were also significant with State anxiety (r= -0.27, p= 0.05, n= 56) but somewhat weaker for depression (r= -0.20, p= 0.13, n= 56). Preliminary analyses on a subset of cases (n= 25) suggested parallel results for enzyme activity. Conclusions: These findings provide evidence for an association between prenatal maternal mood and downregulation of placental 11β-HSD2. Results are consistent with raised maternal anxiety being associated with increased fetal exposure to maternal cortisol, and support the hypothesis that this may be one mechanism underlying fetal programming by prenatal stress. ? 2011 Elsevier Ltd.","author":[{"dropping-particle":"","family":"O'Donnell","given":"Kieran J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bugge Jensen","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freeman","given":"Laura","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khalife","given":"Natasha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Connor","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Glover","given":"Vivette","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Psychoneuroendocrinology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012"]]},"page":"818-826","publisher":"Elsevier Ltd","title":"Maternal prenatal anxiety and downregulation of placental 11β-HSD2","type":"article-journal","volume":"37"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0039791","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"22761903","abstract":"Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14-20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain.","author":[{"dropping-particle":"","family":"Pe?a","given":"Catherine Jensen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Monk","given":"Catherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Champagne","given":"Frances A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2012"]]},"page":"1-9","title":"Epigenetic effects of Prenatal stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and fetal brain","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"[29,30]","plainTextFormattedCitation":"[29,30]","previouslyFormattedCitation":"[29,30]"},"properties":{"noteIndex":0},"schema":""}[29,30]. Additionally, in the case of glucocorticoid treatment, synthetic glucocorticoids (see above) are poor substrates of HSD2, and as such, are not inactivated. Importantly, the downregulation of HSD2 consistently elicits fetal growth restriction and strongly associates with adverse health outcomes in later life, highlighting that feto-placental HSD2 is a critical mediator between neonatal environment and adult outcomes. Mutations of HSD2 in the human population lead, most notably, to the syndrome of apparent mineralocorticoid excess through the unrestricted binding of glucocorticoids to MR in the distal tubules of the kidney ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.96.22.12790","ISBN":"0027-8424 (Print)\\r0027-8424 (Linking)","ISSN":"0027-8424","PMID":"10536001","abstract":"Our research team and laboratories have concentrated on two inherited endocrine disorders, congenital adrenal hyperplasia (CAH) and apparent mineralocorticoid excess, in thier investigations of the pathophysiology of adrenal steroid hormone disorders in children. CAH refers to a family of inherited disorders in which defects occur in one of the enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, adrenocorticotropic hormone levels rise due to impairment of a negative feedback system, which results in hyperplasia of the adrenal cortex. The majority of cases is due to 21-hydroxylase deficiency (21-OHD). Owing to the blocked enzymatic step, cortisol precursors accumulate in excess and are converted to potent androgens, which are secreted and cause in utero virilization of the affected female fetus genitalia in the classical form of CAH. A mild form of the 21-OHD, termed nonclassical 21-OHD, is the most common autosomal recessive disorder in humans, and occurs in 1/27 Ashkenazic Jews. Mutations in the CYP21 gene have been identified that cause both classical and nonclassical CAH. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11beta-hydroxysteroid dehydrogenase type 2. In 1998, we reported a mild form of this disease, which may represent an important cause of low-renin hypertension.","author":[{"dropping-particle":"","family":"New","given":"M. I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilson","given":"R. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-1","issue":"22","issued":{"date-parts":[["1999"]]},"page":"12790-12797","title":"Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess","type":"article-journal","volume":"96"},"uris":[""]}],"mendeley":{"formattedCitation":"[31]","plainTextFormattedCitation":"[31]","previouslyFormattedCitation":"[31]"},"properties":{"noteIndex":0},"schema":""}[31]. The majority of these mutations lie in the COOH-terminus half of the gene ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00020.2012","ISSN":"0031-9333","author":[{"dropping-particle":"","family":"Chapman","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2013"]]},"page":"1139-1206","title":"11?-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action","type":"article-journal","volume":"93"},"uris":[""]}],"mendeley":{"formattedCitation":"[18]","plainTextFormattedCitation":"[18]","previouslyFormattedCitation":"[18]"},"properties":{"noteIndex":0},"schema":""}[18]. Polymorphisms of the HSD2 gene (HSD11B2) have been investigated in relation to neuroaffective disorders. A study of schizophrenia risk in relation to HSD2 genotype found an interaction between early life stress exposure and the rs5479 genotype in children aged 3–9 years which conveyed an increased risk of the disorder ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.psyneuen.2015.05.013","ISBN":"1873-3360 0306-4530","ISSN":"18733360","PMID":"26115144","abstract":"Background: To examine the risk of schizophrenia in a Danish population after exposure to early life stress, and whether this risk is modified by DNA sequence variation, specifically two single nucleotide polymorphisms (SNPs) (rs5479 and rs56303414) from the gene HSD11B2. This gene encodes the enzyme 11-β hydroxysteroid dehydrogenase type 2 which converts active cortisol into inactive cortisone. Methods: A two-stage analysis involving (1) a population-based cohort study, and (2) a nested case-control study using genotype information. Stage 1 included 1,141,447 people here, we calculated incidence rate ratios (IRR) for the risk of schizophrenia among children of mothers who experienced loss or serious illness of close relatives before, during, and after pregnancy. In stage 2, we genotyped rs5479 and rs56303414 among 1275 schizophrenia cases and 1367 controls, and investigated interactions between genotypes and early life stress on the risk of schizophrenia. Results: In stage 1, no increased risk of schizophrenia was found in offspring after exposure during pregnancy, but offspring exposed to early life stress at age 0-2 years had a significantly increased risk of schizophrenia (adjusted IRR 1.18, 95% confidence interval 1.07-1.31). For rs5479, the minor allele was nucleotide A, and the major allele was nucleotide C. No interaction was found between rs5479 and exposure during pregnancy. Individuals with the minor A allele of rs5479, however, had a significantly increased risk of schizophrenia after exposure to early life stress at age 3-9 years (adjusted IRR 2.06, 1.04-4.06). No interaction was found between rs56303414 and exposure in any of the time periods. Conclusion: No association was found between exposure to early life stress during pregnancy and schizophrenia in the offspring investigated, whereas individuals exposed to early life stress within the first two years of life had an increased risk. No interaction was found between HSD11B2 and exposure during pregnancy, but individuals with the A allele of rs5479 had an increased risk of schizophrenia after exposure at age 3-9 years.","author":[{"dropping-particle":"","family":"Debost","given":"Jean Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Petersen","given":"Liselotte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grove","given":"Jakob","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hedemand","given":"Anne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khashan","given":"Ali","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henriksen","given":"Tine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mors","given":"Ole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hollegaard","given":"Mads","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hougaard","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nyegaard","given":"Mette","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"B?rglum","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mortensen","given":"Preben Bo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Psychoneuroendocrinology","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"18-27","publisher":"Elsevier Ltd","title":"Investigating interactions between early life stress and two single nucleotide polymorphisms in HSD11B2 on the risk of schizophrenia","type":"article-journal","volume":"60"},"uris":[""]}],"mendeley":{"formattedCitation":"[32]","plainTextFormattedCitation":"[32]","previouslyFormattedCitation":"[32]"},"properties":{"noteIndex":0},"schema":""}[32]. In a prospective study of cortisol in pregnancy, the functional HSD11B2[CA]n polymorphism in fetuses was shown to be associated with increased maternal cortisol ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000355761","ISBN":"1423-0143 (Electronic)\\n1420-4096 (Linking)","ISSN":"14230143","PMID":"24685985","abstract":"BACKGROUND/AIMS: Cortisol plays an important role during pregnancy. It controls maternal glucose metabolism and fetal development. Cortisol metabolism is partially controlled by the 11b-HSD2. This enzyme is expressed in the kidney and human placenta. The activity of the enzyme is partially controlled by functional polymorphisms: the HSD11B2[CA]n microsatellite polymorphism. The impact of this functional gene polymorphism on cortisol metabolism and potential effects on the newborn's is unknown so far.\\n\\nMETHODS: In the current prospective birth cohort study in southern Asia, we analyzed the association of the HSD11B2[CA]n microsatellite polymorphisms in 187 mothers and their newborn's on maternal and newborn's serum cortisol concentrations.\\n\\nRESULTS: Using multivariable regression analyses considering known confounding (gestational age, newborn's gender, the labor uterine contraction states and the timing during the day of blood taking), we showed that the fetal HSD11B2[CA]n microsatellite polymorphisms in the first intron was related to maternal cortisol concentration (R2=0.26, B=96.27, p=0.007), whereas as the newborn's cortisol concentrations were independent of fetal and maternal HSD11B2[CA]n microsatellite polymorphism.\\n\\nCONCLUSIONS: Our study showed for the first time that the fetal HSD11B2[CA]n microsatellite polymorphism of the HSD11B2 gene in healthy uncomplicated human pregnancy is associated with maternal cortisol concentration. This indicates that fetal genes controlling cortisol metabolism may affect maternal cortisol concentration and hence physiology in healthy pregnant women.","author":[{"dropping-particle":"","family":"Li","given":"Jian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"You Peng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Zi Neng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Bin","family":"Liu","given":"Tie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Dan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dong","given":"Yun Peng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hocher","given":"Berthold","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Kidney and Blood Pressure Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014"]]},"page":"132-141","title":"A functional fetal HSD11B2[CA]n microsatellite polymorphism is associated with maternal serum cortisol concentrations in pregnant women","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":"[33]","plainTextFormattedCitation":"[33]","previouslyFormattedCitation":"[33]"},"properties":{"noteIndex":0},"schema":""}[33]. Hence, manipulation of HSD2 expression in mice provides a platform for examining the effects of early glucocorticoid exposure on the fetus without artificially elevating glucocorticoids. This also enables control of the site of premature glucocorticoid exposure to either mother, feto-placental unit or fetus alone. Homozygous matings of HSD2-/- mice generated offspring with low birthweight, reduced neonatal cerebellar growth and as adults exhibit the Syndrome of Apparent Mineralocorticoid Excess and a depressive and anxious phenotype ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1523/JNEUROSCI.4464-05.2006","ISSN":"0270-6474","author":[{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neuroscience","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2006"]]},"page":"3840-3844","title":"The Mother or the Fetus? 11beta-Hydroxysteroid Dehydrogenase Type 2 Null Mice Provide Evidence for Direct Fetal Programming of Behavior by Endogenous Glucocorticoids","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"[10]","plainTextFormattedCitation":"[10]","previouslyFormattedCitation":"[10]"},"properties":{"noteIndex":0},"schema":""}[10]. Heterozygous mating of these mice, giving three genotypes of offspring in the same litter (HSD2+/+, HSD2+/-, HSD2-/-), found no significant differences between heterozygous mice and HSD2+/+ mice, illustrating that maternal phenotype was not influencing the offspring and that reduction of the placental barrier to 50% failed to alter fetal outcomes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1523/JNEUROSCI.4464-05.2006","ISSN":"0270-6474","author":[{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neuroscience","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2006"]]},"page":"3840-3844","title":"The Mother or the Fetus? 11beta-Hydroxysteroid Dehydrogenase Type 2 Null Mice Provide Evidence for Direct Fetal Programming of Behavior by Endogenous Glucocorticoids","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"[10]","plainTextFormattedCitation":"[10]","previouslyFormattedCitation":"[10]"},"properties":{"noteIndex":0},"schema":""}[10]. However, HSD2-/- mice are exposed to glucocorticoids at an inappropriate time in gestation, as they lack placental and fetal protection. In this genotype, birthweight is reduced, highlighting that glucocorticoids are affecting development ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1523/JNEUROSCI.4464-05.2006","ISSN":"0270-6474","author":[{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neuroscience","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2006"]]},"page":"3840-3844","title":"The Mother or the Fetus? 11beta-Hydroxysteroid Dehydrogenase Type 2 Null Mice Provide Evidence for Direct Fetal Programming of Behavior by Endogenous Glucocorticoids","type":"article-journal","volume":"26"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1111/apha.12187","ISSN":"17481708","author":[{"dropping-particle":"","family":"Cottrell","given":"E. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wyrwoll","given":"C. S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Acta Physiologica","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2014"]]},"page":"288-295","title":"Foetal and placental 11 <i>β</i> -HSD2: a hub for developmental programming","type":"article-journal","volume":"210"},"uris":[""]}],"mendeley":{"formattedCitation":"[10,34]","plainTextFormattedCitation":"[10,34]","previouslyFormattedCitation":"[10,34]"},"properties":{"noteIndex":0},"schema":""}[10,34]. Furthermore, as adults HSD2-/- mice display an anxiety-like phenotype in both open field and elevated plus maze assessments ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1523/JNEUROSCI.4464-05.2006","ISSN":"0270-6474","author":[{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neuroscience","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2006"]]},"page":"3840-3844","title":"The Mother or the Fetus? 11beta-Hydroxysteroid Dehydrogenase Type 2 Null Mice Provide Evidence for Direct Fetal Programming of Behavior by Endogenous Glucocorticoids","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"[10]","plainTextFormattedCitation":"[10]","previouslyFormattedCitation":"[10]"},"properties":{"noteIndex":0},"schema":""}[10] and depression-like behaviour in tail suspension and forced swim tests ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000331345","ISBN":"1423-0194","ISSN":"00283835","PMID":"22042385","abstract":"Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal 'programming' of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety- and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroendocrinology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2012"]]},"page":"47-55","title":"Prenatal excess glucocorticoid exposure and adult affective disorders: A role for serotonergic and catecholamine pathways","type":"article-journal","volume":"95"},"uris":[""]}],"mendeley":{"formattedCitation":"[35]","plainTextFormattedCitation":"[35]","previouslyFormattedCitation":"[35]"},"properties":{"noteIndex":0},"schema":""}[35]. Dysfunction of the HPA axis is commonly seen in offspring following prenatal stress exposure, and furthermore, is often considered a marker of prenatal stress ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1196/annals.1314.006","ISBN":"0077-8923 (Print)\\r0077-8923 (Linking)","ISSN":"0077-8923","PMID":"15677396","abstract":"Epidemiological evidence suggests that an adverse fetal environment permanently programs physiology, leading to increased risks of cardiovascular, metabolic, and neuroendocrine disorders in adulthood. Prenatal glucocorticoid excess or stress might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal glucocorticoid exposure or inhibition of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the fetoplacental \"barrier\" to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis (HPA) activity and behavior resembling anxiety. In humans, 11beta-HSD2 gene mutations cause low birth weight and reduced placental 11beta-HSD2 activity associated with intrauterine growth retardation. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors; key is the glucocorticoid receptor itself. Differential programming of the glucocorticoid receptor in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the glucocorticoid receptor gene. Overall, the data suggest that either pharmacological or physiological exposure to excess glucocorticoids prenatally programs pathologies in adult life.","author":[{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meaney","given":"M J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Ann N Y Acad Sci","id":"ITEM-1","issue":"44","issued":{"date-parts":[["2004"]]},"page":"63-84","title":"Glucocorticoid programming","type":"article-journal","volume":"1032"},"uris":[""]}],"mendeley":{"formattedCitation":"[36]","plainTextFormattedCitation":"[36]","previouslyFormattedCitation":"[36]"},"properties":{"noteIndex":0},"schema":""}[36]. Yet while HSD2-/- offspring exhibit behaviours classically associated with HPA axis dysfunction, no changes in the HPA axis have been observed ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1523/JNEUROSCI.4464-05.2006","ISSN":"0270-6474","author":[{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neuroscience","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2006"]]},"page":"3840-3844","title":"The Mother or the Fetus? 11beta-Hydroxysteroid Dehydrogenase Type 2 Null Mice Provide Evidence for Direct Fetal Programming of Behavior by Endogenous Glucocorticoids","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"[10]","plainTextFormattedCitation":"[10]","previouslyFormattedCitation":"[10]"},"properties":{"noteIndex":0},"schema":""}[10]. HSD2 expression in the adult mouse brain is limited to the nucleus tractus solitarius (NTS) where it maintains aldosterone selectivity of MR ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Bailey","given":"Matthew A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Curr Hypertens Rep","id":"ITEM-1","issue":"100","issued":{"date-parts":[["2017"]]},"publisher":"Current Hypertension Reports","title":"11 β -Hydroxysteroid Dehydrogenases and Hypertension in the Metabolic Syndrome","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"[37]","plainTextFormattedCitation":"[37]","previouslyFormattedCitation":"[37]"},"properties":{"noteIndex":0},"schema":""}[37]. The majority of glucocorticoid effects on the brain in the HSD2-/- are, therefore, likely developmental in origin. The global knockout of HSD2 provides an insight into the role that the HSD2 plays in neurodevelopment and the programming of adult behaviour, but the phenotypes observed, though likely to involve neurodevelopment, are confounded by the effects of HSD2 removal from other body systems in the adult. Furthermore, the deletion of HSD2 in the fetus generates an AME phenotype, of increased blood pressure ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1523/JNEUROSCI.4464-05.2006","ISSN":"0270-6474","author":[{"dropping-particle":"","family":"Holmes","given":"M. C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Neuroscience","id":"ITEM-1","issue":"14","issued":{"date-parts":[["2006"]]},"page":"3840-3844","title":"The Mother or the Fetus? 11beta-Hydroxysteroid Dehydrogenase Type 2 Null Mice Provide Evidence for Direct Fetal Programming of Behavior by Endogenous Glucocorticoids","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"[10]","plainTextFormattedCitation":"[10]","previouslyFormattedCitation":"[10]"},"properties":{"noteIndex":0},"schema":""}[10] together with increased salt appetite mediated by the loss of HSD2 in the brain ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1161/HYPERTENSIONAHA.110.163782","ISSN":"1524-4563","PMID":"21282561","abstract":"Salt sensitivity of blood pressure is an independent risk factor for cardiovascular morbidity. Mechanistically, abnormal mineralocorticoid action and subclinical renal impairment may blunt the natriuretic response to high sodium intake, causing blood pressure to rise. 11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) controls ligand access to the mineralocorticoid receptor, and ablation of the enzyme causes severe hypertension. Polymorphisms in HSD11B2 are associated with salt sensitivity of blood pressure in normotensives. In this study, we used mice heterozygote for a null mutation in Hsd11b2 (Hsd11b2(+/-)) to define the mechanisms linking reduced enzyme activity to salt sensitivity of blood pressure. A high-sodium diet caused a rapid and sustained increase in blood pressure in Hsd11b2(+/-) mice but not in wild-type littermates. During the adaptation to high-sodium diet, heterozygotes displayed impaired sodium excretion, a transient positive sodium balance, and hypokalemia. After 21 days of high-sodium feeding, Hsd11b2(+/-) mice had an increased heart weight. Mineralocorticoid receptor antagonism partially prevented the increase in heart weight but not the increase in blood pressure. Glucocorticoid receptor antagonism prevented the rise in blood pressure. In Hsd11b2(+/-) mice, high-sodium feeding caused suppression of aldosterone and a moderate but sustained increase in corticosterone. This study demonstrates an inverse relationship among 11βHSD2 activity, heart weight, and blood pressure in a clinically important context. Reduced activity causes salt sensitivity of blood pressure, but this does not reflect illicit activation of mineralocorticoid receptors by glucocorticoids. Instead, we have identified a novel interaction among 11βHSD2, dietary salt, and circulating glucocorticoids.","author":[{"dropping-particle":"","family":"Bailey","given":"Matthew a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Craigie","given":"Eilidh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Livingstone","given":"Dawn E W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Kotelevtsev","given":"Yuri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Al-Dujaili","given":"Emad a S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kenyon","given":"Christopher J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullins","given":"John J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hypertension","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2011"]]},"page":"515-20","title":"Hsd11b2 haploinsufficiency in mice causes salt sensitivity of blood pressure.","type":"article-journal","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"[38]","plainTextFormattedCitation":"[38]","previouslyFormattedCitation":"[38]"},"properties":{"noteIndex":0},"schema":""}[38]. Additionally, HSD2-/- does not provide a distinction between the two hubs of HSD2 expression in gestation; the placenta and the fetus. The relative importance of the two hubs of HSD2 expression in development in the programming of neurological conditions are discussed below (figure 1).The Placenta Orchestrates Fetal Development and Adult Health OutcomesThe placenta is the interface between mother and fetus, regulating nutrient and waste transfer, endocrine and immunological responses, thus ensuring maternal adaptations and fetal development. These placental functions are by no means passive and the placenta has a remarkable plasticity, capable of adaptations to mitigate an adverse in utero environment. Furthermore, fetal sex influences the plasticity of the placenta ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.placenta.2016.12.008","ISSN":"15323102","PMID":"27979377","abstract":"Exposure of the embryo or fetus to perturbations in utero can result in intrauterine growth restriction, a primary risk factor for the development of adult disease. However, despite similar exposures, males and females often have altered disease susceptibility or progression from different stages of life. Fetal growth is largely mediated by the placenta, which, like the fetus is genetically XX or XY. The placenta and its associated trophoblast lineages originate from the trophectoderm (TE) of the early embryo. Rodent models (rat, mouse, spiny mouse), have been used extensively to examine placenta development and these have demonstrated the growth trajectory of the placenta in females is generally slower compared to males, and also shows altered adaptive responses to stressful environments. These placental adaptations are likely to depend on the type of stressor, duration, severity and the window of exposure during development. Here we describe the divergent developmental pathways between the male and female placenta contributing to altered differentiation of the TE derived trophoblast subtypes, placental growth, and formation of the placental architecture. Our focus is primarily genetic or environmental perturbations in rodent models which show altered placental responsiveness between sexes. We suggest that perturbations during early placental development may have greater impact on viability and growth of the female fetus whilst those occurring later in gestation may preferentially affect the male fetus. This may be of great relevance to human pregnancies which result from assisted reproductive technologies or complications such as pre-eclampsia and diabetes.","author":[{"dropping-particle":"","family":"Kalisch-Smith","given":"J. I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simmons","given":"D. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dickinson","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moritz","given":"K. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Placenta","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"10-16","publisher":"Elsevier Ltd","title":"Review: Sexual dimorphism in the formation, function and adaptation of the placenta","type":"article-journal","volume":"54"},"uris":[""]}],"mendeley":{"formattedCitation":"[39]","plainTextFormattedCitation":"[39]","previouslyFormattedCitation":"[39]"},"properties":{"noteIndex":0},"schema":""}[39]. If normal placental function or adaptation is overcome, this can result in poor fetal outcomes such as intrauterine growth restriction (IUGR). However, the ramifications of inadequate placental function extend far beyond short-term health outcomes. Epidemiological and animal studies show that reduced placental function and weight associate with low birth weight and an increased risk of cardio-metabolic and neuropsychiatric outcomes in adult life ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00029.2015","ISBN":"1522-1210 0031-9333","ISSN":"00319333 (ISSN)","abstract":"Epidemiological evidence links an individual’s susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions. ? 2016 the American Physiological Society.","author":[{"dropping-particle":"","family":"Burton","given":"Graham J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fowden","given":"Abigail L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thornburg","given":"Kent L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2016"]]},"page":"1509-1565","title":"Placental Origins of Chronic Disease","type":"article-journal","volume":"96"},"uris":[""]}],"mendeley":{"formattedCitation":"[40]","plainTextFormattedCitation":"[40]","previouslyFormattedCitation":"[40]"},"properties":{"noteIndex":0},"schema":""}[40] (Figure 1A). Yet despite the critical importance and dynamic responses of the placenta, it remains under-researched and poorly understood.The placenta has an influential role in fetal brain development. IUGR, of which placental function is the major determinant, is associated with adverse neurodevelopmental outcomes. Children born following IUGR have a greater chance of cognitive impairment at school age (affecting boys more) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1542/peds.2010-1821","ISBN":"1098-4275 (Electronic)\r0031-4005 (Linking)","ISSN":"0031-4005","PMID":"21382944","abstract":"OBJECTIVE: To evaluate the effects of intrauterine growth restriction (IUGR) with absent or reversed end-diastolic blood flow in the umbilical artery and very preterm birth on cognitive outcome at 5 to 8 years of age. METHODS: We studied 34 children with IUGR born at a median of 26.9 gestational weeks (GWs) (range: 24-29 GWs) (PT-IUGR), 34 matched preterm appropriate-for-gestational age (PT-AGA) children, and 34 term AGA children (T-AGA) by using the Wechsler Preschool and Primary Scale of Intelligence, Wechsler Intelligence Scale for Children, Strengths and Difficulties Questionnaire, and Brown's attention-deficit disorder (ADD) scales. RESULTS: The PT-IUGR group had mean (SD) scores on the verbal IQ (VIQ) and full-scale IQ (FSIQ) of 83.8 (17.3) and 78.9 (16.6), respectively, compared with the PT-AGA group, which had scores of 96.0 (14.5) and 90.1 (14.2) (P = .003 and P < .007), and the T-AGA group, which had scores of 101.3 (12) and 102.9 (13.2) (P < .001 and P < 001), respectively. The VIQ difference remained significant after adjustment for parental level of education, gestational age at birth, and neonatal morbidity. Performance IQ (PIQ) did not differ between the PT-IUGR and PT-AGA groups; their mean PIQs were lower than that of the T-AGA group (P < .001). Boys in the PT-IUGR group scored lower than girls in VIQ and FSIQ (P = .005 and .007, respectively). Behavior and ADD scores did not differ between the preterm groups. CONCLUSIONS: Children born very preterm after IUGR have an increased risk for cognitive impairment at early school age compared with children delivered very preterm for other reasons. Differences in cognitive outcome were restricted to boys who may have been especially vulnerable to the influence of IUGR and very preterm birth.","author":[{"dropping-particle":"","family":"Morsing","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Asard","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ley","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stjernqvist","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marsal","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatrics","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2011"]]},"page":"e874-e882","title":"Cognitive Function After Intrauterine Growth Restriction and Very Preterm Birth","type":"article-journal","volume":"127"},"uris":[""]}],"mendeley":{"formattedCitation":"[41]","plainTextFormattedCitation":"[41]","previouslyFormattedCitation":"[41]"},"properties":{"noteIndex":0},"schema":""}[41] and a delay in fetal behavioural milestones ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/uog.9008","ISBN":"1469-0705 (Electronic)\\n0960-7692 (Linking)","ISSN":"09607692","PMID":"21520312","abstract":"Placental dysfunction leading to fetal growth restriction (FGR) is an important risk factor for neurodevelopmental delay. Recent observations clarify that FGR evolves prenatally from a preclinical phase of abnormal nutrient and endocrine milieu to a clinical phase that differs in characteristics in preterm and term pregnancies. Relating childhood neurodevelopment to these prenatal characteristics offers potential advantages in identifying mechanisms and timing of critical insults. Based on available studies, lagging head circumference, overall degree of FGR, gestational age, and umbilical artery (UA), aortic and cerebral Doppler parameters are the independent prenatal determinants of infant and childhood neurodevelopment. While head circumference is important independent of gestational age, overall growth delay has the greatest impact in early onset FGR. Gestational age has an overriding negative effect on neurodevelopment until 32-34 weeks' gestation. Accordingly, the importance of Doppler status is demonstrated from 27 weeks onward and is greatest when there is reversed end-diastolic velocity in the UA or aorta. While these findings predominate in early-onset FGR, cerebral vascular impedance changes become important in late onset FGR. Abnormal motor and neurological delay occur in preterm FGR, while cognitive effects and abnormalities that can be related to specific brain areas increase in frequency as gestation advances, suggesting different pathophysiology and evolving vulnerability of the fetal brain. Observational and management studies do not suggest that fetal deterioration has an independent impact on neurodevelopment in early-onset FGR. In late-onset FGR further research needs to establish benefits of perinatal intervention, as the pattern of vulnerability and effects of fetal deterioration appear to differ in the third trimester.","author":[{"dropping-particle":"","family":"Baschat","given":"A. A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Ultrasound in Obstetrics and Gynecology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2011"]]},"page":"501-514","title":"Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction","type":"article-journal","volume":"37"},"uris":[""]}],"mendeley":{"formattedCitation":"[42]","plainTextFormattedCitation":"[42]","previouslyFormattedCitation":"[42]"},"properties":{"noteIndex":0},"schema":""}[42]. Furthermore, a recent retrospective study of placental MRI data found an association between reduced placental apparent diffusion coefficient and fetal CNS pathology ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.crad.2018.05.004","ISSN":"1365229X","PMID":"29895388","abstract":"Aim: To investigate if magnetic resonance imaging (MRI) features of the placenta are different in fetuses with and without central nervous system (CNS) abnormalities. Material and methods: Institutional research ethics board approval was obtained. Fetal MRI of 97 singleton pregnancies were analysed retrospectively (19–25 weeks gestation), 65 with CNS morphological abnormalities and 32 controls. Placental T2 signal intensity, placental and fetal volumes, placental-to-fetal volume ratio, and placental apparent diffusion coefficient (ADC) values were assessed. Measurements were compared with the presence or absence of CNS fetal abnormalities using the Mann–Whitney test. Separate slopes models and intercept models were used to check for significant differences in the slopes and intercepts, respectively, among the groups. Results: Placental ADC values were significantly lower in placentas of fetuses with CNS abnormalities compared to controls (p=0.04). Placental T2 signal intensity, fetal and placental volumes did not differ between the two groups. The rate of increase in fetal-to-placental volume ratio with gestational age (GA) was greater among the controls. Conclusion: The presence of fetal CNS abnormalities is associated with reduced ADC values of the placenta. Moreover, placentas of fetuses with CNS abnormalities show a less rapid increase in fetal to placental volume ratio with GA. Therefore, ADC mapping, as well as different growth kinetics of the placenta relative to the fetus, may potentially serve as early markers of pathological neurodevelopment.","author":[{"dropping-particle":"","family":"Shapira-Zaltsberg","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grynspan","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Quintana","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dominguez","given":"P. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reddy","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davila","given":"J. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Radiology","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2018"]]},"page":"836.e9-836.e15","publisher":"Elsevier Ltd","title":"MRI features of the placenta in fetuses with and without CNS abnormalities","type":"article-journal","volume":"73"},"uris":[""]}],"mendeley":{"formattedCitation":"[43]","plainTextFormattedCitation":"[43]","previouslyFormattedCitation":"[43]"},"properties":{"noteIndex":0},"schema":""}[43]. In animal models of IUGR, reduced blood flow to the placenta has been found to cause a variety of structural and behavioural changes in rodents ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/dmcn.12599","ISBN":"0012-1622","ISSN":"14698749","PMID":"25330710","abstract":"AIM: This review explores the molecular, neurological, and behavioural outcomes in animal models of uterine artery ligation. We analyse the relevance of this type of model to the pathological and functional phenotypes that are consistent with cerebral palsy and its developmental comorbidities in humans.\\n\\nMETHOD: A literature search of the PubMed database was conducted for research using the uterine artery ligation model published between 1990 and 2013. From the studies included, any relevant neuroanatomical and behavioural deficits were then summarized from each document and used for further analysis.\\n\\nRESULTS: There were 25 papers that met the criteria included for review, and several outcomes were summarized from the results of these papers. Fetuses with growth restriction demonstrated a gradient of reduced body weight with a relative sparing of brain mass. There was a significant reduction in the size of the somatosensory cortex, hippocampus, and corpus callosum. The motor cortex appeared to be spared of identifiable deficits. Apoptotic proteins were upregulated, while those important to neuronal survival, growth, and differentiation were downregulated. Neuronal apoptosis and astrogliosis occurred diffusely throughout the brain regions. White matter injury involved oligodendrocyte precursor maturation arrest, hypomyelination, and an aberrant organization of existing myelin. Animals with growth restriction demonstrated deficits in gait, memory, object recognition, and spatial processing.\\n\\nINTERPRETATION: This review concludes that neuronal death, white matter injury, motor abnormalities, and cognitive deficits are important outcomes of uterine artery ligation in animal models. Therefore, this is a clinically relevant type of model, as these findings resemble deficits in human cerebral palsy.","author":[{"dropping-particle":"","family":"Basilious","given":"Alfred","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yager","given":"Jerome","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fehlings","given":"Michael G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Developmental Medicine and Child Neurology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2015"]]},"page":"420-430","title":"Neurological outcomes of animal models of uterine artery ligation and relevance to human intrauterine growth restriction: A systematic review","type":"article-journal","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"[44]","plainTextFormattedCitation":"[44]","previouslyFormattedCitation":"[44]"},"properties":{"noteIndex":0},"schema":""}[44]. Additionally, in genetic mouse models where lethality occurs before E14.5, placental deficit is common and correlates with neurodevelopmental and cardiovascular defects in the embryo ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nature26002","ISSN":"14764687","PMID":"29539633","abstract":"Analysis of embryonic lethal and sub-viable mouse knockout lines reveals that ablation of many genes affects placental development, and that the occurrence of placental defects is co-associated with abnormal brain, heart and vascular system development.","author":[{"dropping-particle":"","family":"Perez-Garcia","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fineberg","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilson","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mazzeo","given":"Cecilia Icoresi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tudor","given":"Catherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sienerth","given":"Arnold","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"White","given":"Jacqueline K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuck","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryder","given":"Edward J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gleeson","given":"Diane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siragher","given":"Emma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wardle-Jones","given":"Hannah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Staudt","given":"Nicole","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wali","given":"Neha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Collins","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geyer","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Busch-Nentwich","given":"Elisabeth M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galli","given":"Antonella","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"James C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robertson","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adams","given":"David J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weninger","given":"Wolfgang J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mohun","given":"Timothy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hemberger","given":"Myriam","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature","id":"ITEM-1","issue":"7697","issued":{"date-parts":[["2018"]]},"page":"463-468","publisher":"Nature Publishing Group","title":"Placentation defects are highly prevalent in embryonic lethal mouse mutants","type":"article-journal","volume":"555"},"uris":[""]}],"mendeley":{"formattedCitation":"[45]","plainTextFormattedCitation":"[45]","previouslyFormattedCitation":"[45]"},"properties":{"noteIndex":0},"schema":""}[45]. Moreover, the placenta contributes directly to brain development through the transport and synthesis of serotonin in early gestation ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nature09972","ISBN":"1476-4687 (Electronic)\\n0028-0836 (Linking)","ISSN":"00280836","PMID":"21512572","abstract":"Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1 ??'/??' (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes. ? 2011 Macmillan Publishers Limited. All rights reserved.","author":[{"dropping-particle":"","family":"Bonnin","given":"Alexandre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goeden","given":"Nick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Kevin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilson","given":"Melissa L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"King","given":"Jennifer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shih","given":"Jean C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blakely","given":"Randy D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deneris","given":"Evan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levitt","given":"Pat","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature","id":"ITEM-1","issue":"7343","issued":{"date-parts":[["2011"]]},"page":"347-350","publisher":"Nature Publishing Group","title":"A transient placental source of serotonin for the fetal forebrain","type":"article-journal","volume":"472"},"uris":[""]}],"mendeley":{"formattedCitation":"[46]","plainTextFormattedCitation":"[46]","previouslyFormattedCitation":"[46]"},"properties":{"noteIndex":0},"schema":""}[46]. This source of serotonin supports forebrain development in the period prior to the complete arborisation of Raphe nuclei neurons in the fetal brain. The placenta has a complicated genetic make-up that includes genes from the fetus and imprinted genes from both parents. Glucocorticoids can alter gene expression through epigenetic changes. Interestingly, female placentas are less sensitive to these effects than male which could provide a basis for the sexually dimorphic penetrance of neurodevelopmental diseases which are regularly more prevalent in males ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41467-018-04992-1","ISSN":"2041-1723","PMID":"29967448","abstract":"Although sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. In utero insults are more likely to produce detrimental health outcomes for males versus females. In our mouse model of prenatal stress, male offspring experience long-term dysregulation of body weight and hypothalamic pituitary adrenal stress axis dysfunction, endophenotypes of male-biased neurodevelop-mental disorders. Placental function is critical for healthy fetal development, and we pre-viously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Here we show that one mechanism whereby sex differences in OGT confer variation in vulnerability to prenatal insults is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. We demon-strate that high levels of H3K27me3 in the female placenta create resilience to the altered hypothalamic programming associated with prenatal stress exposure.","author":[{"dropping-particle":"","family":"Nugent","given":"Bridget M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O 'donnell","given":"Carly M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neill Epperson","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bale","given":"Tracy L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Communications","id":"ITEM-1","issue":"2018","issued":{"date-parts":[["2018"]]},"page":"1-10","publisher":"Springer US","title":"Placental H3K27me3 establishes female resilience to prenatal insults","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.biopsych.2017.10.005","ISBN":"0006-3223","ISSN":"18732402","PMID":"29198470","abstract":"Parental stress exposures are implicated in the risk for offspring neurodevelopmental and neuropsychiatric disorders, prompting critical examination of preconception and prenatal periods as vulnerable to environmental insults such as stress. Evidence from human studies and animal models demonstrates the influence that both maternal and paternal stress exposures have in changing the course of offspring brain development. Mechanistic examination of modes of intergenerational transmission of exposure during pregnancy has pointed to alterations in placental signaling, including changes in inflammatory, nutrient-sensing, and epigenetic pathways. Transmission of preconception paternal stress exposure is associated with changes in epigenetic marks in sperm, with a primary focus on the reprogramming of DNA methylation, histone posttranslational modifications, and small noncoding RNAs. In this review, we discuss evidence supporting the important contribution of intergenerational parental stress in offspring neurodevelopment and disease risk, and the currently known epigenetic mechanisms underlying this transmission.","author":[{"dropping-particle":"","family":"Chan","given":"Jennifer C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nugent","given":"Bridget M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bale","given":"Tracy L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biological Psychiatry","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2018"]]},"page":"886-894","publisher":"Elsevier Inc","title":"Parental Advisory: Maternal and Paternal Stress Can Impact Offspring Neurodevelopment","type":"article-journal","volume":"83"},"uris":[""]}],"mendeley":{"formattedCitation":"[47,48]","plainTextFormattedCitation":"[47,48]","previouslyFormattedCitation":"[47,48]"},"properties":{"noteIndex":0},"schema":""}[47,48]. Recent work has suggested that resilience of the female hypothalamus and HPA axis to prenatal stress is down to high levels of histone H3 methylation in the female placenta ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41467-018-04992-1","ISSN":"2041-1723","PMID":"29967448","abstract":"Although sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. In utero insults are more likely to produce detrimental health outcomes for males versus females. In our mouse model of prenatal stress, male offspring experience long-term dysregulation of body weight and hypothalamic pituitary adrenal stress axis dysfunction, endophenotypes of male-biased neurodevelop-mental disorders. Placental function is critical for healthy fetal development, and we pre-viously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Here we show that one mechanism whereby sex differences in OGT confer variation in vulnerability to prenatal insults is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. We demon-strate that high levels of H3K27me3 in the female placenta create resilience to the altered hypothalamic programming associated with prenatal stress exposure.","author":[{"dropping-particle":"","family":"Nugent","given":"Bridget M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O 'donnell","given":"Carly M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neill Epperson","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bale","given":"Tracy L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Communications","id":"ITEM-1","issue":"2018","issued":{"date-parts":[["2018"]]},"page":"1-10","publisher":"Springer US","title":"Placental H3K27me3 establishes female resilience to prenatal insults","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"[47]","plainTextFormattedCitation":"[47]","previouslyFormattedCitation":"[47]"},"properties":{"noteIndex":0},"schema":""}[47]. Perhaps most relevant is the robust finding that glucocorticoids downregulate placental HSD2 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0039791","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"22761903","abstract":"Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14-20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain.","author":[{"dropping-particle":"","family":"Pe?a","given":"Catherine Jensen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Monk","given":"Catherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Champagne","given":"Frances A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012"]]},"page":"1-9","title":"Epigenetic effects of Prenatal stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and fetal brain","type":"article-journal","volume":"7"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.psyneuen.2011.09.014","ISBN":"0306-4530","ISSN":"03064530","PMID":"22001010","abstract":"Background: Raised maternal anxiety during pregnancy is associated with increased risk of adverse neurodevelopmental outcomes for her child. The mechanisms underlying this are not known but animal studies suggest prenatal stress may alter the function of the placenta. Here we determined whether maternal prenatal anxiety was associated with a downregulation of placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme which metabolises cortisol. Methods: We recruited mothers the day before delivery by elective caesarean, and gave them the Spielberger Trait and State anxiety and Edinburgh Depression self-rating scales. Placentae were collected and aliquots stored for later analysis. Results: Prenatal Trait anxiety was negatively correlated with placental 11β-HSD2 mRNA expression (r= -0.40, p< 0.01, n= 56). Results were similar with male and female fetuses (r= -0.39, p= 0.04, n= 28; r= -0.40, p= 0.03, n= 28) respectively. Results were also significant with State anxiety (r= -0.27, p= 0.05, n= 56) but somewhat weaker for depression (r= -0.20, p= 0.13, n= 56). Preliminary analyses on a subset of cases (n= 25) suggested parallel results for enzyme activity. Conclusions: These findings provide evidence for an association between prenatal maternal mood and downregulation of placental 11β-HSD2. Results are consistent with raised maternal anxiety being associated with increased fetal exposure to maternal cortisol, and support the hypothesis that this may be one mechanism underlying fetal programming by prenatal stress. ? 2011 Elsevier Ltd.","author":[{"dropping-particle":"","family":"O'Donnell","given":"Kieran J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bugge Jensen","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freeman","given":"Laura","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khalife","given":"Natasha","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Connor","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Glover","given":"Vivette","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Psychoneuroendocrinology","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2012"]]},"page":"818-826","publisher":"Elsevier Ltd","title":"Maternal prenatal anxiety and downregulation of placental 11β-HSD2","type":"article-journal","volume":"37"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1371/journal.pone.0033794","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"22432047","abstract":"BACKGROUND: There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P?=?0.04), and this increasing methylation was associated with reduced scores of quality of movement (P?=?0.04).\\n\\nCONCLUSIONS/SIGNIFICANCE: These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health.","author":[{"dropping-particle":"","family":"Marsit","given":"Carmen J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maccani","given":"Matthew A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Padbury","given":"James F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lester","given":"Barry M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2012"]]},"page":"1-9","title":"Placental 11-beta hydroxysteroid dehydrogenase methylation is associated with newborn growth and a measure of neurobehavioral outcome","type":"article-journal","volume":"7"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1038/ejhg.2013.226","ISBN":"1018-4813\\r1476-5438","ISSN":"14765438","PMID":"24129435","abstract":"Intrauterine growth restriction (IUGR) is associated with detrimental effects on neurodevelopmental progress in childhood and higher risk of degenerative diseases in adulthood. Placental 11β-hydroxysteroid dehydrogenase (HSD11B2) is a key gene involved in glucocorticoid metabolism, which in turn seems to be related to fetal growth impairment. As reduction of placental HSD11B2 gene expression has been associated with reduced human fetal growth, and methylation of HSD11B2 gene promoter has been shown to have an important role in HSD11B2 gene repression, we seek to investigate the relationship between IUGR and HSD11B2 gene promoter methylation in human placentas. We found that methylation levels of all studied CpG sites were significantly higher in IUGR newborns than those in controls. Further, methylation levels of the first and the third CpG sites were inversely associated with measures of fetal growth (birth weight and ponderal index). In addition, consistent with the above negative correlation, methylation levels of the first and the third CpG sites were inversely associated with HSD11B2 gene expression. These results together show a link between the site-specific methylation of placental HSD11B2 promoter and the development of IUGR.","author":[{"dropping-particle":"","family":"Zhao","given":"Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gong","given":"Xia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Li","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Luxi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liang","given":"Yuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Shangqin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Yunhui","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Human Genetics","id":"ITEM-4","issue":"6","issued":{"date-parts":[["2014"]]},"page":"734-740","publisher":"Nature Publishing Group","title":"Site-specific methylation of placental HSD11B2 gene promoter is related to intrauterine growth restriction","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"[29,30,49,50]","plainTextFormattedCitation":"[29,30,49,50]","previouslyFormattedCitation":"[29,30,49,50]"},"properties":{"noteIndex":0},"schema":""}[29,30,49,50]. This, coupled with the increase in placental CRH creates something of a positive feedback loop that acts to further increase fetal glucocorticoid exposure.Glucocorticoids Alter Placental FunctionAs outlined above, the placenta regulates the transfer of glucocorticoids between the mother and fetus in the early stages of pregnancy. Classically, the primary focus of the adverse effects of glucocorticoids on fetal development is argued in the context of disruption in placental HSD2 leading to direct effects of glucocorticoids on fetal tissues. While this is true, the placenta itself, however, is also sensitive to elevated glucocorticoids. Thus, given that placental function is a critical regulator of fetal growth and development, an aspect of the adverse effects of elevated glucocorticoids on fetal outcomes must be due to perturbations within the placenta itself. Indeed, placental angiogenesis of fetal capillaries is markedly downregulated in animal models of glucocorticoid excess, possibly through downregulation of angiogenic factors such as vascular endothelial growth factor (VEGF) A and PPAR? ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/en.2006-0825","ISBN":"0013-7227; 0013-7227","ISSN":"00137227","PMID":"16959835","abstract":"Increased glucocorticoid exposure reduces fetal growth and predisposes to an increased risk of disease in later life. In addition to direct effects on fetal growth, glucocorticoids also compromise fetal growth indirectly via detrimental effects on placental growth and function. The current study investigated the effects of dexamethasone-induced intrauterine growth restriction on placental vascular development and expression of the endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF). Separate analyses were conducted for the three main VEGF isoforms (VEGF120, VEGF164, and VEGF188) in the two functionally and morphologically distinct regions of the rat placenta, the basal and labyrinth zones. Quantitative PCR and immunohistochemical analysis demonstrated that expression of VEGF was markedly up-regulated specifically in the rapidly growing labyrinth zone over the final third of normal pregnancy. Unbiased stereological analyses showed an associated increase in the volume and surface area of maternal and fetal blood spaces, including vascular remodeling of the fetal capillary network near term. In contrast, dexamethasone-induced fetal and placental growth restriction reduced expression of the Vegf120 and Vegf188 isoforms and prevented normal labyrinthine vascular development near term. Most notably, dexamethasone impaired the normal increase in fetal vessel density over the final third of pregnancy, with no effect on the density of maternal blood spaces. Overall, this study quantifies the labyrinth zone-specific increases in placental VEGF expression and vascular development during normal pregnancy, and shows that these increases are prevented by maternal dexamethasone treatment. Our data suggest that glucocorticoid-induced restriction of fetal and placental growth is mediated, in part, via inhibition of placental VEGF expression and an associated reduction in placental vascularization.","author":[{"dropping-particle":"","family":"Hewitt","given":"Damien P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mark","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waddell","given":"Brendan J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2006"]]},"page":"5568-5574","title":"Glucocorticoids prevent the normal increase in placental vascular endothelial growth factor expression and placental vascularity during late pregnancy in the rat","type":"article-journal","volume":"147"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1095/biolreprod.105.045914","ISBN":"0006-3363; 0006-3363","ISSN":"0006-3363","PMID":"16135695","abstract":"Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Recent gene deletion studies indicate that PPARG and PPARD play critical roles in rodent development, including effects on placental vascularization. In this study we investigated the expression of the PPAR isoforms and their heterodimeric partner, RXRA, in the two functionally and morphologically distinct zones of the rat placenta during normal gestation and after glucocorticoid-induced fetal and placental growth restriction. Real-time reverse transcription-polymerase chain reaction and immunohistochemical analysis demonstrated markedly higher expression of Ppara, Pparg, and Rxra mRNA in labyrinth zone trophoblast as compared with basal zone near term. There was also a marked increase in Pparg (65%, P < 0.05) and Ppara (91%, P < 0.05) mRNA specifically in the labyrinth zone over the final third of pregnancy. In contrast, expression of Ppard mRNA fell (P < 0.001) in both placental zones over the same period. Maternal dexamethasone treatment (1 ??g/ml in drinking water; Days 13?€“22, term = 23 days) reduced placental (44%) and fetal (31%) weights and resulted in a fall in Pparg (37%, P < 0.05) mRNA expression specifically in the labyrinth zone at Day 22. Placental expression of Ppara, Ppard, and Rxra was unaffected by dexamethasone treatment. These data suggest that PPARG:RXRA heterodimers play important roles in labyrinth zone growth late in pregnancy, possibly supporting vascular development. Moreover, glucocorticoid inhibition of placental growth appears to be mediated, in part, via a labyrinth-zone-specific suppression of PPARG.Placental expression of PPARG increases in the rapidly growing labyrinth zone over the final third of rat pregnancy but is reduced after glucocorticoid-induced fetal growth restriction.","author":[{"dropping-particle":"","family":"Hewitt","given":"Damien P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mark","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waddell","given":"Brendan J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biology of Reproduction","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2006"]]},"page":"23-28","title":"Placental Expression of Peroxisome Proliferator-Activated Receptors in Rat Pregnancy and the Effect of Increased Glucocorticoid Exposure1","type":"article-journal","volume":"74"},"uris":[""]}],"mendeley":{"formattedCitation":"[51,52]","plainTextFormattedCitation":"[51,52]","previouslyFormattedCitation":"[51,52]"},"properties":{"noteIndex":0},"schema":""}[51,52]. Similarly, removal of HSD2, while increasing the exposure of the fetus to glucocorticoids, also increases the exposure of the placenta. This increased placental exposure to glucocorticoids also manifests in a marked reduction in fetal capillary development at the end of gestation, which decreases the nutrient and waste exchange capacity of the placenta ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/en.2008-1100","ISBN":"0013-7227","ISSN":"00137227","PMID":"18845627","abstract":"Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal “programming” of adult cardiometabolic and neuropsychiatric disorders. Regulation of fetal glucocorticoid exposure is achieved by the placental glucocorticoid “barrier,” which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Thus, the absence of placental 11β-HSD2 may impact on fetal and placental development. The current study investigated transport of amino acids and glucose, key factors required for fetal growth, and vascular development in placentas from 11β-HSD2+/+, +/?, and ?/? fetuses derived from 11β-HSD2+/? matings. At embryonic d 15 (E15) (term = E19), 11β-HSD2?/? fetal weight was maintained in comparison to 11β-HSD2+/+ fetuses. The maintenance of 11β-HSD2?/? fetal weight occurred despite a reduction in placental weight, suggesting that compensatory changes occur in the placenta to maintain function. However, by E18, 11β-HSD2?/? fetal and placental weights were both reduced. Transport studies revealed up-regulation of placental amino acid transport to 11β-HSD2?/? offspring at E15, coinciding with an increase in the expression of the amino acid transporters. Furthermore, at E18, placental glucose transport to 11β-HSD2?/? offspring was markedly reduced, correlating with lower fetal weight and a decrease in glucose transporter 3 expression. Stereological analyses of the labyrinth zone of the placenta revealed that the reduction in placental weight at E18 was associated with restriction of the normal increase in fetal vessel density over the final third of pregnancy. Our data suggest that restriction of fetal growth in 11β-HSD2?/? mice is mediated, at least in part, via altered placental transport of nutrients and reduction in placental vascularization.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2009"]]},"page":"1287-1293","title":"Altered placental function of 11beta-hydroxysteroid dehydrogenase 2 knockout mice","type":"article-journal","volume":"150"},"uris":[""]}],"mendeley":{"formattedCitation":"[53]","plainTextFormattedCitation":"[53]","previouslyFormattedCitation":"[53]"},"properties":{"noteIndex":0},"schema":""}[53]. Furthermore, this reduction in fetal capillary development is accompanied by reduced umbilical cord flow and altered nutrient transport A, thus contributing to the reduction in fetal weight of the HSD2-/- offspring ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/en.2008-1100","ISBN":"0013-7227","ISSN":"00137227","PMID":"18845627","abstract":"Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal “programming” of adult cardiometabolic and neuropsychiatric disorders. Regulation of fetal glucocorticoid exposure is achieved by the placental glucocorticoid “barrier,” which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Thus, the absence of placental 11β-HSD2 may impact on fetal and placental development. The current study investigated transport of amino acids and glucose, key factors required for fetal growth, and vascular development in placentas from 11β-HSD2+/+, +/?, and ?/? fetuses derived from 11β-HSD2+/? matings. At embryonic d 15 (E15) (term = E19), 11β-HSD2?/? fetal weight was maintained in comparison to 11β-HSD2+/+ fetuses. The maintenance of 11β-HSD2?/? fetal weight occurred despite a reduction in placental weight, suggesting that compensatory changes occur in the placenta to maintain function. However, by E18, 11β-HSD2?/? fetal and placental weights were both reduced. Transport studies revealed up-regulation of placental amino acid transport to 11β-HSD2?/? offspring at E15, coinciding with an increase in the expression of the amino acid transporters. Furthermore, at E18, placental glucose transport to 11β-HSD2?/? offspring was markedly reduced, correlating with lower fetal weight and a decrease in glucose transporter 3 expression. Stereological analyses of the labyrinth zone of the placenta revealed that the reduction in placental weight at E18 was associated with restriction of the normal increase in fetal vessel density over the final third of pregnancy. Our data suggest that restriction of fetal growth in 11β-HSD2?/? mice is mediated, at least in part, via altered placental transport of nutrients and reduction in placental vascularization.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2009"]]},"page":"1287-1293","title":"Altered placental function of 11beta-hydroxysteroid dehydrogenase 2 knockout mice","type":"article-journal","volume":"150"},"uris":[""]}],"mendeley":{"formattedCitation":"[53]","plainTextFormattedCitation":"[53]","previouslyFormattedCitation":"[53]"},"properties":{"noteIndex":0},"schema":""}[53], in turn affecting fetal cardiac function in the HSD2-/- offspring ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.1520356113","ISBN":"0027-8424","ISSN":"0027-8424","PMID":"27185937","abstract":"Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11beta-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/-), and Hsd11b2(-/-) littermates from heterozygous (Hsd11b(+/-)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11beta-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(-/-) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(-/-) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noble","given":"June","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomson","given":"Adrian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tesic","given":"Dijana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Mark R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rog-Zielinska","given":"Eva A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moran","given":"Carmel M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chapman","given":"Karen E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2016"]]},"page":"6265-6270","title":"Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess","type":"article-journal","volume":"113"},"uris":[""]}],"mendeley":{"formattedCitation":"[54]","plainTextFormattedCitation":"[54]","previouslyFormattedCitation":"[54]"},"properties":{"noteIndex":0},"schema":""}[54]. The neurodevelopmental phenotype at this stage of gestation, including any fetal brain haemodynamic changes, remains to be characterised. It is an important consideration however, as it may give further insight into the mechanisms underlying the behavioural phenotype of the adult HSD2-/- offspring.Strikingly, the reduced fetal-placental capillary development, weight and altered cardiac phenotype of the HSD2KO fetuses can be rescued by administration of pravastatin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.1520356113","ISBN":"0027-8424","ISSN":"0027-8424","PMID":"27185937","abstract":"Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11beta-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/-), and Hsd11b2(-/-) littermates from heterozygous (Hsd11b(+/-)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11beta-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(-/-) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(-/-) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noble","given":"June","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomson","given":"Adrian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tesic","given":"Dijana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Mark R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rog-Zielinska","given":"Eva A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moran","given":"Carmel M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chapman","given":"Karen E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2016"]]},"page":"6265-6270","title":"Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess","type":"article-journal","volume":"113"},"uris":[""]}],"mendeley":{"formattedCitation":"[54]","plainTextFormattedCitation":"[54]","previouslyFormattedCitation":"[54]"},"properties":{"noteIndex":0},"schema":""}[54]. Pravastatin is an HMG-CoA reductase inhibitor approved for use in lowering LDL-cholesterol ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2165/00003088-200847070-00003","ISBN":"0312-5963 (Print) 0312-5963","ISSN":"03125963","PMID":"18563955","abstract":"HMG-CoA reductase inhibitors (statins) dose-dependently lower both the level of low-density lipoprotein cholesterol and risk of cardiovascular disease. In 2004, the UK approved a low-dose over-the-counter (OTC) simvastatin, but the US has rejected applications for non-prescription preparations of statins. The pharmacokinetics and interaction potentials of the possible OTC candidate statins simvastatin, lovastatin, fluvastatin and pravastatin are clearly different. Simvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A, fluvastatin is metabolized by CYP2C9, and pravastatin is excreted largely unchanged. Several cell membrane transporters can influence the disposition of statins, e.g. the organic anion transporting polypeptide (OATP) 1B1 enhances their hepatic uptake. The c.521T>C (p.Val174Ala) genetic polymorphism of SLCO1B1 (encoding OATP1B1) considerably increases the plasma concentrations of simvastatin acid and moderately increases those of pravastatin but seems to have no significant effect on fluvastatin. Strong inhibitors of CYP3A (itraconazole, ritonavir) greatly (up to 20-fold) increase plasma concentrations of simvastatin, lovastatin and their active acid forms, thus enhancing the risk of myotoxicity. Weak or moderately potent CYP3A inhibitors such as verapamil, diltiazem and grapefruit juice can be used cautiously with low doses of simvastatin or lovastatin, but their concomitant use needs medical supervision. Potent inducers of CYP3A can greatly decrease plasma concentrations of simvastatin and simvastatin acid, and probably those of lovastatin and lovastatin acid. Although fluvastatin is metabolized by CYP2C9, its concentrations are changed less than 2-fold by inhibitors or inducers of CYP2C9. Pravastatin plasma concentrations are not significantly affected by any CYP inhibition and only slightly affected by inducers. Ciclosporin inhibits CYP3A, P-glycoprotein and OATP1B1. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. Ciclosporin and gemfibrozil increase plasma concentrations of statins and the risk of their myotoxicity, but fluvastatin seems to carry a smaller risk than other statins. Inhibitors of OATP1B1 may decrease the benefit-risk ratio of simvastatin, lovastatin and pravastatin by interfering with their (active acid forms) entry into hepatocytes. Understanding the differences in the pharmacokinetics and interaction potential of various statins helps in their selection for possible non-prescription …","author":[{"dropping-particle":"","family":"Neuvonen","given":"Pertti J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backman","given":"Janne T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Niemi","given":"Mikko","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Pharmacokinetics","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2008"]]},"page":"463-474","title":"Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin","type":"article-journal","volume":"47"},"uris":[""]}],"mendeley":{"formattedCitation":"[55]","plainTextFormattedCitation":"[55]","previouslyFormattedCitation":"[55]"},"properties":{"noteIndex":0},"schema":""}[55], which has also been shown to increase the serum levels of VEGF in a mouse model of preeclampsia ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0013663","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"21048973","abstract":"BACKGROUND: Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE). DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels) that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF) signaling by soluble VEGF receptor 1 (sFlt-1) is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies.\\n\\nCONCLUSIONS/SIGNIFICANCE: We described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.","author":[{"dropping-particle":"","family":"Ahmed","given":"Abdulwahab","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singh","given":"Jameel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khan","given":"Ysodra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Seshan","given":"Surya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Girardi","given":"Guillermina","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2010"]]},"page":"1-9","title":"A new mouse model to explore therapies for preeclampsia","type":"article-journal","volume":"5"},"uris":[""]}],"mendeley":{"formattedCitation":"[56]","plainTextFormattedCitation":"[56]","previouslyFormattedCitation":"[56]"},"properties":{"noteIndex":0},"schema":""}[56], as well as elevating placental expression in our HSD2-/- model ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.1520356113","ISBN":"0027-8424","ISSN":"0027-8424","PMID":"27185937","abstract":"Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11beta-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/-), and Hsd11b2(-/-) littermates from heterozygous (Hsd11b(+/-)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11beta-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(-/-) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(-/-) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noble","given":"June","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomson","given":"Adrian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tesic","given":"Dijana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Mark R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rog-Zielinska","given":"Eva A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moran","given":"Carmel M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chapman","given":"Karen E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2016"]]},"page":"6265-6270","title":"Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess","type":"article-journal","volume":"113"},"uris":[""]}],"mendeley":{"formattedCitation":"[54]","plainTextFormattedCitation":"[54]","previouslyFormattedCitation":"[54]"},"properties":{"noteIndex":0},"schema":""}[54]. Whether the ameliorating effects that pravastatin has on vascular and growth parameters in the face of glucocorticoid excess extends to the neurological phenotype of the HSD2-/- mice remains unknown. Encouragingly, a recent study of pravastatin in a model of preeclampsia found that the drug prevented the long-term health effects of the model on the offspring of the preeclamptic pregnancies, including reduced brain microglia activation at P10 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/jci.insight.120147","ISSN":"2379-3708","PMID":"29669946","abstract":"Preeclampsia (PE), associates with long-term increased risk for cardiovascular disease in women, suggesting that PE is not an isolated disease of pregnancy. It is not known if increased risk for long-term diseases is due to PE-specific factors or to prepregnancy renal and cardiovascular risk factors. We used a mouse model in which a WT female with normal prepregnancy health develops PE to investigate if preeclampsia causes long-term cardiovascular consequences after pregnancy for mothers and offspring. Mothers exhibited endothelial dysfunction and hypertension after PE and had glomerular injury that not only persisted but deteriorated, leading to fibrosis. Left ventricular (LV) remodeling characterized by increased collagen deposition and MMP-9 expression and enlarged cardiomyocytes were also detected after PE. Increased LV internal wall thickness and mass, increased end diastolic and end systolic volumes, and increased stroke volume were observed after PE in the mothers. Placenta-derived bioactive factors that modulate vascular function, markers of metabolic disease, vasoconstrictor isoprostane-8, and proinflammatory mediators were increased in sera during and after a preeclamptic pregnancy in the mother. Offspring of PE mice developed endothelial dysfunction, hypertension, and signs of metabolic disease. Microglia activation was increased in the neonatal brains after PE, suggesting neurogenic hypertension in offspring. Prevention of placental insufficiency with pravastatin prevented PE-associated cardiovascular complications in both mothers and offspring. In conclusion, factors that develop during PE have long-term, cardiovascular effects in the mother and offspring independent of prepregnancy risk factors.","author":[{"dropping-particle":"","family":"Garrett","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pombo","given":"Joaquim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umpierrez","given":"Michelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clark","given":"James E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simmons","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Girardi","given":"Guillermina","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JCI insight","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2018"]]},"title":"Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice.","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"[57]","plainTextFormattedCitation":"[57]","previouslyFormattedCitation":"[57]"},"properties":{"noteIndex":0},"schema":""}[57].While these studies have highlighted the importance of feto-placental HSD2 in determining placental function, fetal growth and later life outcomes, they have not definitively ascribed a specific role of placental HSD2 in these associations. This is as HSD2 is absent from both placental and fetal tissues and as such, the relative influence of each of these compartments as well as potential for cross-talk cannot be teased apart in HSD2-/- fetuses. Furthermore, the confounding effects of HSD2 absence in the offspring kidneys, as discussed above, obfuscates our association between early life HSD2 absence and later health outcomes. To overcome this, we need to investigate the effects of specific removal of placental HSD2 on neonatal and adult phenotype, as well as the effects of specific removal of HSD2 from the fetal brain (HSD2BKO). We have developed both these models in our laboratory and while the model of placental HSD2 removal is still being characterised, our findings on the HSD2BKO highlight some implications for early life neural glucocorticoid exposure in determining brain outcomes. Specific Effects of Prenatal Glucocorticoids on the Fetal BrainTo determine the role of inappropriate glucocorticoid overexposure (both timing and magnitude) within the developing fetal brain, we generated a brain specific knock out of HSD2 (HSD2BKO) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.psyneuen.2015.05.003","ISSN":"03064530","PMID":"26036451","abstract":"Summary Stress or elevated glucocorticoids during sensitive windows of fetal development increase the risk of neuropsychiatric disorders in adult rodents and humans, a phenomenon known as glucocorticoid programming. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of glucocorticoids in the placenta, controls access of maternal glucocorticoids to the fetal compartment, placing it in a key position to modulate glucocorticoid programming of behavior. However, the importance of the high expression of 11β-HSD2 within the midgestational fetal brain is unknown. To examine this, a brain-specific knockout of 11β-HSD2 (HSD2BKO) was generated and compared to wild-type littermates. HSD2BKO have markedly diminished fetal brain 11β-HSD2, but intact fetal body and placental 11β-HSD2 and normal fetal and placental growth. Despite normal fetal plasma corticosterone, HSD2BKO exhibit elevated fetal brain corticosterone levels at midgestation. As adults, HSD2BKO show depressive-like behavior and have cognitive impairments. However, unlike complete feto-placental deficiency, HSD2BKO show no anxiety-like behavioral deficits. The clear mechanistic separation of the programmed components of depression and cognition from anxiety implies distinct mechanisms of pathogenesis, affording potential opportunities for stratified interventions.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keith","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noble","given":"June","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevenson","given":"Paula L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bombail","given":"Vincent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crombie","given":"Sandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Evans","given":"Louise C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bailey","given":"Matthew a.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wood","given":"Emma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Psychoneuroendocrinology","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"59-70","publisher":"Elsevier Ltd","title":"Fetal brain 11β-hydroxysteroid dehydrogenase type 2 selectively determines programming of adult depressive-like behaviors and cognitive function, but not anxiety behaviors in male mice","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"[58]","plainTextFormattedCitation":"[58]","previouslyFormattedCitation":"[58]"},"properties":{"noteIndex":0},"schema":""}[58] (Figure 1B). The consequences of HSD2 deletion in the brain will be largely developmental (only one discreet region of adult mouse brain expresses HSD2, namely the NTS, which is involved in salt appetite and blood pressure ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.1520356113","ISBN":"0027-8424","ISSN":"0027-8424","PMID":"27185937","abstract":"Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11beta-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/-), and Hsd11b2(-/-) littermates from heterozygous (Hsd11b(+/-)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11beta-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(-/-) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(-/-) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noble","given":"June","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomson","given":"Adrian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tesic","given":"Dijana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Mark R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rog-Zielinska","given":"Eva A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moran","given":"Carmel M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chapman","given":"Karen E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-1","issue":"22","issued":{"date-parts":[["2016"]]},"page":"6265-6270","title":"Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess","type":"article-journal","volume":"113"},"uris":[""]}],"mendeley":{"formattedCitation":"[54]","plainTextFormattedCitation":"[54]"},"properties":{"noteIndex":0},"schema":""}[54]) and hence serves to show the relevance of fetal HSD2 in neurodevelopment, independent of placental HSD2. In this model, at E15.5 glucocorticoids are elevated in the HSD2BKO fetal head but no different from controls in the rest of the body; this difference normalises again by E17.5 when HSD2 expression naturally declines in the controls ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.psyneuen.2015.05.003","ISSN":"03064530","PMID":"26036451","abstract":"Summary Stress or elevated glucocorticoids during sensitive windows of fetal development increase the risk of neuropsychiatric disorders in adult rodents and humans, a phenomenon known as glucocorticoid programming. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of glucocorticoids in the placenta, controls access of maternal glucocorticoids to the fetal compartment, placing it in a key position to modulate glucocorticoid programming of behavior. However, the importance of the high expression of 11β-HSD2 within the midgestational fetal brain is unknown. To examine this, a brain-specific knockout of 11β-HSD2 (HSD2BKO) was generated and compared to wild-type littermates. HSD2BKO have markedly diminished fetal brain 11β-HSD2, but intact fetal body and placental 11β-HSD2 and normal fetal and placental growth. Despite normal fetal plasma corticosterone, HSD2BKO exhibit elevated fetal brain corticosterone levels at midgestation. As adults, HSD2BKO show depressive-like behavior and have cognitive impairments. However, unlike complete feto-placental deficiency, HSD2BKO show no anxiety-like behavioral deficits. The clear mechanistic separation of the programmed components of depression and cognition from anxiety implies distinct mechanisms of pathogenesis, affording potential opportunities for stratified interventions.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keith","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noble","given":"June","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevenson","given":"Paula L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bombail","given":"Vincent","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crombie","given":"Sandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Evans","given":"Louise C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bailey","given":"Matthew a.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wood","given":"Emma","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"Jonathan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Psychoneuroendocrinology","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"59-70","publisher":"Elsevier Ltd","title":"Fetal brain 11β-hydroxysteroid dehydrogenase type 2 selectively determines programming of adult depressive-like behaviors and cognitive function, but not anxiety behaviors in male mice","type":"article-journal","volume":"59"},"uris":[""]},{"id":"ITEM-2","itemData":{"author":[{"dropping-particle":"","family":"Brown","given":"R W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diaz","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Robson","given":"A C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Kotelevtsev","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mullins","given":"J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"M H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-2","issue":"2","issued":{"date-parts":[["1996"]]},"page":"794-797","title":"The Ontogeny of 11beta-Hydroxysteroid Dehydrogenase Type 2 and Mineralocorticoid Receptor Gene Expression Reveal Intricate Control of Glucocorticoid Action in Development","type":"article-journal","volume":"137"},"uris":[""]}],"mendeley":{"formattedCitation":"[20,58]","plainTextFormattedCitation":"[20,58]","previouslyFormattedCitation":"[20,58]"},"properties":{"noteIndex":0},"schema":""}[20,58]. In this model, some aspects of the global HSD2 knockout and other models of prenatal glucocorticoid excess are recapitulated. Thus, HSD2BKO mice present with depression, a mild memory deficit and a decrease 5-HT1A receptor expression in the adult hippocampus. They do not however, exhibit anxiety-like behaviour which is pronounced in global HSD2-/- offspring. No alterations to HPA axis function have been observed in this model, nor do birthweights differ between knockouts and littermate controls. This first and foremost demonstrates that fetal brain HSD2 has an important role in neurodevelopment and further that glucocorticoids can exert an effect on the fetal brain even when the placental HSD2 barrier and circulating fetal glucocorticoids are unaffected. Thus, the focus on the relative importance of placental HSD2 acting as a “protective barrier” needs to be widened (or even questioned) to take into consideration the significance of fetal tissue HSD2. However, given that the global knockout phenotype is only partly recapitulated by removing HSD2 from the fetal brain, suggests there is a role for placental HSD2 expression in influencing aspects of brain development and function. Conversely, it may be that the absence of renal HSD2 is the culprit for the anxiety in HSD2-/- offspring.HSD2 and Sex differencesGiven that prenatal stress has a sex specific effect on behaviour of offspring, with male offspring being more susceptible to affective behaviours than females, it questions the mechanism underpinning these effects. In section 4, we have argued that the placental structure and function is differentially affected by stress in male and female fetuses – where male foetuses respond to stress more poorly and have poorer disease outcomes, than females. Human females born 72h after glucocorticoid administration increased placental HSD2 expression compared to males ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/en.2015-1227","ISSN":"19457170","PMID":"26241064","abstract":"The placenta is an ephemeral but critical organ for the survival of all eutherian mammals and marsupials. It is the primary messenger system between the mother and fetus, where communicational signals, nutrients, waste, gases, and extrinsic factors are exchanged. Although the placenta may buffer the fetus from various environmental insults, placental dysfunction might also contribute to detrimental developmental origins of adult health and disease effects. The placenta of one sex over the other might possess greater ability to respond and buffer against environmental insults. Given the potential role of the placenta in effecting the lifetime health of the offspring, it is not surprising that there has been a resurging interest in this organ, including the Human Placental Project launched by the National Institutes of Child Health and Human Development. In this review, we will compare embryological development of the laboratory mouse and human chorioallantoic placentae. Next, evidence that various species, including humans, exhibit normal sex-dependent structural and functional placental differences will be examined followed by how in utero environmental changes (nutritional state, stress, and exposure to environmental chemicals) might interact with fetal sex to affect this organ. Recent data also suggest that paternal state impacts placental function in a sex-dependent manner. The research to date linking placental maladaptive responses and later developmental origins of adult health and disease effects will be explored. Finally, we will focus on how sex chromosomes and epimutations may contribute to sex-dependent differences in placental function, the unanswered questions, and future directions that warrant further consideration.","author":[{"dropping-particle":"","family":"Rosenfeld","given":"Cheryl S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Endocrinology","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"3422-3434","title":"Sex-specific placental responses in fetal development","type":"article-journal","volume":"156"},"uris":[""]}],"mendeley":{"formattedCitation":"[59]","plainTextFormattedCitation":"[59]","previouslyFormattedCitation":"[59]"},"properties":{"noteIndex":0},"schema":""}[59], suggesting females have a protective mechanism against stress and glucocorticoid exposure. One mechanism underpinning the down regulation of HSD2, in response to social adversity, is increased methylation of placental HSD11B2, particularly in male placentas ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0074691","author":[{"dropping-particle":"","family":"Marsit","given":"Carmen J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Padbury","given":"James F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lester","given":"Barry M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Armstrong","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lesseur","given":"Corina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Joyce","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Appleton","given":"Allison A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2013"]]},"page":"e74691","title":"Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"[60]","plainTextFormattedCitation":"[60]","previouslyFormattedCitation":"[60]"},"properties":{"noteIndex":0},"schema":""}[60]. In a rodent model of prenatal stress, placental Hsd11b2 mRNA was decreased and methylation of the promoter increased, however, altered methylation of Hsd11b2 promoter region was observed in some brain regions with little effect on Hsd11b2 mRNA levels ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0039791","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"22761903","abstract":"Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14-20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain.","author":[{"dropping-particle":"","family":"Pe?a","given":"Catherine Jensen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Monk","given":"Catherine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Champagne","given":"Frances A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012"]]},"page":"1-9","title":"Epigenetic effects of Prenatal stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and fetal brain","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"[30]","plainTextFormattedCitation":"[30]","previouslyFormattedCitation":"[30]"},"properties":{"noteIndex":0},"schema":""}[30]. In this study no sex-specific effects of maternal stress on Hsd11b2 expression or DNA methylation were observed, but this study may be underpowered to observe these differences. Intriguingly, placental methylation levels did predict corresponding changes in the brain. Due to the importance of sex differences for the programmed phenotype, it is essential that more work be done on sex differences in the HSD2 and other programming models.Prenatal Glucocorticoids Cause Long-Lasting Alterations to the Serotonin System A common thread linking the affective phenotypes seen in the HSD2 knockout models, glucocorticoids and the role of the placenta in development is serotonin. In development, serotonin has a crucial role to play in the fetal brain. It supports cell growth, survival, migration and the guidance of axons ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nn1896","ISBN":"1097-6256 (Print)\\n1097-6256 (Linking)","ISSN":"10976256","PMID":"17450135","abstract":"Modifying serotonin (5-HT) abundance in the embryonic mouse brain disrupts the precision of sensory maps formed by thalamocortical axons (TCAs), suggesting that 5-HT influences their growth. We investigated the mechanism by which 5-HT influences TCAs during development. 5-HT(1B) and 5-HT(1D) receptor expression in the fetal forebrain overlaps with that of the axon guidance receptors DCC and Unc5c. In coculture assays, axons originating from anterior and posterior halves of the embryonic day 14.5 dorsal thalamus responded differently to netrin-1, reflecting the patterns of DCC and Unc5c expression. 5-HT converts the attraction exerted by netrin-1 on posterior TCAs to repulsion. Pharmacological manipulation of 5-HT(1B/1D) receptors and intracellular cAMP showed the signaling cascade through which this modulation occurs. An in vivo correlate of altered TCA pathfinding was obtained by transient manipulation of 5-HT(1B/1D) receptor expression abundance in the dorsal thalamus by in utero electroporation. These data demonstrate that serotonergic signaling has a previously unrecognized role in the modulation of axonal responsiveness to a classic guidance cue.","author":[{"dropping-particle":"","family":"Bonnin","given":"Alexandre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Torii","given":"Masaaki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Lilly","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rakic","given":"Pasko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levitt","given":"Pat","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Neuroscience","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2007"]]},"page":"588-597","title":"Serotonin modulates the response of embryonic thalamocortical axons to netrin-1","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"[61]","plainTextFormattedCitation":"[61]","previouslyFormattedCitation":"[61]"},"properties":{"noteIndex":0},"schema":""}[61]. Mice lacking serotonin in the central nervous system display increased anxiety and aggression, though no obvious structural abnormalities in the brain ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0896-6273(02)01167-4","ISBN":"0896-6273","ISSN":"08966273","PMID":"12546819","abstract":"The central serotonin (5-HT) neurotransmitter system is an important modulator of diverse physiological processes and behaviors; however, the transcriptional mechanisms controlling its development are largely unknown. The Pet-1 ETS factor is a precise marker of developing and adult 5-HT neurons and is expressed shortly before 5-HT appears in the hindbrain. Here we show that in mice lacking Pet-1, the majority of 5-HT neurons fail to differentiate. Remaining ones show deficient expression of genes required for 5-HT synthesis, uptake, and storage. Significantly, defective development of the 5-HT system is followed by heightened anxiety-like and aggressive behavior in adults. These findings indicate that Pet-1 is a critical determinant of 5-HT neuron identity and implicate a Pet-1-dependent program in serotonergic modulation of behavior.","author":[{"dropping-particle":"","family":"Hendricks","given":"Timothy J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Fyodorov","given":"Dmitry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wegman","given":"Lauren J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lelutiu","given":"Nadia B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pehek","given":"Elizabeth A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yamamoto","given":"Bryan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Silver","given":"Jerry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weeber","given":"Edwin J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sweatt","given":"J. David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deneris","given":"Evan S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuron","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2003"]]},"page":"233-247","title":"Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior","type":"article-journal","volume":"37"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.placenta.2015.11.013","ISSN":"15323102","PMID":"26691753","abstract":"Fetuses are exposed to many environmental perturbations that can influence their development. These factors can be easily identifiable such as drugs, chronic diseases or prenatal maternal stress. Recently, it has been demonstrated that the serotonin synthetized by the placenta was crucial for fetal brain development. Moreover, many studies show the involvement of serotonin system alteration in psychiatric disease during childhood and adulthood. This review summarizes existing studies showing that prenatal maternal stress, which induces alteration of serotonin systems (placenta and fetal brain) during a critical window of early development, could lead to alteration of fetal development and increase risks of psychiatric diseases later in life. This phenomenon, termed fetal programming, could be moderated by the sex of the fetus. This review highlights the need to better understand the modification of the maternal, placental and fetal serotonin systems induced by prenatal maternal stress in order to find early biomarkers of psychiatric disorders.","author":[{"dropping-particle":"","family":"St-Pierre","given":"Joey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laurent","given":"Laetitia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"King","given":"Suzanne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vaillancourt","given":"Cathy","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Placenta","id":"ITEM-2","issued":{"date-parts":[["2016"]]},"page":"S66-S71","publisher":"Elsevier Ltd","title":"Effects of prenatal maternal stress on serotonin and fetal development","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"[62,63]","plainTextFormattedCitation":"[62,63]","previouslyFormattedCitation":"[62,63]"},"properties":{"noteIndex":0},"schema":""}[62,63]. In early development, the fetal brain expresses serotonin receptors though does not yet produce its own serotonin. There are, however, measurable levels of serotonin and serotonin activity at this time, the source of which is the placenta. Thus, the placenta transports serotonin from maternal circulation and produces it in a temporal fashion, supporting development of the fetal forebrain until the serotonin neurones of the Raphe nuclei are fully developed ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nature09972","ISBN":"1476-4687 (Electronic)\\n0028-0836 (Linking)","ISSN":"00280836","PMID":"21512572","abstract":"Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1 ??'/??' (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes. ? 2011 Macmillan Publishers Limited. All rights reserved.","author":[{"dropping-particle":"","family":"Bonnin","given":"Alexandre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goeden","given":"Nick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Kevin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wilson","given":"Melissa L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"King","given":"Jennifer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shih","given":"Jean C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blakely","given":"Randy D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deneris","given":"Evan S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levitt","given":"Pat","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature","id":"ITEM-1","issue":"7343","issued":{"date-parts":[["2011"]]},"page":"347-350","publisher":"Nature Publishing Group","title":"A transient placental source of serotonin for the fetal forebrain","type":"article-journal","volume":"472"},"uris":[""]}],"mendeley":{"formattedCitation":"[46]","plainTextFormattedCitation":"[46]","previouslyFormattedCitation":"[46]"},"properties":{"noteIndex":0},"schema":""}[46]. In HSD2-/- mice, serotonin levels are elevated in diencephalic regions of the adult male brain ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1159/000331345","ISBN":"1423-0194","ISSN":"00283835","PMID":"22042385","abstract":"Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal 'programming' of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety- and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways.","author":[{"dropping-particle":"","family":"Wyrwoll","given":"Caitlin S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holmes","given":"Megan C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroendocrinology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2012"]]},"page":"47-55","title":"Prenatal excess glucocorticoid exposure and adult affective disorders: A role for serotonergic and catecholamine pathways","type":"article-journal","volume":"95"},"uris":[""]}],"mendeley":{"formattedCitation":"[35]","plainTextFormattedCitation":"[35]","previouslyFormattedCitation":"[35]"},"properties":{"noteIndex":0},"schema":""}[35]. In the HSD2BKO model, depressive-like behaviours are accompanied by downregulation of the serotonin receptor 5-HT1A in the hippocampus, an effect also seen in the HSD2-/- model and in prenatally stressed rats ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.brainres.2006.03.057","ISBN":"0006-8993 (Print)\\r0006-8993 (Linking)","ISSN":"00068993","PMID":"16677618","abstract":"Exposure of a pregnant woman to physical and/or psychological stress might affect her offspring by promoting the development of various learning, behavioral and/or mood disorders in later life. The 5-HT1Aand 5-HT2Areceptors are prominently implicated in the modulation of anxiety and mood-related behaviors. Using a semi-quantitative radiolabel immunocytochemical analysis (immunobinding), we studied the effect of prenatal stress on binding of these two receptor subtypes in the hippocampus of 4-week-old male and female Fischer 344 rats. Levels of 5-HT1Aimmunobinding in the ventral hippocampus, which is primarily implicated in emotional processing, were significantly decreased in male offspring after prenatal stress. A trend towards a decrease was observed in the ventral hippocampus of females. In contrast, 5-HT1Aimmunobinding within the dorsal hippocampus, which is mainly related to learning and memory, was not affected by prenatal stress in offspring of either gender. Likewise, no significant differences between control and prenatally stressed rats were observed for levels of 5-HT2Aimmunobinding in either part of the hippocampus or gender. The observed reduction in hippocampal 5-HT1Areceptor binding in male offspring after prenatal stress may have important consequences for adult anxiety- and depressive-like behavior. ? 2006 Elsevier B.V. All rights reserved.","author":[{"dropping-particle":"","family":"Hove","given":"D. L A","non-dropping-particle":"Van den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lauder","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scheepens","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prickaerts","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanco","given":"C. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinbusch","given":"H. W M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Brain Research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2006"]]},"page":"29-34","title":"Prenatal stress in the rat alters 5-HT1A receptor binding in the ventral hippocampus","type":"article-journal","volume":"1090"},"uris":[""]}],"mendeley":{"formattedCitation":"[64]","plainTextFormattedCitation":"[64]","previouslyFormattedCitation":"[64]"},"properties":{"noteIndex":0},"schema":""}[64]. This receptor is downregulated by glucocorticoids in a number of species and under normal conditions has a complex time course of expression ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cbpa.2013.01.014","ISSN":"10956433","PMID":"23360731","abstract":"In both mammals and teleost fish, serotonin stimulates cortisol secretion via the 5-HT1Areceptor. Additionally, a negative feedback loop exists in mammals whereby increased circulating levels of cortisol inhibit 5-HT1Areceptor activity. To investigate the possibility of such a feedback mechanism in teleosts, plasma cortisol levels and signaling in Gulf toadfish (Opsanus beta) were manipulated and the role of cortisol in the control of 5-HT1Aevaluated. Despite a significant 4-fold increase in plasma [cortisol], crowded toadfish expressed similar amounts of 5-HT1AmRNA transcript as uncrowded toadfish; whereas, cortisol-implanted fish possessed 41.8% less 5-HT1AmRNA transcript compared to vehicle-implanted controls. This cortisol effect appeared to be reversed in RU486-injected fish, which blocks glucocorticoid receptors, as these fish expressed nearly twice as much 5-HT1Areceptor transcript as the vehicle-injected fish despite significantly elevated cortisol levels. The binding affinity for the 5-HT1Areceptor in the brain did not vary between any groups; however, maximum binding was significantly higher in uncrowded toadfish compared to crowded, and the same significant difference was observed between the maximum binding of vehicle and cortisol-implanted fish. The opposite trend was seen in RU486-injected and vehicle-injected fish, with RU486-injected fish having significantly higher maximal binding compared to vehicle-injected controls. Injection with the 5-HT1Areceptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin revealed an inhibition of cortisol secretion that was independent of 5-HT1Atranscript and protein binding. These results suggest that cortisol plays a role in regulating the 5-HT1Areceptor via GR-mediated pathways; however, further study is necessary to elucidate how and where this inhibition is mediated. ? 2013.","author":[{"dropping-particle":"","family":"Medeiros","given":"Lea R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McDonald","given":"M. Danielle","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Comparative Biochemistry and Physiology - A Molecular and Integrative Physiology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2013"]]},"page":"612-621","publisher":"Elsevier Inc.","title":"Cortisol-mediated downregulation of the serotonin 1A receptor subtype in the Gulf toadfish, Opsanus beta","type":"article-journal","volume":"164"},"uris":[""]},{"id":"ITEM-2","itemData":{"ISBN":"0270-6474 (Print)","ISSN":"0270-6474","PMID":"8441016","abstract":"Using in situ hybridization techniques, the expression of 5-HT1A receptor mRNA was measured within the hippocampal formation after bilateral adrenalectomy (ADX). After 24 hr ADX, 5-HT1A receptor mRNA expression was significantly increased in all hippocampal subfields in ADX animals relative to sham-operated controls (SHAM). The magnitude of the increase was most pronounced within CA2 (127%) and CA3/4 (94%)-subfields of dorsal hippocampus, intermediate in the dentate gyrus (73%), and least within CA1 (60%). Administration of exogenous corticosterone (CORT) at the time of ADX maintained the level of 5-HT1A receptor mRNA expression within the range of SHAM animals. In vitro receptor autoradiographic analysis of 5-HT1A receptors in adjacent sections from the same animals indicated a simultaneous increase in 5-HT1A binding throughout the hippocampus in response to ADX. 5-HT1A binding increased to a similar extent (approximately 30%) in CA subfields and dentate gyrus but remained within SHAM levels in CORT-replaced animals. 5-HT1A receptor mRNA levels were also increased in hippocampal subregions of 1 week ADX animals relative to SHAM animals. Within both CA1 and CA2 subfields, the increments were approximately double those observed after 1 d ADX. 5-HT1A receptor binding was increased in every hippocampal subfield to a similar extent as that observed after 1 d ADX. Increases in both 5-HT1A receptor mRNA expression and 5-HT1A receptor binding were preventable by administration of exogenous CORT at the time of ADX. Hippocampal 5-HT1C receptor mRNA and D1 receptor mRNA expression were not significantly altered by either acute or chronic ADX treatment. These data indicate that adrenal steroids may selectively regulate hippocampal 5-HT1A receptors at the level of 5-HT1A receptor mRNA expression.","author":[{"dropping-particle":"","family":"Chalmers","given":"D T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwak","given":"S P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mansour","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akil","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watson","given":"S J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of neuroscience : the official journal of the Society for Neuroscience","id":"ITEM-2","issue":"3","issued":{"date-parts":[["1993"]]},"page":"914-23","title":"Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression.","type":"article-journal","volume":"13"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.neuroscience.2006.04.036","ISBN":"0306-4522 (Print)\\r0306-4522 (Linking)","ISSN":"03064522","PMID":"16824687","abstract":"Serotonin (5-HT) is implicated in several aspects of brain development, yet the ontogenetic expression patterns of 5-HT receptors responsible for transducing specific effects have largely not been characterized. Fifteen different 5-HT receptor genes have been cloned; therefore any spatial and/or temporal combination of their developmental expression could mediate a wide array of 5-HT effects. We undertook a detailed analysis of expression mapping of the Gi/o-coupled 5-HT1 (5-HT1A, 1B, 1D and 1F) receptor subtypes in the fetal and early postnatal mouse forebrain. Using receptor subtype-specific riboprobes and in situ hybridization, we observed that all 5-HT1 receptor subtypes are expressed as early as embryonic day (E) 14.5 in the forebrain, typically in gradients within specific structures. Among 5-HT1 receptors, the 5-HT1A receptor transcript is expressed densely in E14.5-16.5 thalamus, in hippocampus, and in a medial to lateral gradient in cortex, whereas the 5-HT1B receptor mRNA is expressed in more lateral parts of the dorsal thalamus and in the striatum at these ages. The 5-HT1D receptor transcript, which also is expressed heavily in E14.5-E16.5 thalamus, appears to be down-regulated at birth. The 5-HT1F receptor transcript is present in proliferative regions such as the cortical ventricular zone, ganglionic eminences, and medial aspects of the thalamus at E14.5-16.5, and otherwise presents similarities to the expression patterns of 5-HT1B and 1D receptor transcripts. Overall, the 5-HT1 subfamily of Gi/o-coupled 5-HT receptors displays specific and dynamic expression patterns during embryonic forebrain development. Moreover, all members of the 5-HT1 receptor class are strongly and transiently expressed in the embryonic dorsal thalamus, which suggests a potential role for serotonin in early thalamic development. ?? 2006 IBRO.","author":[{"dropping-particle":"","family":"Bonnin","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peng","given":"W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hewlett","given":"W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Levitt","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Neuroscience","id":"ITEM-3","issue":"2","issued":{"date-parts":[["2006"]]},"page":"781-794","title":"Expression mapping of 5-HT1 serotonin receptor subtypes during fetal and early postnatal mouse forebrain development","type":"article-journal","volume":"141"},"uris":[""]}],"mendeley":{"formattedCitation":"[65–67]","plainTextFormattedCitation":"[65–67]","previouslyFormattedCitation":"[65–67]"},"properties":{"noteIndex":0},"schema":""}[65–67]. Timing of glucocorticoid exposure is critical to determining the effects that the steroids have on development. Thus, the coincidence of elevated glucocorticoids and expression of glucocorticoid regulated 5-HT1A receptors ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0169-328X(97)00002-8","ISBN":"0169-328X (Print)\r0169-328X (Linking)","ISSN":"0169328X","PMID":"9191104","abstract":"Corticosterone is known to suppress levels of 5-HT(1A) receptor mRNA in rat hippocampus. We describe hippocampal 5-HT(1A) receptor mRNA regulation in mice that have a targeted disruption of the glucocorticoid receptor gene. 5-HT(1A) receptor mRNA levels as well as binding of [3H]8-OH-DPAT, were measured in the hippocampus of heterozygous and homozygous GR-deficient mice and in wild-type control mice. The effect of adrenalectomy in wild-type mice and heterozygous knockouts was also studied. We hypothesized that if the glucocorticoid receptor is important as a mediator of the suppressive effect of corticosterone, this would be revealed by changed (enhanced) expression of 5-HT(1A) receptor mRNA in mice with a genetically changed glucocorticoid receptor status. It was found that 5-HT(1A) receptor mRNA levels and 5-HT(1A) receptor binding were not different in GR-deficient mice. The 5-HT(1A) receptor mRNA levels were responsive to corticosterone, as adrenalectomy led to increased levels of hippocampal 5-HT(1A) receptor mRNA both in wild-type as in heterozygous knockout mice. These increases were paralleled by small but statistically significant changes in [3H]8-OH-DPAT binding. These results support a suppressive control of B over 5-HT(1A) receptor expression in the hippocampus of the mouse, which is predominantly mediated via the mineralocorticoid receptor. The data indicates that no interaction between the two corticosteroid receptors is required for this effect of corticosterone, and that mineralocorticoid receptor-mediated suppression of gene expression can take place in the complete absence of glucocorticoid receptor.","author":[{"dropping-particle":"","family":"Meijer","given":"Onno C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cole","given":"Timothy J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmid","given":"Wolfgang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schütz","given":"Günther","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jo?ls","given":"Marian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kloet","given":"E. Ronald","non-dropping-particle":"De","parse-names":false,"suffix":""}],"container-title":"Molecular Brain Research","id":"ITEM-1","issue":"1-2","issued":{"date-parts":[["1997"]]},"page":"290-296","title":"Regulation of hippocampal 5-HT(1A) receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor","type":"article-journal","volume":"46"},"uris":[""]}],"mendeley":{"formattedCitation":"[68]","plainTextFormattedCitation":"[68]","previouslyFormattedCitation":"[68]"},"properties":{"noteIndex":0},"schema":""}[68] may be determinant factors in the programming of serotonin mediated affective disorders in later life. How glucocorticoid exposure affects the placental serotonin system is unknown but could be crucial to understanding the interplay of these two factors in development. Indeed, expression of serotonin transporter in the placenta was shown to be related to infant regulatory behaviours, though not maternal depressive symptoms ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1017/S003329171500121X","ISBN":"0033291715001","ISSN":"14698978","PMID":"26096463","abstract":"BACKGROUND: Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and 'programming' of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors. METHOD: Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days. RESULTS: Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13-0.69, p = 0.005], HSD1B11 (0.30, 0.03-0.57, p = 0.03), NR3C1 (0.44, 0.19-0.68, p = 0.001) and SLC6A4 (0.26, 0.00-0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05). CONCLUSIONS: Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.","author":[{"dropping-particle":"","family":"R?ikk?nen","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pesonen","given":"A. K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"O'Reilly","given":"J. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuovinen","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lahti","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kajantie","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Villa","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laivuori","given":"H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"H?m?l?inen","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seckl","given":"J. R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reynolds","given":"R. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Psychological Medicine","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2015"]]},"page":"3217-3226","title":"Maternal depressive symptoms during pregnancy, placental expression of genes regulating glucocorticoid and serotonin function and infant regulatory behaviors","type":"article-journal","volume":"45"},"uris":[""]}],"mendeley":{"formattedCitation":"[69]","plainTextFormattedCitation":"[69]","previouslyFormattedCitation":"[69]"},"properties":{"noteIndex":0},"schema":""}[69]. Moreover, by inducing insulin receptor deficiency in the placentas of mice, Bronson and colleagues demonstrated reduced expression of serotonin related genes TPH1 and SLC6A4 in male placentas at E12.5, accompanied by reduced sensorimotor gating in the prepulse inhibition test and increased HPA axis response to stress in the adult ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.biopsych.2016.12.025","ISBN":"2158981369","ISSN":"18732402","PMID":"28168960","abstract":"Background Diabetes, obesity, and overweight are prevalent pregnancy complications that predispose offspring to neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder, and schizophrenia. Although male individuals are three to four times more likely than female individuals to develop these disorders, the mechanisms driving the sex specificity of disease vulnerability remain unclear. Because defective placental insulin receptor (InsR) signaling is a hallmark of pregnancy metabolic dysfunction, we hypothesized that it may be an important contributor and novel mechanistic link to sex-specific neurodevelopmental changes underlying disease risk. Methods We used Cre/loxP transgenic mice to conditionally target InsRs in fetally derived placental trophoblasts. Adult offspring were evaluated for effects of placental trophoblast-specific InsR deficiency on stress sensitivity, cognitive function, sensorimotor gating, and prefrontal cortical transcriptional reprogramming. To evaluate molecular mechanisms driving sex-specific outcomes, we assessed genome-wide expression profiles in the placenta and fetal brain. Results Male, but not female, mice with placental trophoblast-specific InsR deficiency showed a significantly increased hypothalamic-pituitary-adrenal axis stress response and impaired sensorimotor gating, phenotypic effects that were associated with dysregulated nucleotide metabolic processes in the male prefrontal cortex. Within the placenta, InsR deficiency elicited changes in gene expression, predominantly in male mice, reflecting potential shifts in vasculature, amino acid transport, serotonin homeostasis, and mitochondrial function. These placental disruptions were associated with altered gene expression profiles in the male fetal brain and suggested delayed cortical development. Conclusions Together, these data demonstrate the novel role of placental InsRs in sex-specific neurodevelopment and reveal a potential mechanism for neurodevelopmental disorder risk in pregnancies complicated by maternal metabolic disorders, including diabetes and obesity.","author":[{"dropping-particle":"","family":"Bronson","given":"Stefanie L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chan","given":"Jennifer C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bale","given":"Tracy L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biological Psychiatry","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2017"]]},"page":"127-138","publisher":"Elsevier Inc.","title":"Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor Gating","type":"article-journal","volume":"82"},"uris":[""]}],"mendeley":{"formattedCitation":"[70]","plainTextFormattedCitation":"[70]","previouslyFormattedCitation":"[70]"},"properties":{"noteIndex":0},"schema":""}[70].Conclusions:The specific roles of placental HSD2 and fetal HSD2 are not yet clearHSD2 clearly protects the fetus from the deleterious effects of inappropriate glucocorticoid exposure. This has been confirmed in clinical and preclinical experiments, whether HSD2 is inactivated, removed or bypassed, fetal and later-life health is affected. Expression of prenatal HSD2 is found in the placenta and throughout the fetus itself. Fetal HSD2 is often ignored in the literature, with discussion focused on the protective role of the placenta, however, it is now clear from tissue specific knockout of fetal HSD2 that, while important, placental HSD2 is not the entire story in defending the fetus from early glucocorticoid exposure. Placental dysfunction following glucocorticoid exposure has been experimentally linked to neurodevelopmental disorder, but depression-like behaviour can be induced in mice by removing HSD2 just from the fetal brain. This suggests specific pathways to disease that are defended differentially by the different compartments of HSD2 expression. Specific removal of HSD2 from the placenta will be necessary to determine if this is the case. Strikingly, pravastatin treatment can reverse the placental vascular phenotypes observed in the global HSD2 knockout model. How this drug might affect the brain specific knockout is not yet known. In a model of preeclampsia – the C1q knockout mouse – cardiovascular outcomes for both the mother and fetus were improved by pravastatin ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/jci.insight.120147","ISSN":"2379-3708","PMID":"29669946","abstract":"Preeclampsia (PE), associates with long-term increased risk for cardiovascular disease in women, suggesting that PE is not an isolated disease of pregnancy. It is not known if increased risk for long-term diseases is due to PE-specific factors or to prepregnancy renal and cardiovascular risk factors. We used a mouse model in which a WT female with normal prepregnancy health develops PE to investigate if preeclampsia causes long-term cardiovascular consequences after pregnancy for mothers and offspring. Mothers exhibited endothelial dysfunction and hypertension after PE and had glomerular injury that not only persisted but deteriorated, leading to fibrosis. Left ventricular (LV) remodeling characterized by increased collagen deposition and MMP-9 expression and enlarged cardiomyocytes were also detected after PE. Increased LV internal wall thickness and mass, increased end diastolic and end systolic volumes, and increased stroke volume were observed after PE in the mothers. Placenta-derived bioactive factors that modulate vascular function, markers of metabolic disease, vasoconstrictor isoprostane-8, and proinflammatory mediators were increased in sera during and after a preeclamptic pregnancy in the mother. Offspring of PE mice developed endothelial dysfunction, hypertension, and signs of metabolic disease. Microglia activation was increased in the neonatal brains after PE, suggesting neurogenic hypertension in offspring. Prevention of placental insufficiency with pravastatin prevented PE-associated cardiovascular complications in both mothers and offspring. In conclusion, factors that develop during PE have long-term, cardiovascular effects in the mother and offspring independent of prepregnancy risk factors.","author":[{"dropping-particle":"","family":"Garrett","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pombo","given":"Joaquim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umpierrez","given":"Michelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Clark","given":"James E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simmons","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Girardi","given":"Guillermina","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"JCI insight","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2018"]]},"title":"Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice.","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"[57]","plainTextFormattedCitation":"[57]","previouslyFormattedCitation":"[57]"},"properties":{"noteIndex":0},"schema":""}[57], suggesting that its effects are long-lasting, but whether it can affect neuropsychiatric phenotypes will require further investigation to determine.HSD2 Expression Protects the Serotonin System in DevelopmentThe neurological phenotypes that result from inappropriate fetal glucocorticoid exposure may involve the serotonin system. Glucocorticoids interact with serotonin in development and the serotonin receptor 5-HT1A is downregulated in the absence of HSD2 activity in the fetal brain. The persistence of this effect into the adult brain and the role that serotonin has to play in affective disorder suggests that it may be crucial to the programming of these disorders by glucocorticoids. Further investigation is necessary to ascertain how precisely serotonin signalling is altered and what affect this has on brain development. Moreover, the placenta supports the serotonin mediated development of the fetal forebrain in early gestation at a time when the fetus particularly vulnerable to environmental assault. Should serotonin be central to the programming effects of glucocorticoids, the differential role of each compartment may be linked to how serotonin is affected in each of these compartments. HSD2 is undoubtedly essential for the protection of the fetus during gestation. The placenta is central to development and its expression of HSD2 not only shields the fetus but also protects the placenta itself from the deleterious effects of glucocorticoids. It is becoming increasingly clear, however, that fetal expression of HSD2 is also necessary for the proper regulation of fetal glucocorticoid exposure. The serotonin system seems particularly vulnerable to failure of fetal HSD2 expression in the brain. This should be considered when attempting therapeutic intervention against the neurodevelopmental effects of inappropriate glucocorticoid exposure. While pravastatin improves fetal outcomes when glucocorticoids exert their effects on the placenta, it remains to be seen if this is still the case when the fetus, and not the placenta, is exposed.AcknowledgementsWe would like to acknowledge funding from the Wellcome Trust (WT 07900) and European Commission, Seventh Framework Programme, project acronym: DORIAN, grant agreement n°278603. MCH and FS are members of The University of Edinburgh Centre for Cognitive Aging and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. FJGS is supported on a CCACE MRC PhD studentship We acknowledge the support of the UoE BHF Centre of Research Excellence.Statement of EthicsAll animal experiments were approved by the University of Edinburgh Ethical Review Committee and studies were carried out in strict accordance with the UK Home Office Animals (Scientific Procedures) Act 1986 and the European Communities Council Directive of 22 September 2010 (Directive 2010/63/EU)Disclosure StatementThe authors have no conflict of interest to declare.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Barker DJ. Fetal origins of coronary heart disease. Br Med J. 1995;311:171–4. 2. 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