Prospective Cohort Study

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Summary Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.

Type 1 diabetes

We review a significant body of evidence from independent prospective studies that if a mother is stressed while pregnant, her child is substantially more likely to have emotional or cognitive problems, including an increased risk of attentional deficit/hyperactivity, anxiety, and language delay. These findings are independent of effects due to maternal postnatal depression and anxiety. We still do not know what forms of anxiety or stress are most detrimental, but research suggests that the relationship with the partner can be important in this respect. The magnitude of these effects is clinically significant, as the attributable load of emotional/behavioral problems due to antenatal stress and/or anxiety is approximately 15%. Animal models suggest that activity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and its hormonal end-product cortisol are involved in these effects in both mother and offspring. The fetal environment can be altered if stress in the mother changes her hormonal profile, and in humans, there is a strong correlation between maternal and fetal cortisol levels. However, many problems remain in understanding the mechanisms involved in this interaction. For example, maternal cortisol responses to stress decline over the course of pregnancy, and earlier in pregnancy, the link between maternal and fetal cortisol is less robust. It is possible that the effects of maternal anxiety and stress on the developing fetus and child are moderated by other factors such as a maternal diet (e.g., protein load). It is suggested that extra vigilance or anxiety, readily distracted attention, or a hyper-responsive HPA axis may have been adaptive in a stressful environment during evolution, but exists today at the cost of vulnerability to neurodevelopmental disorders.

Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?

State-Trait Anxiety Inventoryによるペインクリニック外来患者の不安の評価

Prenatal exposure to maternal stress, anxiety, and depression can have lasting effects on infant development with risk of psychopathology. Although the impact of prenatal maternal distress has been well documented, the potential mechanisms through which maternal psychosocial variables shape development have yet to be fully elucidated. Advances in molecular biology have highlighted the role of epigenetic mechanisms in regulating gene activity, neurobiology, and behavior and the potential role of environmentally induced epigenetic variation in linking early life exposures to long-term biobehavioral outcomes. In this article, we discuss evidence illustrating the association between maternal prenatal distress and both fetal and infant developmental trajectories and the potential role of epigenetic mechanisms in mediating these effects. Postnatal experiences may have a critical moderating influence on prenatal effects, and we review findings illustrating prenatal–postnatal interplay and the developmental and epigenetic consequences of postnatal mother–infant interactions. The in utero environment is regulated by placental function and there is emerging evidence that the placenta is highly susceptible to maternal distress and a target of epigenetic dysregulation. Integrating studies of prenatal exposures, placental function, and postnatal maternal care with the exploration of epigenetic mechanisms may provide novel insights into the pathophysiology induced by maternal distress.

Linking prenatal maternal adversity to developmental outcomes in infants: The role of epigenetic pathways

Although postnatal psychologic distress has been widely studied for many years, particularly with a focus on postpartum depression, symptoms of maternal depression, stress, and anxiety are not more common or severe after childbirth than during pregnancy. This paper reviews the newer body of research

/pdf/impact-of-maternal-stress-depression-and-anxiety-on-fetal-24673v6roz.pdf

Impact of maternal stress, depression and anxiety on fetal neurobehavioral development.

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.

/pdf/epigenetic-effects-of-prenatal-stress-on-11b-hydroxysteroid-2ner9b7jzx.pdf

Epigenetic Effects of Prenatal Stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain

This study examined the effect of an acute maternal stress response and anxiety on fetal heart rate. Seventeen healthy, 3rd-trimester pregnant women (mean age = 26 +/- 6 years) were instrumented for continuous electrocardiography, blood pressure (BP), respiration, and fetal heart rate (HR). Subjects completed the state anxiety subscale of the State Trait Personality Inventory (STPI), then rested quietly in a semirecumbent position for a 5-min baseline period, followed by either a 5-min arithmetic or Stroop color-word task. Over the entire 5-min stress period and when averaged across all subjects, the stressors led to significant increases in maternal systolic BP and respiratory rate but changes in maternal HR, diastolic BP, and fetal HR were not significant. However, when subjects were dichotomized into groups that had above or below average anxiety scores [ANX(+) and ANX(-)], both groups had similar respiration rate increases to the stressors, but the BP and fetal heart rate (FHR) responses were significantly different. Women in the ANX(-) group had significantly greater BP responses compared to women in the ANX(+) group whereas the fetuses of ANX(+) women showed significant HR increases and the fetuses of ANX(-) women exhibited nonsignificant decreases. These findings suggest that women's acute emotional reactivity during pregnancy can influence fetal HR patterns and that a stress-induced increase in maternal BP is not the primary signal by which a women's stress response is transduced to her fetus. The results are consistent with the hypothesis that maternal psychological variables may shape the neurobehavioral development of the fetus.

Maternal stress responses and anxiety during pregnancy: effects on fetal heart rate.

Objective:Increased risk of psychopathology is observed in children exposed to maternal prenatal distress, and elevated maternal cortisol and epigenetic regulation of placental glucocorticoid-pathway genes are potential mechanisms. The authors examined maternal distress and salivary cortisol in relation to fetal movement and heart rate (“coupling”) and DNA methylation of three glucocorticoid pathway genes—HSD11B2, NR3C1, and FKBP5—in term placentas.Method:Mood questionnaires and salivary cortisol were collected from 61 women between 24–27 gestational weeks, and fetal assessment was conducted at 34–37 weeks. Placental CpG methylation in the three genes was analyzed using 450K Beadchips and bisulfite sequencing; correlations between maternal and fetal variables and DNA methylation were tested; and maternal distress effects on fetal behavior via DNA methylation were investigated.Results:Perceived stress (Perceived Stress Scale), but not cortisol, was associated with altered CpG methylation in placentas. In t...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2015.15091171

Catherine Monk

Papers

Linking prenatal maternal adversity to developmental outcomes in infants: The role of epigenetic pathways

Impact of maternal stress, depression and anxiety on fetal neurobehavioral development.

Epigenetic Effects of Prenatal Stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain

Maternal stress responses and anxiety during pregnancy: effects on fetal heart rate.

Distress During Pregnancy: Epigenetic Regulation of Placenta Glucocorticoid-Related Genes and Fetal Neurobehavior