Search

Background: Maternal depression and anxiety during pregnancy may enhance fetal exposure to glucocorticoids (GCs) and harm neurodevelopment. We tested whether a novel cross-tissue polyepigenetic biomarker indicative of in utero exposure to GC is associated with mental and behavioral disorders and their severity in children, possibly mediating the associations between maternal prenatal depressive and anxiety symptoms and these child outcomes. Methods: Children (n = 814) from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study were followed-up from birth to age 7.1–10.7 years. A weighted polyepigenetic GC exposure score was calculated based on the methylation profile of 24 CpGs from umbilical cord blood. Child diagnosis of mental and behavioral disorder (n = 99) and its severity, defined as the number of days the child had received treatment (all 99 had received outpatient treatment and 8 had been additionally in inpatient treatment) for mental or behavioral disorder as the primary diagnosis, came from the Care Register for Health Care. Mothers (n = 408) reported on child total behavior problems at child's age of 2.3–5.8 years and their own depressive and anxiety symptoms during pregnancy (n = 583). Results: The fetal polyepigenetic GC exposure score at birth was not associated with child hazard of mental and behavioral disorder (HR = 0.82, 95% CI 0.54; 1.24, p = 0.35) or total behavior problems (unstandardized beta = −0.10, 95% CI -0.31; 0.10, p = 0.33). However, for one standard deviation decrease in the polyepigenetic score, the child had spent 2.94 (95%CI 1.59; 5.45, p < 0.001) more days in inpatient or outpatient treatment with any mental and behavioral disorder as the primary diagnosis. Criteria for mediation tests were not met. Conclusions: These findings suggest that fetal polyepigenetic GC exposure score at birth was not associated with any mental or behavioral disorder diagnosis or mother-rated total behavior problems, but it may contribute to identifying children at birth who are at risk for more severe mental or behavioral disorders. publishedVersion

Dynamic adaptation to stressful life events requires the co-ordinated action of the central stress response, which is mediated by the hypothalamic-pituitary-adrenal (HPA) axis, to restore and maintain homeostasis. Excessive exposure to stress or traumatic life events, such as childhood maltreatment, has been linked to HPA axis dysfunction increasing the risk of developing stress-related psychopathologies such as major depressive disorder and post-traumatic-stress-disorder. Mounting evidence supports the notion that stressors throughout pre- and postnatal development as well as adulthood can induce neuroepigenetic regulation of gene expression within key nodes of the brain, which may in part mediate such HPA axis dysfunction. Neuroepigenetic mechanisms, particularly DNA methylation and small non-coding RNAs, are therefore considered to be molecular mechanisms by which stressful life events may perpetuate aberrant behavioral phenotypes associated with psychiatric disorders throughout one's life and even across generations. In this chapter we outline the progress made toward understanding the effects of stress-induced neuroepigenetic changes upon HPA axis function and highlight the need for novel research strategies to deepen our understanding of the establishment, maintenance and reversibility of neuroepigenetic regulation following stress to enable realization of potential novel therapeutic and preventative strategies for stress-related psychiatric disorders.

Reported exposure to traumatic event is relatively common within the general population (40-90%), but only a fraction of individuals will develop posttraumatic stress disorder (PTSD). Indeed, the lifetime prevalence of PTSD is estimated to range between 7% and 12%. The factors influencing risk or resilience to PTSD after exposure to traumatic events are likely both environmental, such as type, timing, and extent of trauma, and genetic. Recently, epigenetic mechanisms have been implicated in mediating altered risk for PTSD as they can reflect both genetic and environmental influences. In this chapter, we describe the accumulating evidences for epigenetic factors in PTSD highlighting the importance of sensitive periods as well as methodological aspects such as tissue availabilities for such studies. We describe studies using a candidate gene approach focusing mainly on key players in the stress hormone regulation that show epigenetic alterations both in humans and in animal models for PTSD. We also summarize the results of epigenome-wide studies reporting associations with PTSD. For the above, we focus on one epigenetic mechanism, DNA methylation, as it is so far the best studied for this disorder. Finally, we describe how epigenetic mechanisms could be responsible for the long-lasting effects of gene-environment interactions observed in PTSD.