Abstract
BackgroundA history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.MethodsWe examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.ResultsDisruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).ConclusionsThese findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.
Highlights
Many decades of research in rodents, non-human primates, and humans have documented the impact of early experiences on the neurobiological mechanisms regulating stress responses and mood and anxiety disorders
We report here that childhood adversity is associated with greater NR3C1 methylation, and that individuals with greater levels of NR3C1 methylation have attenuated cortisol responses to the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test
Potential Covariates Age was correlated with greater methylation at several CpG sites
Summary
Many decades of research in rodents, non-human primates, and humans have documented the impact of early experiences on the neurobiological mechanisms regulating stress responses and mood and anxiety disorders. Chronic alterations of HPA axis activity have been shown in rodents and non-human primates exposed to disruptions of parental care such as maternal separation [6,7] and maternal neglect [8], and in humans with childhood parental loss, and neglect or other forms of childhood maltreatment [2,9,10,11,12,13,14,15,16,17]. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans
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