Associations Between Early Life Stress and Gene Methylation in Children

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Abstract

Children exposed to extreme stress are at heightened risk for developing mental and physical disorders. However, little is known about mechanisms underlying these associations in humans. An emerging insight is that children's social environments change gene expression, which contributes to biological vulnerabilities for behavioral problems. Epigenetic changes in the glucocorticoid receptor gene, a critical component of stress regulation, were examined in whole blood from 56 children aged 11–14 years. Children exposed to physical maltreatment had greater methylation within exon 1 _F in the NR3C1 promoter region of the gene compared to nonmaltreated children, including the putative NGFI-A (nerve growth factor) binding site. These results highlight molecular mechanisms linking childhood stress with biological changes that may lead to mental and physical disorders.

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The link between childhood trauma and depression: insights from HPA axis studies in humans.

Christine Heim, D Newport, Tanja M. Mletzko … (2008)

Childhood trauma is a potent risk factor for developing depression in adulthood, particularly in response to additional stress. We here summarize results from a series of clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor (CRF) activity, immune activation, and reduced hippocampal volume, closely paralleling several of the neuroendocrine features of depression. Neuroendocrine changes secondary to early-life stress likely reflect risk to develop depression in response to stress, potentially due to failure of a connected neural circuitry implicated in emotional, neuroendocrine and autonomic control to compensate in response to challenge. However, not all of depression is related to childhood trauma and our results suggest the existence of biologically distinguishable subtypes of depression as a function of childhood trauma that are also responsive to differential treatment. Other risk factors, such as female gender and genetic dispositions, interfere with components of the stress response and further increase vulnerability for depression. Similar associations apply to a spectrum of other psychiatric and medical disorders that frequently coincide with depression and are aggravated by stress. Taken together, this line of evidence demonstrates that psychoneuroendocrine research may ultimately promote optimized clinical care and help prevent the adverse outcomes of childhood trauma.

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Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses.

Tim Oberlander, Joanne Weinberg, Michael Papsdorf … (2015)

In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal(HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age three months were examined. Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age and pre and postnatal maternal mood. The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n = 33), infants of depressed nontreated mothers (n = 13) and infants of non depressed/non treated mothers (n = 36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at three months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time. Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.

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Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life.

Ian Weaver, Frances Champagne, Shelley Brown … (2005)

Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 1(7) glucocorticoid receptor (GR) promoter. To examine whether such epigenetic programming is reversible in adult life, we centrally infused the adult offspring with the essential amino acid L-methionine, a precursor to S-adenosyl-methionine that serves as the donor of methyl groups for DNA methylation. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 1(7) promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GR expression, and stress responses in the adult offspring. These results demonstrate that, despite the inherent stability of the epigenomic marks established early in life through behavioral programming, they are potentially reversible in the adult brain.

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Author and article information

Journal

Journal ID (nlm-ta): Child Dev

Journal ID (iso-abbrev): Child Dev

Journal ID (publisher-id): cdev

Title: Child Development

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 0009-3920

ISSN (Electronic): 1467-8624

Publication date (Print): January 2015

Publication date (Electronic): 24 July 2014

Volume: 86

Issue: 1

Pages: 303-309

Affiliations

University of Wisconsin–Madison

Author notes

Correspondence concerning this article should be addressed to Seth Pollak, Department of Psychology and Waisman Center, University of Wisconsin–Madison, 1500 Highland Avenue, Madison, WI 53706. Electronic mail may be sent to spollak@ 123456wisc.edu .

This study was supported by the National Institute of Mental Health through Grant R01MH61285 to S.D.P., a predoctoral fellowship (F31MH088111) to S.E.R, and the Early Experience, Stress and Neurobehavioral Development Center (P50MH078105). Infrastructure support was provided by the Waisman Center, University of Wisconsin through the National Institute of Child Health and Human Development (P30HD03352). We thank Victoria Browning, Karla Knobel, and Elim Lau for their assistance with sample processing and Mark Siegel for his assistance with data collection.

Article

DOI: 10.1111/cdev.12270

PMC ID: 4305348

PubMed ID: 25056599

SO-VID: 0b557e37-ecb6-47c4-b593-2805ed5bc37d

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Associations Between Early Life Stress and Gene Methylation in Children

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Most cited references 30

The link between childhood trauma and depression: insights from HPA axis studies in humans.

Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses.

Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life.

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