|Epigenetic Changes From Childhood Adversity Stressors|
|SciMed - Genetics & Genome|
|TS-Si News Service|
|Tuesday, 28 February 2012 15:00|
Providence, RI, USA. A genetic alteration has been discovered that helps explain how major stressors during childhood can change the biological risk for psychiatric disorders.
The research published in PLoS ONE suggests that childhood adversity may lead to epigenetic changes in the human glucocorticoid receptor gene, an important regulator of the biological stress response.
The genetic alteration at the root of the association between childhood adversity, including parental loss and childhood maltreatment, and risk for psychiatric disorders such as depression and anxiety has been established in multiple studies. However, researchers have yet to define how and why this association exists in humans. "We need to understand the biology of this effect in order to develop better treatment and prevention programs," said Audrey Tyrka, MD, PhD, director of the Laboratory for Clinical and Translational Neuroscience at Butler Hospital and associate professor of Psychiatry and Human Behavior at Brown University.
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Epigenetic Mechanisms are affected by several factors and processes including development (both in utero and during childhood), environmental chemicals, pharmaceuticals and drugs, aging, and diet.
Image and text courtesy of the National Institutes of Health (NIH)."Our research group turned to the field of epigenetics to determine how environmental conditions in childhood can influence the biological stress response," said Tyrka. Epigenetics is the study of genomic changes that do not alter the DNA sequence, but influence whether genes will be expressed (turned on) or silenced.
Knowing that the connection between childhood maltreatment and psychiatric disorders has been linked to the hormone system that coordinates biological stress responses, the researchers sought to identify the root cause at a genetic level. The glucocorticoid receptor is an important regulator of the stress response, and methylation is a particularly stable type of epigenetic modification.
"We knew that epigenetic changes to this gene could be affected by childhood parenting experiences because previous animal research showed that rodents with low levels of maternal care had increased methylation of this gene, and consequently, as adults these animals had greater stress sensitivity and fear in stressful situations," said Tyrka.
The researchers looked at 99 healthy adults, some of whom had a history of parental loss or childhood maltreatment. DNA was extracted from each of the participants using a blood sample, then analyzed to identify epigenetic changes to the glucocorticoid receptor.
They then performed a standardized hormone provocation test to measure the stress hormone, cortisol, finding that adults with a history of childhood adversity maltreatment or parental loss had increased methylation of the glucocorticoid receptor (GR) gene, which is thought to change the way this gene is expressed on a long-term basis.
They also found that greater methylation was linked to blunted cortisol responses to the hormone provocation test.
"Our results suggest that exposure to stressful experiences during childhood may actually alter the programming of an individual's genome. This concept may have broad public health implications, as it could be a mechanism for the association of childhood trauma with poor health outcomes, including psychiatric disorders as well as medical conditions such as cardiovascular disease," said Tyrka.
In early studies of animals, researchers have identified drugs that can reverse methylation effects. "More research is needed to better understand the epigenetic mechanism behind this association," said Tyrka, noting a larger scale study currently underway at Butler Hospital and a study of this association in children. "This line of research may allow us to better understand who is most at risk and why, and may allow for the development of treatments that could reverse epigenetic effects of childhood adversity."
FundingFunding for this study was provided by the National Institute of Mental Health (NIMH) grants to Audrey R. Tyrka and Linda L. Carpenter, and a Centers of Biomedical Research Excellence (COBRE) grant to Carmen Marsit.
Acthrel was purchased at a discounted rate for research from Ferring Pharmaceuticals, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
CitationChildhood Adversity and Epigenetic Modulation of the Leukocyte Glucocorticoid Receptor: Preliminary Findings in Healthy Adults. Audrey R. Tyrka, Lawrence H. Price, Carmen Marsit, Oakland C. Walters, Linda L. Carpenter. PLoS ONE 2012; 7(1): e30148. doi:10.1371/journal.pone.0030148
Background. A 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.
Methods. We 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.
Results. Disruption 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).
Conclusions. These 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.
|Last Updated on Tuesday, 28 February 2012 14:22|