Laboratory for Clinical Neuroscience, Mood Disorders Research Program, Butler Hospital, Providence, Rhode Island, United States of America.
PLoS One. 2012;7(1):e30148. doi: 10.1371/journal.pone.0030148. Epub 2012 Jan 25.
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.
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.
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).
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.
早期不良经历史是成年精神病理学的一个重要风险因素。应激敏感性和下丘脑-垂体-肾上腺（HPA）轴功能的变化可能是应激与精神障碍风险之间关联的基础。啮齿动物的临床前研究将低水平的母体关怀与糖皮质激素受体（GR）基因启动子区域的甲基化增加以及对压力的激素和行为反应过度联系起来。最近的研究开始研究早期生活压力是否会导致人类 GR 基因的表观遗传修饰。
我们检查了 99 名健康成年人白细胞 DNA 中 GR 基因（NR3C1）启动子区域的甲基化程度。参与者报告了他们的童年经历，包括父母行为、父母死亡或遗弃以及儿童期虐待。在另一天，参与者完成了地塞米松/促肾上腺皮质激素释放激素（Dex/CRH）测试，这是一种标准化的神经内分泌挑战测试。
父母丧失、儿童期虐待和父母关爱等不足或缺乏的养育方式与 NR3C1 启动子甲基化增加有关（p<.05）。此外，NR3C1 启动子甲基化与皮质醇对 Dex/CRH 测试的反应减弱有关（p<.05）。
这些发现表明，儿童虐待或逆境可能导致人类 GR 基因的表观遗传修饰。该基因甲基化的改变可能是儿童期逆境、应激反应改变和精神病理学风险之间关联的基础。
