Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses
Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses
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DOI：
10.4161/epi.3.2.6034
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发表时间：
2008-03-01
期刊：
影响因子：
3.7
通讯作者：
Devlin, Angela M.
中科院分区：
文献类型：
--
作者：
Oberlander, Tim F.;Weinberg, Joanne;Devlin, Angela M.
背景：在动物模型中，早期孕产妇护理的变化与后代下丘脑-垂体-肾上腺（HPA）应激反应的差异相关，这种应激反应是通过糖皮质激素受体（GR）基因（Nr3c1）表达的表观遗传调控的变化来介导的。目的：在人类中研究这一点，产前暴露于孕产妇情绪与人类GR基因启动子和外显子1F中富含CpG区域的甲基化状态之间的关系对新生儿中的 (NR3C1) 和三个月大时的 HPA 应激反应性进行了检查。结果：产前暴露于妊娠晚期母亲抑郁/焦虑情绪增加与 NR3C1 在预测的 NGFI-A 结合位点甲基化增加相关。该位点的 NR3C1 甲基化增加还与 3 个月时唾液皮质醇应激反应增加相关，控制产前 SRI 暴露、产后年龄以及产前和产后母亲情绪。方法：通过亚硫酸氢盐焦磷酸测序对接受 5-羟色胺治疗的抑郁母亲的婴儿进行定量，对脐带血单核细胞基因组 DNA 中 NR3C1 基因富含 CpG 的区域（包括外显子 1F）的甲基化状态进行定量再摄取抑制剂抗抑郁药 (SRI) (n = 33)、未接受治疗的抑郁母亲的婴儿 (n = 13) 和非抑郁/未接受治疗的母亲的婴儿 (n = 36)。为了研究新生儿 NR3C1 甲基化状态的功能意义，我们使用在非有害应激源之前和之后以及下午晚些时候基础时间获得的唾液皮质醇在三个月时评估了 HPA 功能。结论：新生儿中人类 NR3C1 基因的甲基化状态对产前母亲情绪敏感，并可能提供一个潜在的表观遗传过程，将产前母亲情绪与婴儿期改变的 HPA 应激反应性联系起来。
Background: 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.Objective: 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.Results: 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.Methods: 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 non treated 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.Conclusions: 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.