Prenatal Multi-Level Stressors and Alterations in Maternal and Fetal Epigenomes

 描述(申请人提供)：越来越多的证据表明，母亲怀孕期间的心理社会压力，如抑郁、焦虑和应激性生活事件与不良的出生结局有关。然而，母体压力和儿童健康结果之间潜在的表观遗传机制在很大程度上仍未被探索。我们提出了一项跨学科的研究，以检验这一假设，即母亲的心理社会应激因素可以影响母亲和新生儿的DNA甲基化情况，在分娩时可以检测到。具体地说，我们建议调查1)母体情绪障碍，包括严重的抑郁症和焦虑症，以及2)母体心理社会应激源(如应激生活事件、目睹暴力、不良社会支持)与母体和新生儿DNA甲基化模式改变的关系。此外，我们还将比较母亲和新生儿甲基化特征的异同。这项建议的一个独特之处是，我们将使用全基因组和候选基因方法来检查母婴对DNA甲基化中情感和心理社会应激源的反应，并将评估母子二元在应对压力方面是如何协调的。另一项创新是，我们将研究广泛的母性心理压力源。这项拟议研究的成功完成将为一项关于出生时和出生后期间的表观遗传学变化及其与一系列儿童健康和发育结果的联系的前瞻性研究奠定基础。这项建议的一个特别优点是，我们将利用 波士顿出生队列(BBC)，一个持续的大型纵向出生队列，主要是城市非裔美国人出生的队列(现在由大约8500对母婴组成)。这项研究将利用大量高质量的流行病学和临床数据，以及英国广播公司已经获得的生物标本。BBC非常适合于解决研究假设，因为怀孕期间母亲心理社会应激源的高流行率，怀孕并发症和不良妊娠结局的高比率。我们已经测量了来自BBC的400名母亲和400名婴儿的全基因组DNA甲基化，并证明了母体应激源和DNA甲基化之间在基因组范围和特定候选基因中都有很好的相关性。我们期望这项拟议的研究将确定母亲心理社会应激源的DNA甲基化特征，并将为进一步研究母亲应激引起的母亲和她的孩子的DNA甲基化变化的长期健康后果奠定基础。

 DESCRIPTION (provided by applicant): Growing evidence indicates that maternal psychosocial stressors during pregnancy, e.g. depression, anxiety, and stressful life events are related to poor birth outcomes. However, the epigenetic mechanisms underlying associations between maternal stress and child health outcomes remain largely unexplored. We propose a trans-disciplinary study to test the hypothesis that maternal psychosocial stressors can affect both maternal and newborn DNA methylation profiles, detectable at the time of delivery. Specifically, we propose to investigate 1) maternal emotional disorders, including major depression and anxiety disorders and 2) maternal psychosocial stressors (e.g. stressful life events, witnessing violence, poor social support), in relation to altered maternal and newborn DNA methylation patterns. In addition, we will 3) compare similarities and differences in the methylation signatures of mothers and their newborns. A unique feature of this proposal is that we will examine responses to emotional and psychosocial stressors in DNA methylation in mother-infant pairs using both genome-wide and candidate gene approaches, and will evaluate how maternal-child dyads coordinate in coping with stress. Another innovation is that we will examine a broad spectrum of maternal psychological stressors. Successful completion of this proposed study will establish a foundation for a prospective study on epigenetic changes at birth and during the postnatal period, and their link with a range of child health and developmental outcomes. A particular strength of this proposal is that we will leverage the existing resources of the Boston Birth Cohort (BBC), an ongoing large longitudinal, predominantly urban African-American birth cohort (now consisting of ~8500 mother-infant pairs). This study will leverage extensive high-quality epidemiological and clinical data, along with biospecimens already obtained by the BBC. The BBC is well-suited for addressing the study hypotheses due to a high prevalence of maternal psychosocial stressors during pregnancy, high rates of pregnancy complications and adverse pregnancy outcomes. We have already measured genome-wide DNA methylation in 400 mothers and 400 babies from the BBC and demonstrated promising associations between maternal stressors and DNA methylation both at the genome-wide scale and in specific candidate genes. We expect that this proposed study will identify DNA methylation signatures of maternal psychosocial stressors and will lay a foundation to further investigate the long-term health consequences of maternal stress-induced DNA methylation changes in both the mother and her child.