Prenatal stress: the epigenetic basis of maternal and perinatal effects

描述（由申请人提供）：近一半的美国人一生中会符合精神障碍的标准，17人中有1人患有严重的使人衰弱的疾病。越来越多地，这些精神病理被概念化为异常发育过程的晚期最终形成，这些异常发育过程是由基因和经验的复杂相互作用形成的，包括那些发生在子宫内的过程。数十年来对怀孕动物的研究表明，压力引起的母体生物学紊乱会影响后代的发育，导致其行为和生理上的应激反应增强。从对生活压力的检查到对精神障碍的检查，对孕妇的痛苦的研究在很大程度上反映了这些发现。尽管有充分的证据表明母体的产前功能与后代的结局有关，但这种在子宫内对儿童神经发育影响的机制途径仍然未知，特别是对人类受试者。新兴的表观遗传学领域——检测环境经验的分子效应——仅很少应用于孕妇，但可能为理解精神疾病风险的胎儿起源机制提供了重要的联系。本项目的目的是利用近年来表观遗传基因调控的研究进展，确定介导孕产妇痛苦对围产期发育影响的生物学机制。目的1：确定孕妇窘迫对围产期发育相关表观遗传基因调控的影响。具体来说，为了确定（a)产前窘迫（通过个人数字助理（PDA）使用24小时生态瞬间评估（EMA）评估怀孕期间3次的日常生活压力）和临床医生访谈引起的情绪症状）是否预测女性的压力激素水平(皮质醇（来自3次，48小时内12次唾液样本）和CRH（3次采血）以及PBL（3次采血）中的基因表达；(b)妇女应激激素水平和PBL基因表达改变的时间和程度预测胎盘基因表达；(c)这些情绪依赖性的生物学改变与DNA甲基化的表观遗传机制有关。目的2：确定孕妇痛苦的围产期后果。具体来说，(a)女性痛苦相关的hpa轴激素水平、PBL和胎盘基因表达/表观遗传变异的改变，能否预测胎儿脐带血基因表达/表观遗传变异，以及以对新事物反应性增强为特征的神经行为特征（胎儿和新生儿自主神经和中枢神经系统对刺激的调节）。目的3：建立表观遗传修饰对后代神经发育的因果影响。具体来说，我们使用一种啮齿类动物模型，可以直接评估母体慢性产前应激暴露对大脑的影响，我们的目标是确定(a)母体状况对母体pbl、胎盘和胎儿/婴儿大脑中DNA甲基化和基因表达的影响，以及(b)这些组织中的表观遗传变异与出生后ANS和CNS发育之间的关系（以行为和应激激素反应性为指标）。

DESCRIPTION (provided by applicant): Nearly half of the U.S. population will meet criteria for a psychiatric disorder during their lives, and 1 in 17 has a seriously debilitating illness. Increasingly, these psychopathologies are conceptualized as the late-stage cul- mination of aberrant developmental processes shaped by a complex interplay of genes and experience, includ- ing those occurring in utero. Decades of studies with pregnant animals demonstrate that stress-elicited pertur- bations in maternal biology affect offspring development, leading to a profile characterized by heightened be- havioral and physiologic stress responsivity. Studies of distress in pregnant women, which range from exami- nations of life stress to psychiatric disorder, largely mirror these findings. Despite ample evidence linking ante- natal maternal functioning to offspring outcomes, the mechanistic pathways for this in utero influence on chil- dren's neurodevelopment remain unknown, particularly with human subjects. The burgeoning field of epigenet- ics - the detection of the molecular effects of environmental experience - has only minimally been applied to pregnant women, yet may provide a vital link in understanding the mechanisms involved in the fetal origins of psychiatric disease risk. The goal of this project is to use recent advances in studying epigenetic gene regulation to identify the biological mechanisms mediating the impact of maternal distress on perinatal development. Aim 1: Determine the influence of pregnant women's distress on epigenetic gene regula- tion relevant to perinatal development. Specifically, to establish whether (a) prenatal distress (daily life stress assessed 3x in pregnancy using 24-hour Ecological Momentary Assessment (EMA) via a Personal Digi- tal Assistant (PDA)) and mood symptoms elicited by clinician interviews) predict women's stress hormone lev- els (cortisol (from 3x, 12 salivary samples in 48-hours) and CRH (3x blood draws) and gene expression in her PBL (3x blood draws); (b) the timing and degree of women's altered stress hormone levels and PBL gene ex- pression predict placental gene expression; (c) these mood-dependent biological alterations are associated with the epigenetic mechanism of DNA methylation. Aim 2: Determine perinatal consequences of pregnant women's distress. Specifically whether, (a) women's distress-associated altered HPA-axis hormone levels, PBL and placental gene expression/epigenetic variation, predict fetal cord blood gene expression/epigenetic variation, as well as a neurobehavioral profile characterized by heightened reactivity to novelty (fetal and new- born autonomic and central nervous system regulation in response to stimuli). Aim 3: Establish causal influ- ence of epigenetic modification on offspring neurodevelopment. Specifically, using a rodent model in which brain effects of chronic maternal prenatal stress exposure can be directly assessed, we aim to determine (a) the influence of maternal condition on DNA methylation and gene expression in maternal PBLs, placenta, and in the fetal/infant brain and, (b), the relationship between epigenetic variations in these tissues and the de- velopment of the postnatal ANS and CNS as indexed by behavioral and stress-hormone responsivity.