Prenatal stress: the epigenetic basis of maternal and perinatal effects

产前应激：孕产妇和围产期影响的表观遗传基础

• 批准号: 8185485
• 负责人: FRANCES A. CHAMPAGNE
• 金额: $ 71.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185485
• 关键词: 15 year old; Affect; Animals; Anxiety; Behavioral; Biological; Biology; Blood; Brain; CRH gene; Child; Chronic; Complex; DNA Methylation; Data; Detection; Development; Developmental Process; Distress; Endocrine; Epigenetic Process; Fetus; Future; Gatekeeping; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Goals; Health; Hormones; Hour; Human; Hydrocortisone; Infant; Interview; Investigation; Knowledge; Leukocytes; Life Stress; Link; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Methylation; Mission; Modification; Molecular; Moods; Morbidity - disease rate; Neuraxis; Neurons; Newborn Infant; Outcome; Pathway interactions; Perinatal; Personal Digital Assistant; Physiological; Placenta; Population; Prefrontal Cortex; Pregnancy; Pregnant Women; Psychopathology; Public Health; Regulation; Research; Rest; Risk; Rodent; Rodent Model; Role; Salivary; Sampling; School-Age Population; Shapes; Staging; Stimulus; Stress; Symptoms; Testing; Time; Tissues; Umbilical Cord Blood; Woman; Work; base; density; digital; disorder risk; epigenetic variation; experience; fetal; gray matter; hormone regulation; human subject; in utero; indexing; maternal stress; meetings; neurobehavioral; neurodevelopment; offspring; peripheral blood; postnatal; pregnant; prenatal; prenatal experience; prenatal stress; psychosocial; response

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because mechanistic studies of the impact of pregnant women's distress on perinatal neurobehavioral development will greatly increase understanding of the contri- bution of prenatal experience to long-term risk for psychopathology, as well as risk prediction. Thus, the pro- posed research is relevant to NIH's mission that pertains to the development of fundamental knowledge that will reduce the burdens of human illness.

描述（由申请人提供）：近一半的美国人口在其一生中将符合精神疾病的标准，17人中有1人患有严重的衰弱性疾病。这些精神病理学越来越多地被概念化为异常发育过程的晚期形成，这些异常发育过程由基因和经历的复杂相互作用形成，包括发生在子宫内的那些。数十年的妊娠动物研究表明，压力引起的母体生物学扰动会影响后代发育，导致以增强的生物和生理应激反应为特征的特征。从生活压力到精神障碍的孕妇痛苦研究在很大程度上反映了这些发现。尽管有充分的证据将纳塔尔母体功能与后代结果联系起来，但子宫内对儿童神经发育的影响的机制途径仍然未知，特别是对于人类受试者。新兴的表观遗传学领域--检测环境经验的分子效应--只在最低限度上应用于孕妇，但可能为理解精神疾病风险的胎儿起源机制提供重要的联系。该项目的目标是利用最新的进展，在研究表观遗传基因调控，以确定介导的影响围产期发育的孕产妇痛苦的生物学机制。目的1：探讨孕妇的痛苦对围产期发育相关表观遗传基因调控的影响。具体而言，确定是否（a）产前窘迫（通过个人数字助理（PDA）使用24小时生态瞬时评估（EMA）在怀孕期间对日常生活压力进行3次评估）和临床医生访谈引起的情绪症状）预测女性的压力激素水平（皮质醇（来自3x，48小时内12份唾液样本）和CRH（3次抽血）和PBL中的基因表达（3次抽血）;（B）妇女改变的应激激素水平和PBL基因表达的时间和程度预测胎盘基因表达;（c）这些情绪依赖性生物学改变与DNA甲基化的表观遗传机制有关。目的2：确定围产期后果的孕妇的痛苦。具体来说，（a）女性与痛苦相关的HPA轴激素水平改变、PBL和胎盘基因表达/表观遗传变异是否可以预测胎儿脐带血基因表达/表观遗传变异，以及以对新奇事物的高度反应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反应调节）。目的3：确定表观遗传修饰对后代神经发育的因果影响。具体地，使用啮齿动物模型，其中慢性母体产前应激暴露的脑效应可以直接评估，我们的目的是确定（a）母体状况对母体PBL、胎盘和胎儿/婴儿脑中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，如行为和应激激素反应性所示。 公共卫生相关性：拟议的研究与公共卫生相关，因为对孕妇痛苦对围产期神经行为发育影响的机制研究将大大增加对产前经历对精神病理学长期风险以及风险预测的贡献的了解。因此，所提议的研究与NIH的使命有关，该使命涉及到基础知识的发展，这将减少人类疾病的负担。