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: 8448260
• 负责人: FRANCES A. CHAMPAGNE
• 金额: $ 64.35万
• 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/8448260
• 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; epigenome; 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.

描述(由申请人提供)：近一半的美国人在一生中将符合精神障碍的标准，每17人中就有1人患有严重的衰弱疾病。越来越多地，这些精神病理学被概念化为由基因和经验的复杂相互作用塑造的异常发育过程的晚期结果，包括发生在子宫内的那些。几十年来对怀孕动物的研究表明，母体生物学中的应激引起的干扰会影响后代的发育，导致行为和生理应激反应增强。对孕妇痛苦的研究，范围从生活压力的检查到精神障碍，在很大程度上反映了这些发现。尽管有足够的证据将产前母体功能与后代结局联系起来，但子宫内对儿童神经发育的影响机制仍不清楚，特别是在人类受试者中。表观效应--检测环境经验的分子效应--这一新兴领域仅最小限度地应用于孕妇，但可能为理解胎儿精神疾病风险的起源机制提供了一个至关重要的环节。该项目的目标是利用表观基因调控研究的最新进展来确定调节母体痛苦对围产期发育影响的生物学机制。目的1：探讨孕妇宫内窘迫对围产期发育相关表观基因调控的影响。具体地说，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)对怀孕期间的日常生活压力进行3次评估)和临床医生访谈引发的情绪症状是否可以预测妇女的应激激素水平(48小时内从3次唾液样本中提取皮质醇)和CRH(3次抽血)以及其外周血中的基因表达(3次抽血)；(B)妇女应激激素水平和PBL基因表达改变的时间和程度是否可以预测胎盘基因的表达；(C)这些依赖情绪的生物变化与DNA甲基化的表观遗传机制有关。目的2：确定孕妇宫内窘迫的围产期后果。具体地说，(A)妇女与窘迫相关的HPA轴激素水平、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(胎儿和新生儿对刺激的自主神经和中枢神经系统的调节)。目的3：建立表观遗传修饰对子代神经发育的因果影响。具体地说，利用一个可以直接评估孕期慢性应激暴露对大脑影响的啮齿动物模型，我们的目标是确定(A)母体状况对母体外周血淋巴细胞、胎盘和胎儿/婴儿脑中DNA甲基化和基因表达的影响，以及(B)这些组织的表观遗传变异与出生后ANS和中枢神经系统发育的关系，以行为和应激激素反应性为指标。