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）：将近一半的美国人口将符合精神疾病的标准，而17名中有1人患有严重的疾病。这些心理病理学越来越多地被概念化为由基因和经验的复杂相互作用所塑造的异常发育过程的后期插入，包括在子宫内发生的过程。数十年来，对怀孕动物进行的数十年研究表明，孕产妇生物学中的压力引起的伴侣会影响后代的发展，从而导致其特征的特征是增强和生理压力的反应性。孕妇的痛苦研究（从生命压力的检查到精神疾病的检查）在很大程度上反映了这些发现。尽管有足够的证据将孕产妇的功能与后代结果联系起来，但在子宫内对Children神经发育的影响的机理途径尚不清楚，尤其是在人类受试者中。表格的新兴领域 - 对环境经验的分子作用的检测 - 仅将最小应用于孕妇，但可能在理解精神病风险的胎儿起源机制方面提供了至关重要的联系。该项目的目的是利用最近研究表观遗传基因调节的进展来确定介导孕产妇苦难对围产期发育影响的生物学机制。目标1：确定孕妇困扰对与围产期发育有关的表观遗传基因调节的影响。 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绘制）（b）妇女的时间和pbl基因的变化程度预测胎盘基因的表达；和胎盘基因表达/表观遗传变异，预测胎儿血液基因表达/表观遗传学变异，以及神经行为特征，其特征是对新颖性的反应性升高（胎儿和新生自主神经自主神经和中枢神经系统对刺激的响应）。目标3：建立对后代神经发育的表观遗传修饰的因果影响。具体而言，使用啮齿动物模型，可以直接评估慢性母体产前胁迫暴露的大脑影响，我们旨在确定（a）孕产妇条件对孕产妇PBL，胎盘和胎儿/婴儿脑的DNA甲基化和基因表达的影响行为和应力激素的反应。 公共卫生相关性：拟议的研究与公共卫生有关，因为对孕妇困扰对围产期神经行为发展的影响的机理研究将极大地增加对产前经验对长期心理病理学风险的影响以及风险预测的长期风险的理解。因此，研究的研究与NIH的使命有关，该使命与基本知识的发展有关，这将减轻人类疾病的负担。