The Infants of Superstorm Sandy:The Epigenetic and Developmental Impact of Natural Disaster

描述(由申请人提供)：宫内期对大脑发育至关重要，可能会影响一生的心理健康。动物研究表明，怀孕期间的心理社会应激，特别是在妊娠早期和中期，会导致神经行为问题，与中枢神经系统(CNS)发育不佳有关，包括运动技能、唤醒、冲动和情绪调节障碍。然而，这些研究不能直接应用于人类。这项拟议研究的总体目标是基于这样一种假设，即在宫内暴露于心理社会压力可以导致子代在胎儿发育的敏感窗口期间中枢神经系统功能发生变化，从而导致神经发育障碍。这项研究建立在我们正在进行的由美国国立卫生研究院资助的研究的基础上，该研究评估了产前应激作为一个关键的神经发育风险因素。受试者(N=408)居住在皇后区/长岛，那里的超级风暴桑迪造成了破坏，让我们可以进行怀孕期间的自然压力实验。利用现有的基础设施，已建立的生物库，并前瞻性收集灾难后桑迪相关创伤(严重程度、暴露时间、逆境持续时间和心理反应)和正常的(来自日常生活的)怀孕期间经历的心理社会压力的数据，我们建议1)跟踪观察42个月大的后代，以评估他们作为产前应激暴露的神经发育关键区域的功能；2)评估暴露于桑迪创伤的时间是否与不同的神经发育轨迹有关；3)在胎盘和脐带血样本中研究产前应激、儿童神经发育和候选基因的表观/遗传(甲基化和基因表达)调控之间的相互关系，包括5条关键的应激调节和神经发育途径，并进一步探讨这些基因的表观遗传调控是否会导致不同的神经发育轨迹；4)探索儿童早期发育过程中表观遗传标记的稳定性。鉴于基因调控具有不同的生物学功能以及组织和发育阶段特异性，评估出生时胎盘和脐带血以及儿童时期唾液样本中的表观/遗传标记有助于阐明疾病机制。通过展示在生命的不同时期收集周围组织的侵入性较小的方法的实用性，这项研究将推进未来流行病学研究的设计，并有可能改善发展精神病理学的预后和干预措施。使用结构方程模型、多水平生长曲线模型和分层线性模型，我们将阐明儿童早期神经发育不佳的潜在机制，以及与怀孕期间母亲心理社会应激暴露(类型、强度和时机)有关的潜在机制。这项研究最终将帮助我们绘制出从宫内到出生和儿童早期的精神障碍历程， 进一步了解怀孕的关键时期及其对人类分子水平的影响，并为研究早期干预措施奠定了基础，这些干预措施可以预防日后可能出现的精神障碍。

DESCRIPTION (provided by applicant): The intrauterine period is critically important for brain development and may influence mental health throughout life. Animal studies have shown that psychosocial stress during pregnancy, especially in early and mid-stages of gestation, lead to neurobehavioral problems associated with suboptimal Central Nervous System (CNS) development involving motor skills, arousal, impulsivity, and emotional dysregulation. Yet, these studies cannot be directly applied to humans. The overall goal of the proposed study is driven by the hypothesis that exposure to psychosocial stress in utero can program changes in the functioning of the offspring's CNS during sensitive windows of fetal development, leading to neurodevelopmental impairment. This study builds upon our on-going NIH-funded study which assesses prenatal stress as a critical neurodevelopmental risk factor. The participants (N=408) reside in Queens/Long Island, where "Superstorm Sandy" caused devastation, allowing us to conduct a natural experiment of stress during pregnancy. Capitalizing on existing infrastructure, an established biorepository, and prospectively collected data on Sandy-related trauma after the disaster (severity, timing of exposure, duration of adversity, and psychological reactions), and normative (from everyday life) psychosocial stress experienced during pregnancy, we propose to 1) follow offspring through 42 months of age to evaluate key areas of neurodevelopment as a function of their exposure to prenatal stress; 2) evaluate whether timing of exposure to Sandy trauma is associated with different neurodevelopmental trajectories; 3) examine the inter- relations of prenatal stress, child neurodevelopment, and epi/genetic (methylation and gene expression) regulation of candidate genes, encompassing 5 key stress modulation and neuro-development pathways in paired samples of placenta and cord blood, and further explore if epigenetic regulation in those genes induce different trajectories of neurodevelopment; 4) explore stability of epigenetic marks during early development in childhood. Given the distinct biological functions and tissue- and developmental stage-specificity of gene regulation, assessment of epi/genetic marks in paired samples of placenta and cord blood at birth and saliva in childhood could help clarify disease mechanism. By demonstrating the utility of less invasive ways to collect peripheral tissues at different times in life, the study will advance the design for future epidemiologic studies, and potentially improve prognosis and interventions for developmental psychopathology. Using structural equation modeling, multilevel growth curve modeling, and hierarchical linear models, we will elucidate the underlying mechanisms of suboptimal neurodevelopment in early childhood, in association with maternal psychosocial stress exposure (types, intensity, and timing) during the course of pregnancy. The study will ultimately help us chart the course of mental disorders from in utero to birth and early childhood, further our understanding of the critical periods of pregnancy and their effect on a molecular level in humans, and set the stage for research into early interventions that could preempt mental disorders that might emerge later in life.