Prenatal and Early Childhood Pathways To Health:  An Integrated Model of Chemical and Social Exposures, Biological Mechanisms, and Sex-Specific Effects on Neurodevelopment and Respiratory Outcomes

摘要 孕妇每天都暴露于多种化学和非化学压力源，包括空气污染物，邻苯二甲酸酯和心理压力。健康和疾病的发展起源模型（DOHaD）指出，在怀孕期间暴露于这些压力源会影响胎儿发育，从而影响整个生命过程中的后代健康。然而，这些地区的流行病学数据有限，特别是美国的样本。人们也不太清楚这些暴露是否会在产前以独立或组合的方式影响儿童神经发育和气道健康，并且很少涉及可能的影响调节因素，如儿童的性别。我们建议在PATHWAYS研究中统一三个不同的现存妊娠队列-TIDES（N=717，2010-12），GAPPS（N=1133，2012-16）和CANDLE（N=1385，2007-11），合并样本量为3235对母子。PATHWAYS将研究怀孕期间的化学（空气污染物和邻苯二甲酸盐）和非化学（心理社会压力）暴露如何与胎盘基因表达（转录组）和儿童神经发育和气道健康（4-6岁，8-9岁和10-11岁）相关。每个队列都有丰富的产前数据和库存标本（尿液、血液和胎盘）资源，这些资源将被协调用于PATHWAYS研究，并将有助于ECHO联盟。我们将开发一个国家模型，对主要空气污染物具有高时空分辨率，并评估母亲暴露的尿液标志物。一项综合措施将捕捉多层次的母亲心理社会压力在整个怀孕，尿邻苯二甲酸酯和血液应激激素（CRH）水平在第二和第三个三个月 将在潜在的关键时期对这些风险进行单独评估。我们将使用RNA测序来表征胎盘转录组，并将前瞻性地评估儿童中期的神经发育和气道健康。PATHWAYS将在主效应和交互模型中研究这些产前暴露如何与胎盘转录组和儿童健康结果相关，重点是性别特异性关联。对于神经发育和气道健康，我们建议测量健康结果的表型前体（即流体认知，肺功能生长），这产生了建议的关联的维度测试，以及临床上有意义的和政策相关的结果（即哮喘，心理健康）。我们的研究旨在评估化学和非化学应激源的相互作用，并将成为第一个研究产前环境暴露如何与胎盘转录组通路相关的儿童健康结果。这代表了测试DOHaD假设的重大科学进步。对ECHO联盟的主要贡献包括：1）开发最先进的国家空气污染模型，2）一个大型，多样化的怀孕队列，具有广泛的生物储存库和现存的产前和产后生物标志物，胎盘转录组，心理和环境数据，以及3）一个经验丰富的跨学科团队，将为ECHO工作计划做出有意义的贡献。

ABSTRACT Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts—TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone (CRH) levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.