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 孕妇每天暴露在多种化学和非化学应激源中，包括空气污染物、邻苯二甲酸盐和心理社会压力。健康与疾病发育起源模型(DOHAD)指出，怀孕期间暴露于这些应激源会影响胎儿的发育，从而影响后代的整个生命过程的健康。然而，这些地区的流行病学数据有限，特别是美国的样本。人们也很少了解这些暴露是以独立的方式还是以联合的方式影响儿童的神经发育和呼吸道健康，而且很可能是影响的调节因素，如儿童的性别，很少被提及。在路径研究中，我们建议统一三个不同的现有妊娠队列--N=717,2010-12)、GAPPS(N=1133,2012-16)和蜡烛(N=1385,2007-11)，以获得3235个母子二联体的联合样本量。路径将调查怀孕期间接触化学物质(空气污染物和邻苯二甲酸盐)和非化学物质(心理社会应激)与胎盘基因表达(转录组)以及儿童神经发育和呼吸道健康(4-6岁、8-9岁和10-11岁)之间的关系。每个队列都有丰富的产前数据和储存的标本(尿液、血液和胎盘)，这些将被协调用于路径研究，并将为ECHO联盟做出贡献。我们将开发一个具有高时空分辨率的主要空气污染物的国家模式，并评估母亲接触的尿液标志物。一项综合措施将捕捉怀孕期间多水平的母亲心理社会压力，怀孕中期和晚期的尿邻苯二甲酸盐和血液应激激素(CRH)水平将对潜在关键时期的这些暴露提供个人评估。我们将使用RNA测序来描述胎盘转录组的特征，并将前瞻性地评估神经发育和儿童中期的呼吸道健康。路径将考察这些产前暴露如何与胎盘转录组和儿童健康结果在主效应和交互模型中相关，重点是性别相关。对于神经发育和呼吸道健康，我们建议测量健康结果的表型前兆(即液体认知、肺功能增长)，这产生了拟议关联的维度测试，以及临床上有意义和与政策相关的结果(例如哮喘、精神健康)。我们的研究旨在评估化学和非化学应激源的交互作用，并将是第一个表征产前环境暴露如何与胎盘转录组途径相关的儿童健康结局的研究。这代表着在测试DOHaD假说方面取得了重大的科学进步。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)拥有广泛的生物库和现有的产前和产后生物标记物、胎盘转录组、心理社会和环境数据的大型、多样化的妊娠队列；以及3)一支经验丰富的跨学科团队，将对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.