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

产前和幼儿期健康之路：化学和社会暴露、生物机制以及对神经发育和呼吸结果的性别特异性影响的综合模型

• 批准号: 10018122
• 负责人: Nicole Renee Bush
• 金额: $ 733.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018122
• 关键词: Address; Affect; Age; Air Pollutants; Air Pollution; Airway Disease; American; Anxiety; Area; Aromatic Polycyclic Hydrocarbons; Asthma; Attention deficit hyperactivity disorder; Biological; Biological Markers; Biological Specimen Banks; Birth; Blood; Brain; CRH gene; Chemical Models; Chemicals; Child; Child Health; Childhood; Chronic; Clinical; Cognition; Cohort Studies; Corticotropin-Releasing Hormone; Data; Databases; Development; Diagnosis; Diethylhexyl Phthalate; Dimensions; Disease model; Elderly; Elements; Environmental Exposure; Evaluation; Exposure to; Fetal Development; Gene Expression; Genes; Growth; Health; Hormones; Hypersensitivity; IgE; Individual; Inflammatory; Joints; Learning; Life Cycle Stages; Link; Liquid substance; Maternal Exposure; Measures; Mental Depression; Mental Health; Modeling; Morbidity - disease rate; Mothers; Neighborhoods; Obesity; Obstruction; Outcome; Oxidative Stress; Participant; Pathway interactions; Phase; Phenotype; Pilot Projects; Placenta; Plastics; Policies; Positioning Attribute; Pregnancy; Pregnant Women; Process; Protocols documentation; Psychosocial Stress; Resolution; Resources; Respiratory physiology; Sample Size; Sampling; Science; Scientific Advances and Accomplishments; Second Pregnancy Trimester; Stress; Testing; Third Pregnancy Trimester; Tissues; Urine; Wheezing; Woman; Work; ambient air pollution; biobank; cohort; critical period; data warehouse; disorder risk; early childhood; epidemiologic data; experience; follow-up; health data; innovation; middle childhood; multidisciplinary; neurodevelopment; offspring; perinatal outcomes; phthalates; postnatal; prenatal; prenatal environmental exposure; prenatal exposure; programs; prospective; psychosocial; respiratory; respiratory health; sex; social; spatiotemporal; stressor; transcriptome; transcriptome sequencing; urinary; whole genome

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.

抽象的 孕妇每天都会接触多种化学和非化学压力源，包括空气污染物、邻苯二甲酸盐和社会心理压力。健康与疾病的发育起源模型 (DOHaD) 指出，怀孕期间接触这些压力源会影响胎儿的发育，从而影响后代整个生命周期的健康。然而这些地区的流行病学数据有限，特别是美国样本。人们对这些暴露在产前是否以独立或综合的方式影响儿童神经发育和气道健康也知之甚少，而且影响的可能调节因素（例如儿童的性别）也很少得到解决。我们建议统一三个不同的现有妊娠队列——TIDES（N=717，2010-12）、GAPPS（N=1133，2012-16）和CANDLE（N=1385，2007-11），在PATHWAYS研究中合并样本量为3235个母子二人组。 PATHWAYS 将研究怀孕期间化学物质（空气污染物和邻苯二甲酸盐）和非化学物质（社会心理压力）暴露与胎盘基因表达（转录组）以及儿童神经发育和气道健康（4-6 岁、8-9 岁和 10-11 岁）之间的关系。每个队列都拥有丰富的产前数据资源和储存的样本（尿液、血液和胎盘），这些资源将针对 PATHWAYS 研究进行协调，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关键空气污染物国家模型，并评估孕产妇暴露的尿液标记物。综合测量将捕获整个怀孕期间的多层次母亲社会心理压力，而妊娠中期和晚期的尿邻苯二甲酸盐和血液应激激素 (CRH) 水平将为潜在关键时期的这些暴露提供个体评估。我们将使用 RNA 测序来表征胎盘转录组，并将前瞻性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与胎盘转录组和儿童健康结果的关系，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兆（即液体认知、肺功能增长），这会产生所提出的关联的维度测试，以及具有临床意义和政策相关的结果（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，并将成为第一项描述产前环境暴露与胎盘转录组通路（与儿童健康结果相关）之间关系的研究。这代表了检验 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、多样化的妊娠队列，拥有广泛的生物储存库和现有的产前和产后生物标志物、胎盘转录组、社会心理和环境数据，以及 3) 一支经验丰富的跨学科团队，将为 ECHO 的工作计划做出有意义的贡献。