Early Life Exposure to Endocrine Disrupting Chemicals and Child Growth, Adiposity, and Neurodevelopment

项目总结/摘要 儿童肥胖和儿童神经发育障碍（NDD）的迅速增加发生在一个世纪以来。 增加制造和暴露于内分泌干扰化合物（EDCs）的时期，这表明 这些环境暴露可能的病因作用。感兴趣的EDCs包括全氟烷基物质 （PFASs）、多溴联苯醚（PBDEs）和当代有机磷酸盐阻燃剂 （OPFR）。尽管它们被广泛发现，但很少有研究描述子宫内暴露的影响 这些内分泌干扰物在人类中，甚至更少的人已经研究了相关的机制途径。我们将 利用和扩大两个现存的大的种族和民族多样化的怀孕队列， 研究子宫内暴露于EDCs与儿童肥胖和NDD的关系。其中第一个 自2013年以来，PETALS队列招募了1，800名女性，调查苯酚暴露与 妊娠糖尿病和胎儿过度生长第二个项目（KPRB-PC）自2010年以来已招收了约22，000名妇女。 2010年，创建一个与妇女和儿童健康有关的研究资源。NIH环境 对儿童健康结果的影响（ECHO）提供了一个机会，以延长后续行动，并扩大 这两支队伍的工作。在UG 3阶段，我们将重新联系研究参与者并征得其同意，进行初步试验 我们提出的数据收集协议，并与ECHO合作伙伴开发多站点协议。期间 在UH 3阶段，我们将跟踪1，600对母子，以下称为ELEGANT队列。我们将 评估1，600名孕妇的生物样本中的子宫内EDC暴露，并对其进行临床评价。 4岁儿童的生长、肥胖和神经发育。我们的假设是子宫内暴露 到EDC（即，PFASs、PBDEs、OPFRs）单独或联合使用，对儿童生长发育有不利影响 (i.e. BMI）、肥胖（即脂肪量）和神经发育，可能通过共同的途径。在我们的目标中， 我们建议：评估子宫内暴露于单个或组合的EDCs是否与 与儿童生长，肥胖和神经发育，以及这些协会是否因儿童性别而异; 2。 评估是否存在营养过剩（高膳食能量摄入、高妊娠前BMI、高妊娠期体重增加） 和妊娠期糖尿病）改变子宫内暴露于内分泌干扰物与儿童生长、肥胖 和神经发育; 3.评估宫内EDC暴露是否与代谢因素相关 （妊娠期间葡萄糖、胰岛素、瘦素和甲状腺激素水平）以及这些因素是否介导了 子宫内暴露于EDCs与儿童生长、肥胖和神经发育之间的关联;以及4. 测量儿童DNA的全基因组甲基化，以开发敏感和特异的儿童DNA甲基化 产前EDC暴露的标志物，并阐明儿童DNA甲基化的潜在机制作用。我们 当代妊娠队列及其子女的随访是ECHO的重要补充 该联盟将加强对儿童肥胖和NDD起源的认识。

PROJECT SUMMARY/ABSTRACT The rapid rise in childhood obesity and neurodevelopment disorders (NDDs) in children has occurred over a period of increased manufacturing and exposure to endocrine disrupting compounds (EDCs), suggesting a possible etiologic role for these environmental exposures. EDCss of interest include perfluoroalkyl substances (PFASs), polybrominated diphenyl ethers (PBDEs), and contemporary organophosphate flame retardants (OPFRs). Despite their widespread detection, few studies have characterized the effects of in-utero exposure to these EDCs in humans, and even fewer have investigated associated mechanistic pathways. We will leverage and expand two large extant racially and ethnically diverse pregnancy cohorts to prospectively investigate the role of in-utero exposure to EDCs in relation to child obesity and NDDs. The first of these cohorts (PETALS) has enrolled 1,800 women since 2013 to investigate phenol exposure in relation to gestational diabetes and excessive fetal growth. The second (KPRB-PC) has enrolled ~22,000 women since 2010 to create a resource for studies related to women's and children's health. The NIH Environmental Influences on Child Health Outcomes (ECHO) provides an opportunity to extend follow-up and to expand the work of these two cohorts. During the UG3 phase, we will re-contact and consent study participants, pilot test our proposed data collection protocol, and work with ECHO partners to develop the multi-site protocol. During the UH3 phase, we will follow 1,600 mother-child pairs, hereafter referred to as the ELEGANT cohort. We will assess in-utero EDC exposures in biospecimens of 1,600 pregnant women and clinically evaluate their children at age 4 years for growth, adiposity, and neurodevelopment. Our hypothesis is that in-utero exposure to EDCs (i.e., PFASs, PBDEs, OPFRs), individually or in combination, have adverse effects on child growth (i.e. BMI), adiposity (i.e. fat mass), and neurodevelopment, possibly through common pathways. In our Aims, we propose to: 1. evaluate whether in-utero exposures to EDCs, individually or in combination are associated with child growth, adiposity, and neurodevelopment, and whether these associations vary by child sex; 2. evaluate whether overnutrition (high dietary energy intake, high pregravid BMI, high gestational weight gain and gestational diabetes) modifies the associations of in-utero exposure to EDCs and child growth, adiposity and neurodevelopment; 3. evaluate whether in-utero EDC exposures are associated with metabolic factors (pregnancy levels of glucose, insulin, leptin and thyroid hormones) and whether these factors mediate the association between in-utero exposure to EDCs and child growth, adiposity, and neurodevelopment; and 4. measure genome-wide methylation in child DNA, to develop sensitive and specific child DNA methylation markers of prenatal EDC exposure, and to illuminate potential mechanistic roles of child DNA methylation. Our contemporary pregnancy cohorts and follow-up of their children represent a valuable addition to the ECHO consortium and will enhance knowledge of the origins of childhood obesity and NDDs.