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

项目摘要/摘要 儿童肥胖症和神经发育障碍(NDDS)在儿童中的迅速上升发生在 制造和接触内分泌干扰物(EDCs)增加的时期，表明 这些环境暴露的可能病因学作用。感兴趣的EDCs包括全氟烷基物质 全氟辛烷磺酸(PFASs)、多溴联苯醚(PBDEs)和当代有机磷阻燃剂 (OPFR)。尽管它们被广泛检测到，但很少有研究表征宫内暴露的影响 对于人体内的这些内分泌细胞，研究相关机械通路的人就更少了。我们会 利用并扩大现有的两个种族和民族多元化的大型怀孕队列，以期 调查宫内暴露于EDCs与儿童肥胖和NDDS之间的关系。其中的第一个 自2013年以来，队列(花瓣)已招募了1800名女性调查与苯酚接触有关的 妊娠期糖尿病和胎儿过度生长。第二个项目(KPRB-PC)已经招收了大约22,000名妇女 2010年，创建了一个与妇女和儿童健康有关的研究资源。美国国立卫生研究院环境研究所 对儿童健康结局的影响(ECHO)提供了一个延长随访和扩大 这两个群体的工作。在UG3阶段，我们将重新联系并同意研究参与者，进行试点测试 我们建议的数据收集协议，并与ECHO合作伙伴合作开发多站点协议。在.期间 在UH3阶段，我们将跟踪1600对母婴，以下简称优雅队列。我们会 评估1,600名孕妇的宫内EDC暴露，并临床评估其 儿童在4岁时发育、肥胖和神经发育。我们的假设是宫内暴露 对EDCs(即全氟辛烷磺酸、多溴联苯并二苯醚、OPFR)单独或联合使用会对儿童生长发育产生不利影响 (即体重指数)、肥胖症(即脂肪团)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：1.评估宫内单独或联合暴露于EDCs是否相关。 与儿童生长、肥胖和神经发育的关系，以及这些关系是否因儿童性别而异； 评估营养过剩(饮食能量摄入量高、孕前BMI高、孕期体重增加高 和妊娠期糖尿病)改变宫内暴露内皮细胞与儿童生长发育、肥胖的关系 和神经发育；3.评估宫内EDC暴露是否与代谢因素有关 (妊娠期血糖、胰岛素、瘦素和甲状腺激素水平)以及这些因素是否在 宫内暴露于EDCs与儿童生长、肥胖和神经发育之间的关系； 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暴露的标记，并阐明儿童DNA甲基化的潜在机制作用。我们的 当代怀孕队列及其子女的随访是对回声的宝贵补充 并将加强对儿童肥胖症和NDDS的起源的了解。

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.