Exposure to Perfluorinated Compounds and Risk for Autism Spectrum Disorders

项目摘要/摘要 由于很少有人研究自闭症谱系障碍(Asd)的非遗传原因，这项建议寻求 一种新的方法来提高我们对暴露于环境中的ASD复杂病因的认识 化学制品。全氟化合物(PFC)被选为感兴趣的化学类别，因为它们是 普遍存在于消费品中，如食品包装、纺织品和厨具上的不粘涂层，以及 在与实验动物的实验中具有神经或神经发育毒性。此外，至少有500万人 美国人目前饮用的水中全氟碳化物的污染水平超过了健康建议水平。整体而言 该项目的目标是确定在早期发育阶段(怀孕或 哺乳时间)与患自闭症的风险有关。为了检验我们的假设，我们将利用两项研究 被称为“Charge”(遗传和环境导致的儿童自闭症风险)和“弹珠”的人群 《婴儿自闭症风险的标记物-学习早期征兆》一项以人群为基础的病例对照研究 它已经登记了1800多名索引儿童及其家庭，从而提供了大量的案例 (患有自闭症的儿童)和对照组(通常是发育中(TD)儿童)以及母亲的血液样本 当他们的孩子2到4岁的时候。大理石是一个潜在的队列，招募怀孕的女性 已经有一个孩子患有自闭症，因此生下另一个患有自闭症的孩子的风险很高，旨在 确定ASD的原因和早期标志物。从提供大量最终诊断的指控 (ASD或TD)，我们将使用母亲血液中的直接测量作为早期儿童暴露的替代指标 在怀孕和哺乳期间。来自弹珠，提供更准确的特定时间曝光 测量比收费，我们将使用直接测量的母亲在怀孕期间采集的血液和 哺乳期。虽然我们预计孩子2到4岁时母亲的血液水平 由于全氟化碳在体内的消除半衰期相对较长，这将是一个很好的暴露标志，我们将 此外，利用大理石纵向生物标记物测量来重建暴露水平 在怀孕和哺乳期间负责的参与者，然后检验相同的假设 使用重建的估计值。为了实现我们的目标，我们建议对随机选择的血液进行PFC分析 332例自闭症患者和332例对照的母亲样本和336份血液样本。 112名母亲在怀孕期间至少提供了一个，在哺乳期间提供了一个，在 他们的孩子当时2岁。因此，该项目实现了1)大样本量；2)精确表征 在特定发育时期暴露于PFC；以及3)PFC与ASD病例的相关性 由训练有素、研究可靠的临床医生使用黄金标准仪器进行确认。这项研究将 提高对从怀孕到怀孕后头几年身体负担的时间变化的理解 并提供关于早期PFC暴露在ASD中的作用的独特的高质量数据。

Project Summary/Abstract Because few non-genetic causes of autism spectrum disorders (ASD) have been studied, this proposal seeks a novel approach to advance our knowledge of the complex etiology of ASD due to exposure to environmental chemicals. Perfluorinated compounds (PFCs) are selected as a chemical class of interest because they are ubiquitous in consumer products such as food packaging, textiles and non-stick coatings on cookware, and have neurologic or neuro-developmental toxicity in experiments with laboratory animals. Also, at least 5 million U.S. people are currently drinking water contaminated with PFCs above a health advisory level. The overall goal of this project is to determine whether exposure to PFCs at an early developmental stage (pregnancy or breastfeeding periods) is associated with risk for ASD. To test our hypothesis, we will utilize two study populations known as “CHARGE” (CHildhood Autism Risk from Genetics and Environment) and “MARBLES” (Markers of Autism Risk in Babies – Learning Early Signs). CHARGE is a population-based case-control study that has enrolled over 1800 index children and their families and thus provides a large number of cases (children with ASD) and controls (typically developing (TD) children) along with blood samples from mothers when their child was 2 to 4 years old. MARBLES is a prospective cohort, enrolling pregnant women who already have a child with ASD and are therefore at high risk for delivering another child with ASD, designed to identify causes and early markers of ASD. From CHARGE that provides a large number of final diagnoses (ASD or TD), we will use direct measures in the mother's blood as a proxy for early life children's exposure during pregnancy and breastfeeding. From MARBLES that provides more accurate time-specific exposure measurements than CHARGE, we will use direct measures in mother's blood collected during pregnancy and breastfeeding periods. While we anticipate that the mother's level in blood when their child was 2 to 4 years old would be a good marker of exposure due to the relatively long elimination half-life of PFCs in the body, we will additionally capitalize on the MARBLES longitudinal biomarker measurements to reconstruct exposure levels during pregnancy and breastfeeding periods for participants in CHARGE and then test the same hypothesis using reconstructed estimates. To achieve our goals, we propose PFC analysis of randomly selected blood samples from mothers of 332 cases (=ASD) and 332 controls (=TD) in CHARGE and 336 blood samples from 112 MARBLES mothers who provided at least one during pregnancy, one during breastfeeding, and one when their child was 2 years old. This project thereby achieves 1) large sample size; 2) precise characterization of PFC exposures during specific developmental periods; and 3) associations of PFCs with cases of ASD that were confirmed by highly trained, research reliable clinicians using gold standard instruments. This study will improve understanding of temporal changes in body burden from pregnancy through the first few years post- partum and provide uniquely high quality data on the role of early PFC exposures in ASD.