Autism and Prenatal Endocrine Disruptors (A-PED)

项目摘要 自闭症和谱系障碍（ASD）是严重的和衰弱的神经发育障碍， 病人的巨大痛苦和我们的医疗保健系统面临的重大挑战。据估计，ASD 每68名儿童中就有1名受影响，男女比例为4：1。遗传和环境因素 导致ASD，但环境因素尚未得到充分研究。因为环境因素是 潜在的可修改的，它们应该是一个研究的优先事项。这一努力受到以下挑战的阻碍： 在大型、无偏倚的流行病学队列中获得准确和相关的暴露测量。 在人类接触的许多环境中，内分泌干扰化学品 (EDs)可能对儿科人群的神经发育有最著名的影响。几个这样 化学物质，特别是在产前接触时，与自闭症相关的表型和性别有关- 这些关联的差异已被记录在案。ED已被证明会影响GABA， 谷氨酸神经传递，这在ASD中具有突出的作用。因此，ED是有希望的候选人， ASD的环境诱因据我们所知，没有先前的研究已经能够有力地链接产前艾德 接触ASD。 本申请的目的是确定产前暴露于五类ED是否会影响ASD风险。 为了实现这一目标，我们将使用来自瑞典南部血清生物库的储存样本，并将这些样本与 基于人群的登记，包括个体水平的围产期、诊断、医疗和人口统计学 资料（1998-2007年117，318例出生）。我们将随机选择并验证600例ASD病例 （对女性进行过采样，包括200名女性，400名男性）和600名性别和出生年份相似的对照组 分布。通过测定孕妇血清样本中5种化学类别的38种ED浓度， 将解决以下三个综合的具体目标：首先，确定ASD风险之间的关联， 和产前血清浓度我们的目标ED及其混合物;第二，确定性别是否 改变了对产前艾德暴露的敏感性，导致性别二态性ED-ASD关联;第三，确定 ED浓度（单独和组合）是否导致ASD表型差异， 他们的严重性。

PROJECT SUMMARY Autism and spectrum disorders (ASD) are serious and debilitating neurodevelopmental disorders that incur substantial suffering for patients and major challenges to our health care system. It is now estimated that ASD affects about 1 in 68 children, with a male:female ratio of 4:1. Both genetic and environmental factors contribute to ASD, but environmental factors have been understudied. Because environmental factors are potentially modifiable they should be a research priority. This effort has been hampered by the challenges of acquiring accurate and relevant exposure measures in large, unbiased, epidemiologic cohorts. Among the many environmental exposures to which humans are exposed, endocrine disrupting chemicals (EDs) have perhaps the best-known effects on neurodevelopment in pediatric populations. Several of these chemicals, particularly when exposure is prenatal, have been linked to autism-related phenotypes, and sex- differences in these associations have been documented. EDs have been shown to affect GABA and glutamate neurotransmission, which have prominent roles in ASD. Therefore, EDs are promising candidates as environmental triggers for ASD. To our knowledge, no prior study has been able to robustly link prenatal ED exposure to ASD. The goal of this application is to determine whether prenatal exposure to five classes of EDs impacts ASD risk. To achieve this, we will use stored samples from a serum biobank in southern Sweden and link these to population-based registries that include individual-level perinatal, diagnostic, medical, and demographic information (117,318 births in the years 1998-2007). We will randomly select and validate 600 ASD cases (oversampling females to include 200 females, 400 males) and 600 controls with similar sex and birth year distributions. By measuring concentrations of 38 EDs in five chemical classes in maternal serum samples we will address the following three integrated specific aims: First, determine the associations between ASD risk and prenatal serum concentration of our target EDs and their mixtures; Second, determine whether gender modifies sensitivity to prenatal ED exposure resulting in sex-dimorphic ED-ASD associations; Third, determine whether concentrations of EDs, singly and in combination, contribute to differences in ASD phenotype and their severity.