Prenatal Exposure to Phthalates in a High-Risk ASD Pregnancy Cohort

 描述(由申请人提供)：由于对自闭症谱系障碍(ASD)的非遗传原因知之甚少，本提案寻求一种新的方法来提高我们对自闭症的复杂病因的认识，这是由于使用普通消费品而导致的环境化学暴露。邻苯二甲酸酯被选为一类令人感兴趣的化学物质，因为它们普遍存在于个人护理产品(如化妆品、香水、洗发水)和室内居住环境(如聚氯乙烯(PVC)地板和塑料、儿童玩具、乙烯基砖、浴帘)中，已被证明对大脑早期发育至关重要的性类固醇有影响，并对婴儿和儿童具有神经发育毒性。最近的一项流行病学研究还发现，父母或孩子的房间里有聚氯乙烯地板材料(空气中邻苯二甲酸盐的来源)与患自闭症的风险增加有关。该项目的总体目标是确定怀孕期间暴露于邻苯二甲酸盐是否与ASD风险增加有关。为了评估产前邻苯二甲酸酯的暴露，这项研究将利用NIEHS资助的加州大学戴维斯分校儿童环境健康中心发起的一项独特的纵向研究的现有资源，该研究被称为“弹珠”(婴儿自闭症风险的标记物-学习早期迹象)。大理石是一项前瞻性调查，招募已经有自闭症孩子的孕妇，因此生下另一个患有自闭症的孩子的风险很高，旨在确定自闭症的原因和早期标志。从这项研究中，我们有了在整个怀孕期间从母亲那里收集的多个尿样，这是改善每个婴儿和母亲暴露估计的关键特征，因为邻苯二甲酸盐被迅速代谢和排泄，消除半衰期在几个小时的数量级。此外，在R21期间，来自这个怀孕队列的215个孩子将在36个月大的时候被评估为自闭症，这丰富了这些产前生物样本的价值。在第一批147名满36个月的儿童中，近五分之一被确诊患有自闭症。其他发育诊断，包括适应功能和认知发展，也适用于这些儿童。因此，从母亲那里收集的多次妊娠尿液样本和弹珠中确诊的自闭症是非常宝贵的资源，将有助于严格分析产前接触邻苯二甲酸盐与自闭症或其他发育问题风险之间的联系。每名妇女每三个月都要采集多达四个尿样。为了降低分析成本，同时保持一些关于可变性的信息，我们将分析每三个月收集的第一个样本作为单个样本，并将该三个月的所有剩余样本汇集在一起。为了评估孕妇在怀孕期间暴露的可变性，将对9名母亲相隔约一周采集的纵向个体尿样进行邻苯二甲酸盐代谢物水平分析。这项研究将显著促进对一类常见于ASD消费产品中的内分泌干扰化合物的作用的理解。

 DESCRIPTION (provided by applicant): Because little is known about non-genetic causes of autism spectrum disorders (ASD), this proposal seeks a novel approach to advance our knowledge of the complex etiology of autism due to environmental chemical exposures from the use of common consumer products. Phthalates are selected as a chemical class of interest because they are ubiquitous in personal care products (e.g., cosmetics, fragrances, shampoos) and indoor residential environments (e.g., polyvinyl chloride (PVC) flooring and plastics, children's toys, vinyl tiles, shower curtains), have been shown to influence sex steroids critical n early brain development, and have neuro- developmental toxicity in infants and children. A recent epidemiologic study also found that having PVC flooring material (a source of airborne phthalates) in a parent's or child's room was associated with an increased risk of ASD. The overall goal of this project is to determine whether exposure to phthalates during pregnancy is associated with an increased risk of ASD. To estimate prenatal exposure to phthalates, this study will leverage existing resources from a unique longitudinal study initiated under the NIEHS-funded UC Davis Center for Children's Environmental Health known as "MARBLES" (Markers of Autism Risk in Babies - Learning Early Signs). MARBLES is a prospective investigation, enrolling pregnant women who already have a child with ASD and are therefore at high risk for delivering another child with autism, designed to identify causes and early markers of autism. From this study, we have available multiple urine samples collected from the mother throughout pregnancy, a key feature for improving the exposure estimates for each infant and mother due to the fact that phthalates are metabolized and excreted quickly, with elimination half-lives on the order of hours. Moreover, two hundred fifteen of the children from this pregnancy cohort will have been assessed for autism at the age of 36 months during the time of this R21, enriching the value of these prenatal biological samples. Close to one in five of the firt 147 children to reach 36 months has been confirmed with a diagnosis of ASD. Other developmental diagnoses, including adaptive function and cognitive development, are also available for these children. Therefore, multiple gestational urine samples collected from mothers and confirmed diagnoses of autism in MARBLES are invaluable resources that will enable rigorous analyses of the association between prenatal exposure to phthalates and the risk for ASD or other developmental concerns. Up to four urine samples were collected each trimester for each woman. To reduce analytical costs while maintaining some information about variability, we will analyze the first sample collected each trimester as an individual sample and pool all remaining samples for that trimester. To assess variability of maternal exposures during pregnancy, longitudinal individual urine samples collected approximately one week apart from 9 mothers will be analyzed for phthalate metabolite levels. This study will markedly advance understanding of the role of a class of endocrine disrupting compounds common in consumer products on ASD.