Particulate Air Pollutants and Autism Risk: Exposure Characteristics, Indicators of Susceptibility, and Mechanistic Pathways

项目总结/摘要 自闭症谱系障碍（ASD）给家庭带来了巨大的终身社会和经济成本， 社区.对男孩产生不同影响的原因可能是多方面的。为了寻找可改变的风险因素， 几项研究发现ASD风险与产前环境空气污染暴露有关;证据 来自人类流行病学和动物研究的研究正集中在细颗粒物的神经毒性作用上 直径小于2.5微米的物质（PM2.5）。最近，早期生活暴露于目前不受管制的超细 PM0.1被证明会导致男性特有的自闭症样行为特征，但方法尚未获得 研究PM0.1或复杂PM混合物的成分可能是因果关系的影响。我们假设 ASD将与新的PM2.5和PM0.1暴露估计相关， 在孕妇住所和工作场所解决怀孕问题（目标1a），协会将 由特定PM组件驱动（目标1b）。我们将评估这一假设的怀孕-出生队列， 40万对母子在南加州凯撒医疗机构（KPSC）进行了跟踪调查， 资源与标准化算法系统筛查和诊断ASD和妊娠风险 这些因素，可通过一个非常高质量的电子病历。母体免疫激活 (MIA)已被认为是一种常见的机制，连接产前风险因素，包括各种病毒和 细菌感染，哮喘，孕前肥胖，糖尿病，到随后的ASD风险。因为产前PM 暴露和ASD表型，有共同的促炎和氧化应激途径，我们 假设MIA相关的母体合并症会增加胎儿对神经发育的易感性， PM暴露导致ASD的影响（目标2）。这种新的假说只能在大群体中进行研究 研究，如KPSC队列，有足够的力量评估相互作用，共同可以解释一个 ASD的比例远远大于单一危险因素流行病学。最后，ASD流行病学一直是 由于缺乏环境暴露和影响途径的生物标志物，这一研究受到限制。使用 420例新生儿存档干血斑中人血清白蛋白亲电加合物的新测定法 根据暴露情况从队列中选择儿童，我们将检查PM暴露的生物标志物， 氧化应激我们假设PM2.5将与一组目标加合物相关， 暴露和加合物反映氧化应激（目标3a）。我们假设这些目标生物 暴露和途径的标志物，以及在非靶向HSA“内收体”中鉴定的其他标志物，将 与在18个月和24个月时进行的幼儿自闭症异常检查表（CHAT）1相关 KPSC队列中的所有参与者（目标3b）。这项研究将解决在了解 PM和PM成分以及ASD易感性，并将为PM的生物学途径提供线索 对ASD的影响

PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) imposes large lifetime social and economic costs on families and communities. Causes, differentially affecting boys, likely are multifactorial. In search of modifiable risk factors, several studies have found associations of ASD risk with prenatal ambient air pollution exposure; evidence from human epidemiological and animal studies is converging on the neurotoxic effects of fine particulate matter less than 2.5 µm in diameter (PM2.5). Recently, early life exposure to currently unregulated ultrafine PM0.1 was shown to cause autism-like behavioral traits specific to males, but methods have not been available to examine effects of PM0.1 or of components of the complex PM mixture likely to be causal. We hypothesize that ASD will be associated with novel PM2.5 and PM0.1 exposure estimates with high temporal and spatial resolution at maternal residences and workplaces during pregnancy (Aim 1a), and that associations will be driven by specific PM components (Aim 1b). We will assess this hypothesis in a pregnancy-birth cohort of 400,000 mother-offspring pairs followed through Kaiser Permanente Southern California (KPSC), a population resource with standardized algorithms for systematic screening and diagnosis of ASD and gestational risk factors, available through an exceptionally high quality electronic medical record. Maternal immune activation (MIA) has been proposed as a common mechanism linking prenatal risk factors, including diverse viral and bacterial infections, asthma, pre-pregnancy obesity, diabetes, to subsequent ASD risk. Because prenatal PM exposure, and ASD phenotype, have in common pro-inflammatory and oxidative stress pathways, we hypothesize that MIA-related maternal comorbidities will increase fetal susceptibility to neurodevelopmental effects of PM exposure leading to ASD (Aim 2). This novel hypothesis can only be studied in large population studies such as the KPSC cohort with sufficient power for assessing interactions that together could explain a much larger proportion of ASD than single risk factor epidemiology. Finally, ASD epidemiology has been limited by the lack of biological markers both of environmental exposures and of pathways of effects. Using a novel assay for electrophilic adducts to human serum albumin in neonatal archived dried blood spots from 420 children selected from the cohort based on exposure, we will examine biological markers for PM exposure and oxidative stress. We hypothesize that PM2.5 will be associated with a targeted panel of adducts reflecting exposure and with adducts reflecting oxidative stress (Aim 3a). We hypothesize that these targeted biological markers of exposures and pathways, and additional ones identified in an untargeted HSA “adductome”, will be associated with an abnormal Checklist for Autism in Toddlers (CHAT)1 administered at ages 18 and 24 months to all participants in the KPSC cohort (Aim 3b). The study will address critical gaps in knowledge of effects of PM and PM composition, and ASD susceptibility, and will provide clues to biological pathways underlying PM effects on ASD.