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

项目摘要/摘要 自闭症谱系障碍(ASD)给家庭和家庭带来了巨大的终生社会和经济代价 社区。对男孩有不同影响的原因可能是多因素的。在寻找可改变的风险因素时， 几项研究发现自闭症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结果正集中在细颗粒物的神经毒性效应上。 直径小于2.5微米的物质(PM2.5)。最近，早期生命暴露于目前未受监管的超细 PM0.1被证明会导致男性特有的自闭症样行为特征，但目前还没有可用的方法 检查PM0.1或可能是因果关系的复杂PM混合物的成分的影响。我们假设 ASD将与新的PM2.5和PM0.1暴露估计相关，具有较高的时间和空间 在怀孕期间在产妇住所和工作场所解决问题(目标1a)，并将与 由特定的项目管理组件驱动(目标1b)。我们将在一组孕产队列中评估这一假说。 400,000对母子通过南加州凯撒永久(KPSC)人口 系统筛查和诊断ASD和妊娠风险的标准化算法资源 因素，可通过极高质量的电子病历获得。母体免疫激活 (MIA)已被提议作为一种将产前风险因素联系起来的共同机制，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。因为产前月经周期 暴露和ASD表型有共同的促炎和氧化应激途径，我们 假设MIA相关的母体合并症将增加胎儿神经发育的易感性 PM暴露导致ASD的影响(目标2)。这一新的假设只能在大量人口中进行研究 像KPSC队列这样的研究有足够的能力评估相互作用，这些相互作用加在一起可以解释 ASD的比例远大于单危险因素流行病学。最后，自闭症的流行病学已经 由于缺乏环境暴露和影响途径的生物标记物而受到限制。使用 新生儿420个干血点中人血清白蛋白亲电加合物的新检测方法 根据暴露情况从队列中选择儿童，我们将检查PM暴露的生物标记物和 氧化应激。我们假设PM2.5将与一组目标加合物有关，这些加合物反映了 暴露和反映氧化应激的加合物(目标3a)。我们假设这些靶向生物 暴露和途径的标记物，以及在非靶向人血清白蛋白“内收组”中确定的其他标记物，将是 与幼儿自闭症异常检查表(CHAT)相关1在18个月和24个月时进行 KPSC队列中的所有参与者(目标3b)。这项研究将解决在影响的知识方面的关键差距 PM和PM的组成以及ASD的易感性，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.