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

颗粒空气污染物和自闭症风险：暴露特征、易感性指标和机制途径

基本信息

批准号：
10187578
负责人：
ROB S MCCONNELL
金额：
$ 64.29万
依托单位：
KAISER FOUNDATION RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187578
关键词：
2-butenal Address Affect Age Air Pollutants Algorithms Animals Archives Asthma Bacterial Infections Behavioral Biological Biological Assay Biological Markers Biometry Birth Blood Caliber California Case-Control Studies Characteristics Child Childhood Communities Complex Computerized Medical Record Development Diabetes Mellitus Diagnosis Disease Environmental Epidemiology Environmental Exposure Epidemiology Exposure to Family Fetus Future Goals Homocysteine Human Inflammatory Iron Knowledge Life Link Lipid Peroxidation Low Birth Weight Infant Maternal-fetal medicine Metals Methods Mothers Neonatal Neurobiology Obesity Outcome Oxidative Stress Oxidative Stress Pathway Participant Particulate Particulate Matter Pathway interactions Phenotype Placenta Play Population Population Study Pre-Eclampsia Predisposition Pregnancy Prevalence Reactive Oxygen Species Reporting Resolution Resources Risk Risk Factors Role Sample Size Sampling Serum Albumin Source Spottings Standardization Suggestion Sulfonic Acids Toddler Ultrafine Virus Diseases Workplace adduct ambient air pollution ambient particle autism spectrum disorder autistic behaviour base boys cohort comorbidity disorder risk early life exposure economic cost epidemiology study exposure pathway fetal fine particles immune activation in utero male maternal comorbidity modifiable risk multidisciplinary neurodevelopmental effect neuropsychiatric disorder neurotoxic novel offspring particle postnatal prenatal prenatal exposure prenatal risk factor prepregnancy obesity residence screening sex social systematic review systemic inflammatory response trait

项目摘要

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.

项目概要/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成本对男孩产生不同影响的原因可能是多因素的。多项研究发现 ASD 风险与产前环境空气污染暴露之间存在关联；人类流行病学和动物研究的结果正在趋同于细颗粒物的神经毒性作用最近，生命早期暴露于目前不受管制的超细颗粒物质。 PM0.1被证明会导致男性特有的类似自闭症的行为特征，但尚无可用的方法检查 PM0.1 或复杂 PM 混合物中可能存在因果关系的成分的影响。 ASD 将与具有高时间和空间暴露估计值的新 PM2.5 和 PM0.1 暴露估计值相关联怀孕期间母亲住所和工作场所的解决方案（目标 1a），并且协会将由特定的 PM 成分驱动（目标 1b），我们将在怀孕-出生队列中评估这一假设。南加州凯撒医疗机构 (KPSC) 追踪了 40 万对母子具有标准化算法的资源，用于系统性筛查和诊断 ASD 和妊娠风险因素，可通过高质量的母体免疫激活记录获得。（MIA）已被提议作为连接产前危险因素的共同机制，包括各种病毒和细菌感染、哮喘、孕前肥胖、糖尿病以及随后的自闭症谱系障碍 (ASD) 风险。暴露和 ASD 表型具有共同的促炎和氧化应激途径，我们认为与 MIA 相关的母亲合并症会增加胎儿对神经发育的易感性 PM 暴露导致自闭症谱系障碍 (ASD) 的影响（目标 2）这一新假设只能在大量人群中进行研究。像 KPSC 队列这样的研究具有足够的能力来评估相互作用，这些相互作用可以共同解释 ASD 的比例比单一危险因素流行病学要大得多。由于缺乏环境暴露和影响途径的生物标记而受到限制。在新生儿存档的 420 个干血斑中检测人血清白蛋白亲电加合物的新方法根据暴露情况从队列中选出的儿童，我们将检查 PM 暴露的生物标记，并我们勇敢地说，PM2.5 将与一组反映氧化应激的目标加合物相关。暴露以及反映氧化应激的加合物（目标 3a）。暴露和途径的标记，以及在非目标 HSA“加合物组”中鉴定的其他标记，将被与 18 个月和 24 个月时执行的幼儿自闭症检查表 (CHAT)1 异常相关向 KPSC 队列的所有参与者提供（目标 3b）。 PM 和 PM 成分以及 ASD 易感性，并将为 PM 潜在的生物途径提供线索对 ASD 的影响。