The interplay of early life exposure to environmental pollutants and folate system in the etiology of autistic behaviors

生命早期接触环境污染物和叶酸系统在自闭症行为病因学中的相互作用

• 批准号: 10544528
• 负责人: Youssef Oulhote
• 金额: $ 62.78万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544528
• 关键词: 4 year old; Address; Affect; Air Pollutants; Air Pollution; American; Attenuated; Autoantibodies; Award; Birth; Blood; Blood specimen; Brain; Canada; Carbon; Chemical Exposure; Chemically Induced Neurotoxicity; Chemicals; Child; Cities; Clinical; Communication; Complex; Complex Mixtures; Cytotoxic agent; Data; Development; Dietary Intervention; Disease; Environmental Exposure; Environmental Pollutants; Etiology; Europe; Exposure to; FOLR1 gene; Family; First Pregnancy Trimester; Folic Acid; Fostering; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Health; High Prevalence; Individual; Infant; Inflammation; Insecticides; Intake; Intervention; Joints; Life; Link; Measurement; Measures; Mediator; Metabolism; Methylenetetrahydrofolate reductase (NADPH); Mothers; Nitrogen Dioxide; North America; Nutritional; Organophosphates; Oxidative Stress; Particulate Matter; Pesticides; Plasma; Plastics; Play; Polyvinyl Chloride; Population; Predisposition; Pregnancy; Pregnancy Trimesters; Pregnant Women; Prevention strategy; Public Health; Research; Research Personnel; Risk; Risk Factors; Role; Scientist; Statistical Models; System; Testing; Third Pregnancy Trimester; Time; Woman; Work; autism spectrum disorder; autistic; autistic behaviour; autistic children; biobank; blood-brain barrier crossing; career development; chemical association; cohort; early life exposure; environmental chemical; folic acid metabolism; folic acid supplementation; immune activation; instrument; man; modifiable risk; neurodevelopment; particle; personal care products; phthalates; pollutant; population based; population health; prevent; protective effect; repetitive behavior; social; trait; ultrafine particle

Project summary Autism spectrum disorders (ASD) which are multifactorial complex disorders characterized by communication deficits and repetitive behaviors affect between 1 and 2% of children in the US and Canada. Air pollutants, phthalates, and pesticides are suspected of contributing to the etiology of ASD, whereas folic acid supplementation has been shown to play a protective role, particularly in genetically susceptible individuals with inefficient folate metabolism. Despite these critical findings from a few studies, several questions remain unanswered: 1) No previous study investigated these modifiable factors in a comprehensive way; 2) no previous study investigated the critical windows of susceptibility to these exposures; and 3) the interplay between environmental, nutritional, and genetic factors in the etiology of autism is still unclear. Our preliminary data show that folic acid supplementation is associated with lower autistic traits, but only in children of mothers with genetic susceptibility. In addition, we found that adequate folic acid supplementation in first trimester of pregnancy may prevent the detrimental effects of phthalates exposures regarding autistic traits. Building on these findings and a large comprehensively characterized pregnancy and birth cohort implemented in ten Canadian cities, we will examine the individual and joint contribution of identified modifiable risk factors of autism and its associated traits. We will measure phthalates and organophosphate pesticides across the three trimesters of pregnancy, and we will estimate monthly exposures to individual air pollutants such as nitrogen dioxide and particulate matter and its composition across pregnancy and during child’s first year. Additionally, we will measure folate autoantibodies that have been shown to be highly prevalent in mothers of autistic children, and folate levels in maternal blood sample during 1st and 3rd trimesters of pregnancy. Using sophisticated statistical models that can take into account complex mixtures of pollutants and time-varying exposures, we will 1) quantify the individual and cumulative effects of early exposure to multiple air pollutants, phthalates, and organophosphate pesticides on autistic traits; 2) identify whether these contaminants are associated with lower plasma folate levels in pregnant women; and 3) clarify the role of folate-related genetic polymorphisms, folate autoantibodies, and plasma folate in the associations between environmental contaminants and autistic traits. By answering these research questions, we will gain a better understanding of how strongly multiple pollutants and folic acid supplementation are associated with autistic traits, whether these chemicals are associated with circulating folate concentrations, and how these effects of multiple pollutants differ based on folic acid intake, genetic susceptibility, and the presence folate autoantibodies. These findings will have great clinical and public health implications and will be critical in informing better prevention strategies both at the individual and population level.

项目概要 自闭症谱系障碍 (ASD) 是一种以沟通为特征的多因素复杂障碍 缺陷和重复行为影响着美国和加拿大 1% 到 2% 的儿童 空气污染物， 邻苯二甲酸盐和杀虫剂被怀疑是 ASD 的病因，而叶酸 补充剂已被证明具有保护作用，特别是对于遗传易感人群 尽管一些研究得出了这些重要结论，但仍然存在一些问题。 未回答：1）以前没有研究以全面的方式调查这些可改变的因素；2）没有； 先前的研究调查了对这些暴露的敏感性的关键窗口；3) 相互作用； 环境、营养和遗传因素在自闭症病因学中的作用我们的初步研究仍不清楚。 数据显示，补充叶酸与较低的自闭症特征相关，但仅限于母亲的孩子 另外，我们发现孕早期补充足够的叶酸。 怀孕可以预防邻苯二甲酸盐暴露对自闭症特征的困扰。 这些发现以及在 10 年内实施的大规模全面表征的妊娠和出生队列 加拿大城市，我们将检查已确定的可改变风险因素的单独和共同贡献 我们将测量这三种农药中的邻苯二甲酸盐和有机磷农药。 怀孕三个月，我们将估计每月接触个别空气污染物（例如氮）的情况 怀孕期间和孩子第一年期间的二氧化碳和颗粒物及其成分。 我们将测量叶酸自身抗体，这些抗体已被证明在自闭症母亲中非常普遍 儿童以及怀孕第一和第三个月期间母体血液样本中的叶酸水平。 复杂的统计模型，可以考虑污染物的复杂混合物和随时间变化的情况 暴露，我们将 1) 量化早期暴露于多种空气污染物的个体和累积影响， 邻苯二甲酸盐和有机磷杀虫剂对自闭症特征的影响 2) 确定这些污染物是否存在； 与孕妇血浆叶酸水平较低有关；3) 阐明叶酸相关遗传的作用 多态性、叶酸自身抗体和血浆叶酸与环境之间的关联 通过回答这些研究问题，我们将更好地了解污染物和自闭症特征。 多种污染物和叶酸补充剂与自闭症特征的关联程度如何，是否 这些化学物质与循环叶酸浓度相关，以及这些化学物质如何影响多种叶酸浓度 污染物根据叶酸摄入量、遗传易感性和叶酸自身抗体的存在而有所不同。 这些发现将对临床和公共卫生产生重大影响，对于更好地提供信息至关重要 个人和人口层面的预防策略。