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: 10360836
• 负责人: Youssef Oulhote
• 金额: $ 65.4万
• 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 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360836
• 关键词: 4 year old; Address; Affect; Air Pollutants; Air Pollution; American; Attenuated; Autoantibodies; Award; Birth; Blood; Blood - brain barrier anatomy; 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; Environmental Pollution; 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; MTHFR gene; Measurement; Measures; Mediator of activation protein; 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; base; biobank; career development; cohort; early life exposure; environmental chemical; folate-binding protein; folic acid metabolism; folic acid supplementation; immune activation; instrument; man; modifiable risk; neurodevelopment; nutrition related genetics; particle; personal care products; phthalates; pollutant; population based; population health; prevent; protective effect; repetitive behavior; social; trait; ultrafine particle; 4 year old; Address; Affect; Air Pollutants; Air Pollution; American; Attenuated; Autoantibodies; Award; Birth; Blood; Blood - brain barrier anatomy; 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; Environmental Pollution; 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; MTHFR gene; Measurement; Measures; Mediator of activation protein; 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; base; biobank; career development; cohort; early life exposure; environmental chemical; folate-binding protein; folic acid metabolism; folic acid supplementation; immune activation; instrument; man; modifiable risk; neurodevelopment; nutrition related genetics; 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.

项目摘要 自闭症谱系障碍（ASD）是多因素复杂性疾病，以通信为特征 缺陷和重复行为会影响美国和加拿大的1％至2％的儿童。空气污染物， 怀疑邻苯二甲酸盐和农药有助于ASD的病因，而叶酸 补充已被证明起着受保护的作用，特别是在一般易感的个体中 叶酸代谢效率低下。尽管从一些研究中进行了这些关键发现，但仍有几个问题 未解决：1）以前没有研究以全面的方式研究了这些可修改的因素； 2）否 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 自闭症病因中的环境，营养和遗传因素之间仍不清楚。我们的初步 数据表明，补充叶酸与较低的加速性状有关，但仅在母亲的子女中 具有遗传敏感性。此外，我们发现，在头三个月中补充了足够的叶酸 怀孕可能会阻止邻苯二甲酸盐对自闭症性状的暴露效果。建立 这些发现以及十个中实施的全面特征的怀孕和出生队列 加拿大城市，我们将研究确定的可修改风险因素的个人和共同贡献 自闭症及其相关特征。我们将测量三种 怀孕的孕期，我们将估计每月暴露于单个空气污染物（例如氮） 二氧化物及其特定物质及其在整个怀孕期间以及儿童第一年的组成。此外， 我们将测量叶酸自身抗体，这些自动抗体在自动的母亲中非常普遍 儿童和孕产妇血液样本中的叶酸水平在怀孕的第1和第三个三物种期间。使用 复杂的统计模型，可以考虑污染物的复杂组合和随时间变化的混合 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酸盐农药在加速性状上； 2）确定这些污染物是否是 与孕妇的血浆叶酸水平较低有关； 3）阐明叶酸相关通用的作用 环境之间关联的多态性，叶酸自身抗体和血浆叶酸 污染物和加速性状。通过回答这些研究问题，我们将更好地理解 多种污染物和补充叶酸与侵略性性状有关 这些化学物质与循环叶酸浓度以及多种影响有关 基于叶酸摄入，遗传易感性和叶酸自身抗体的存在，污染物不同。 这些发现将具有巨大的临床和公共卫生影响，并且对于通知更好的信息至关重要 在个人和人口水平上的预防策略。