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

项目摘要 自闭症谱系障碍（ASD）是一种以交流为特征的多因素复杂障碍 缺陷和重复行为影响美国和加拿大1%至2%的儿童。空气污染物， 邻苯二甲酸盐和杀虫剂被怀疑是导致ASD的病因，而叶酸 补充剂已被证明具有保护作用，特别是在遗传易感个体中 叶酸代谢效率低下尽管有一些研究得出了这些重要的发现， 未回答：1）以前的研究没有全面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敏感的临界窗口; 3）相互作用 环境、营养和遗传因素在自闭症病因中的作用尚不清楚。我们的初步 数据显示，叶酸补充剂与较低的自闭症特征有关，但仅限于母亲的孩子。 有遗传易感性此外，我们发现，在妊娠早期补充足够的叶酸， 怀孕可以防止邻苯二甲酸酯暴露对自闭症特征的有害影响。基础上 这些发现和一个大型的综合特征的怀孕和出生队列实施了10个 加拿大城市，我们将研究已确定的可改变的风险因素的单独和联合贡献， 自闭症及其相关特征我们将测量这三个地区的邻苯二甲酸盐和有机磷农药， 我们将估计每月暴露于个别空气污染物，如氮， 二氧化碳和颗粒物及其组成在整个怀孕期间和孩子的第一年。此外，本发明还 我们将测量叶酸自身抗体，这些抗体在自闭症儿童的母亲中非常普遍， 在怀孕的第一个和第三个三个月期间，母亲血液样本中的叶酸水平。使用 复杂的统计模型，可以考虑污染物的复杂混合和时变 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效应， 邻苯二甲酸盐和有机磷农药对自闭症特征的影响; 2）确定这些污染物是否 与孕妇较低的血浆叶酸水平有关; 3）阐明叶酸相关的遗传作用， 多态性、叶酸自身抗体和血浆叶酸与环境因素的关系 污染物和自闭症特征通过回答这些研究问题，我们将更好地了解 多种污染物和叶酸补充剂与自闭症特征的关系有多强， 这些化学物质与循环叶酸浓度有关，以及多种叶酸的这些影响是如何产生的。 污染物的不同基于叶酸摄入量、遗传易感性和叶酸自身抗体的存在。 这些发现将具有重大的临床和公共卫生意义，并将在更好地提供信息方面发挥关键作用。 在个人和群体层面的预防战略。

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.