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

项目总结 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 在美国和加拿大，1%到2%的儿童会受到缺陷和重复行为的影响。空气污染物， 邻苯二甲酸盐和杀虫剂被怀疑是导致ASD的原因，而叶酸 补充剂已被证明起到保护作用，特别是在遗传易感人群中。 叶酸代谢效率低下。尽管一些研究得出了这些重要的发现，但仍有几个问题 未回答：1)以前的研究没有对这些可修改因素进行全面调查；2)没有 以前的研究调查了这些暴露的易感性的关键窗口；以及3)相互作用 自闭症病因中的环境、营养和遗传因素之间的关系仍然不清楚。我们的预赛 数据显示，补充叶酸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 怀孕可能会防止邻苯二甲酸盐暴露在自闭症特征方面的有害影响。在基础上建设 这些发现和一个大型综合表征的怀孕和出生队列在十个月内实施 加拿大城市，我们将检查已确定的可修改风险因素的单独和共同贡献 自闭症及其相关特征。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单独的空气污染物，如氮 怀孕期间和婴儿一岁期间的二氧化碳和颗粒物及其组成。另外， 我们将测量在自闭症母亲中高度流行的叶酸自身抗体。 在怀孕的第一个月和第三个三个月期间，母亲的血液样本中的叶酸水平。vbl.使用 复杂的统计模型，可以考虑复杂的污染物混合物和时变 我们将1)量化早期接触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；以及3)阐明叶酸相关基因的作用 多态、叶酸自身抗体和血浆叶酸与环境之间的关系 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与自闭症特征的关联程度有多大？ 这些化学物质与循环中的叶酸浓度有关，以及这些多方面的影响 污染物因叶酸摄入量、遗传易感性和叶酸自身抗体的存在而不同。 这些发现将对临床和公共卫生产生重大影响，并将对更好地提供信息至关重要 个人和人口层面的预防战略。

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.