Exploring Interactions between Folate and Environmental Risk Factors for Autism

描述（由申请人提供）：自闭症谱系障碍（ASD）是一种越来越普遍的神经发育障碍，影响美国1:10 0儿童。尽管环境因素可能会改变ASD的发展和病程，但证据支持遗传因素对ASD的病因有很大的贡献。产前营养和营养-环境相互作用与自闭症病因和风险的关系尚未得到充分研究。作为第一批研究母亲营养与自闭症风险之间关系的研究人员，我们发现自闭症儿童的母亲在怀孕前后服用产前维生素的可能性明显低于正常发育儿童的母亲。此外，他们估计的叶酸总摄入量也较低。本文提出，母亲的营养状况可能通过改变对其他环境因素的易感性而促成自闭症的多因素病因。动物研究表明，补充叶酸可以通过DNA甲基化机制保护胎儿免受环境毒素的侵害。因此，本R21的总体目的是研究与ASD相关的营养状况和环境暴露之间的相互作用，并评估DNA甲基化作为改变易感性的候选机制。重点是与ASD风险增加有关的两类环境暴露：交通相关的空气污染（TRP）和杀虫剂。初步研究结果表明，这些关联衰减从母体围孕期产前维生素补充摄入量。更具体地说，在考虑每次暴露的时间和剂量或水平，并根据混杂因素进行调整的同时，将探讨叶酸状态的两种测量方法，即母亲报告的叶酸摄入量和新生儿血斑叶酸，是否可以作为TRP和农药的效果调节剂。这里的预期是，在怀孕前和怀孕早期以及新生儿叶酸水平较高，将以剂量依赖的方式降低与TRP和农药接触相关的ASD风险。此外，还将测试全球DNA甲基化作为叶酸状态可能改变环境暴露效应易感性的机制。据推测，较高水平的叶酸会

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder affecting 1:110 children in the United States. Evidence supports large heritable contributions to the etiology of ASD, though environmental factors are likely to modify both the development and the course of ASD. Prenatal nutrition and nutrient-environment interactions have been understudied in relation to autism etiology and risk. As the first researchers to examine maternal nutrition in association with autism risk, we found that mothers of children with autism were significantly less likely to report having taken prenatal vitamins around conception than mothers of typically developing (TD) children. Additionally, their estimated total folic acid intake was lower. Here it is proposed that maternal nutrient statu may contribute to the multifactorial etiology of autism by modifying susceptibility to other environmental agents. Animal studies show that folic acid supplementation can protect the fetus from environmental toxins through DNA methylation mechanisms. Thus, the overall purpose of this R21 is to examine interactions between nutrient status and environmental exposures in relation to ASD and to assess DNA methylation as a candidate mechanism for the modification of susceptibility. The focus is on two classes of environmental exposures that have been linked to increased ASD risk: traffic-related air pollution (TRP) and pesticides. Preliminary findings suggest attenuation of these associations from maternal periconceptional prenatal vitamin supplement intake. More specifically an investigation of whether two measures of folate status, maternally-reported folic acid intake and newborn bloodspot folate, act as effect modifiers for TRP and pesticides, while considering timing and dose or level of each exposure, and adjusting for confounders will be explored. Expectations here are that higher levels of folic acid before and during early pregnancy and neonate folate will reduce the risk of ASD associated with TRP and pesticide exposures in a dose-dependent manner. Further, an examination of global DNA methylation as a mechanism by which folate status may modify susceptibility to the environmental exposure effects will be tested. It is hypothesized that higher levels of folate will counter the neurodevelomentally relevant hypomethylation effects of these environmental exposures by providing abundant access to methyl-groups, (reflected in higher global DNA methylation levels in newborn bloodspots), and reducing their associated ASD risk. The proposed study will not only elucidate whether folate is able to reduce the neurodevelopmental consequences of harmful environmental exposures, but will also help reveal critical time periods and mechanisms behind potential protective effects. If the hypotheses are supported, this will be one of the first studies to identify complex relationships among modifiable risk factors for autism to be followed up in a prospective study, where we can assess timing, dose of exposures, and precise mechanisms more thoroughly. As such, it is likely to have a measurable impact on the scientific community, potentially on nutritional and environmental policies, and could potentially identify strategies for ASD prevention. PUBLIC HEALTH RELEVANCE: ASD affects one in every 110 children in the United States. Very little work has been conducted on nutritional factors in the etiology of ASD, and we are aware of none that has assessed nutrient-environment interactions. The proposed study will elucidate whether early maternal supplementation with folate and other B- vitamins have the potential to reduce the neurodevelopmental consequences of certain harmful perinatal environmental exposures, thereby reducing risk for ASD, as our preliminary findings suggest. This research will also help delineate critical time periods and will investigate the role of DNA methylation as a mechanism behind potential protective effects. If our hypotheses are supported, this will be one of the first studies to identify complex relationships among modifiable risk factors for autism to be followed up in a prospective study, where we can assess timing, dose of exposures, and precise mechanisms more thoroughly. As such, it is likely to have a measurable impact on the scientific community, potentially on nutritional and environmental policies, and could potentially identify strategies for ASD prevention.