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)是一种日益普遍的神经发育障碍，在美国有1：110的儿童受到影响。尽管环境因素可能改变ASD的发展和病程，但有证据支持ASD的病因有很大的遗传贡献。在自闭症的病因和风险方面，产前营养和营养-环境相互作用的研究还不够深入。作为第一批研究母亲营养与自闭症风险相关的研究人员，我们发现，自闭症儿童的母亲报告在怀孕期间服用产前维生素的可能性显著低于典型发育中(TD)儿童的母亲。此外，他们估计的叶酸总摄入量较低。在这里，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参与自闭症的多因素病因研究。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伤害。因此，R21的总体目的是检查营养状况和环境暴露之间的相互作用与ASD的关系，并评估DNA甲基化作为修饰易感性的候选机制。重点关注与ASD风险增加有关的两类环境暴露：与交通相关的空气污染(TRP)和杀虫剂。初步研究结果表明，孕妇围孕期补充维生素可减弱这些相关性。更具体地说，将调查叶酸状况的两种衡量标准--母亲报告的叶酸摄入量和新生儿血斑叶酸是否作为色氨酸和杀虫剂的效果修饰剂，同时考虑每次接触的时间和剂量或水平，并调整混杂因素。这里的预期是，在怀孕前和怀孕早期，较高水平的叶酸和新生儿叶酸将以剂量依赖的方式降低与色氨酸和农药暴露相关的自闭症风险。此外，将测试全球DNA甲基化作为叶酸状态可能改变对环境暴露影响的易感性的机制。据推测，较高水平的叶酸将 通过提供大量的甲基基团(反映在新生儿血斑中更高的全球DNA甲基化水平)，并降低与ASD相关的风险，来对抗这些环境暴露的神经发育相关的低甲基化效应。这项拟议的研究不仅将阐明叶酸是否能够减少有害环境暴露的神经发育后果，而且还将有助于揭示潜在保护作用背后的关键时间段和机制。如果这些假设得到支持，这将是首批确定自闭症可改变风险因素之间复杂关系的研究之一 在前瞻性研究中进行跟踪，在那里我们可以更彻底地评估时间、暴露剂量和精确的机制。因此，它可能会对科学界产生可衡量的影响，可能会对营养和环境政策产生影响，并可能确定预防自闭症的战略。 公共卫生相关性：在美国，每110名儿童中就有一名患有自闭症。关于ASD病因学中的营养因素方面的工作很少，我们还没有发现有评估营养与环境相互作用的研究。这项拟议的研究将阐明，正如我们的初步研究结果所表明的那样，早期母亲补充叶酸和其他B族维生素是否有可能减少某些有害的围产期环境暴露造成的神经发育后果，从而降低ASD的风险。这项研究还将有助于描绘关键时间段，并将调查DNA甲基化作为潜在保护作用背后的机制所起的作用。如果我们的假设得到支持，这将是第一批确定可修改的 自闭症的风险因素将在前瞻性研究中得到跟踪，在这项研究中，我们可以更彻底地评估时间、暴露剂量和精确的机制。因此，它可能会对科学界产生可衡量的影响，可能会对营养和环境政策产生影响，并可能确定预防自闭症的战略。

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.