Exploring Interactions between Folate and Environmental Risk Factors for Autism

探索叶酸与自闭症环境风险因素之间的相互作用

• 批准号: 8260107
• 负责人: Rebecca Jean Schmidt
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260107
• 关键词: Address; Affect; Air Pollution; Animals; Attenuated; Autistic Disorder; Birth; California; Carbon; Child; Childhood; Communities; Complex; Conceptions; DNA Methylation; Databases; Development; Dose; Environment; Environmental Exposure; Environmental Policy; Environmental Risk Factor; Etiology; Fetus; Folate; Folic Acid; Genetic Risk; Household; Infant; Intake; Interview; Investigation; Link; Measurable; Measures; Metabolic; Metabolism; Methylation; Modification; Mothers; Neurodevelopmental Disorder; Newborn Infant; Nutrient; Nutritional; Odds Ratio; Participant; Pathway interactions; Perinatal; Pesticides; Predisposition; Pregnancy; Prenatal Nutrition; Prospective Studies; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Structure; Supplementation; Testing; Time; Toxic Environmental Substances; United States; Vitamin B 12; Vitamin B Complex; Vitamin B6; Vitamins; Work; attenuation; autism spectrum disorder; base; disorder prevention; disorder risk; environmental agent; expectation; follow-up; high risk; methyl group; modifiable risk; mother nutrition; neonate; pesticide exposure; population based; prenatal; protective effect; pyrethroid; residence; trafficking

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.

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影响美国1：110儿童的神经发育障碍。证据支持对ASD病因的大量遗传贡献，尽管环境因素可能会改变ASD的发展和过程。在自闭症病因和风险方面已经研究了产前营养和营养环境的相互作用。作为第一个研究与自闭症风险相关的母体营养的研究人员，我们发现自闭症儿童的母亲报告说，与典型发育中（TD）儿童的母亲相比，在构想上服用产前维生素的可能性要小得多。此外，它们估计的总叶酸摄入量较低。在这里提出，孕产妇营养型可能通过修改对其他环境药物的敏感性来为自闭症的多因素病因做出贡献。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影响。因此，该R21的总体目的是检查与ASD相关的营养状况与环境暴露之间的相互作用，并评估DNA甲基化，作为修饰易感性的候选机制。重点是与ASD风险增加有关的两类环境暴露：与交通相关的空气污染（TRP）和农药。初步发现表明，孕产妇周围的产前维生素补充剂摄入中这些关联的衰减。更具体地说，研究是否采用了两种叶酸状态，母体报告的叶酸摄入量和新生儿血液点叶酸，充当TRP和农药的效果修饰符，同时考虑到定时，剂量或每次暴露的水平以及对混杂因素进行调整的调整。这里的期望是，较高的怀孕前后叶酸和新生叶酸叶酸将以剂量依赖性的方式降低与TRP和农药暴露相关的ASD风险。此外，将检验将叶酸状态可改变对环境暴露效应的敏感性的机制的研究。假设较高的叶酸将 通过提供对甲基组的丰富获取（反映在新生儿血液点的较高全球DNA甲基化水平）并降低其相关的ASD风险的情况下，以这些环境暴露对这些环境暴露的神经变性相关的低甲基化作用。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和机制。如果支持假设，这将是最早确定自闭症风险因素之间复杂关系的研究之一 要在一项前瞻性研究中进行跟进，我们可以更彻底地评估时间安排，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，这可能会对营养和环境政策产生可衡量的影响，并有可能确定预防ASD的策略。 公共卫生相关性：ASD影响美国每110名儿童中的一个。关于ASD病因的营养因素的工作很少，我们知道没有评估营养与环境相互作用的研究。拟议的研究将阐明叶酸和其他B-维生素的早期孕产妇补充是否有可能减少某些有害的围产期环境暴露的神经发育后果，从而降低了ASD的风险，如我们的初步发现所示。这项研究还将有助于描绘关键时期，并将研究DNA甲基化作为潜在保护作用背后的机制的作用。如果支持我们的假设，这将是最早确定可修改之间复杂关系的研究之一 自闭症的风险因素在一项前瞻性研究中得到跟踪，我们可以更彻底地评估时间安排，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，这可能会对营养和环境政策产生可衡量的影响，并有可能确定预防ASD的策略。