Prenatal exposure to metals and risk for Autism Spectrum Disorder in MARBLES and EARLI

自闭症谱系障碍（ASD）是美国的一个主要公共卫生负担， 据估计，每68名儿童中就有1名死亡，每年的经济损失超过600亿美元。确定可能的原因 知情的预防和政策是遏制这一流行率上升趋势的最有效途径。大多数研究 迄今为止，人们一直专注于确定自闭症的遗传原因，然而，最近的双胞胎和人口规模的研究， 已经表明基因和环境暴露对ASD风险和病因有同等的影响。 有证据表明，关键的暴露窗口最有可能是在子宫内发育期间，因此重点关注 产前风险因素是非常重要的。环境流行病学长期以来一直认为， 暴露于重金属的影响，一些空气污染研究特别涉及暴露于 怀孕期间的金属是ASD的危险因素。然而，进一步评估产前金属引起的风险， 暴露受到以下因素的限制：（1）缺乏妊娠的前瞻性数据;（2）缺乏直接的 生物学有效剂量;（3）缺乏对母亲或儿童遗传易感性的考虑;（4）缺乏充分的 特征性ASD表型。在这里，我们提出了第一个前瞻性，纵向研究检查 产前暴露于铅（Pb）、镉（Cd）、汞（Hg）、硒（Se）和锰的贡献 (Mn)在解释金属螯合物-ASD关联的潜在遗传修饰的同时， 使用来自两个最大的富集风险，前瞻性，纵向妊娠的456对母子的数据， 美国孤独症人群：早期孤独症风险纵向调查（EARLI）和孤独症风险标记物 早期的迹象（大理石）。我们的目标是：（1）估计之间的前瞻性关联 直接测量围产期铅、镉、汞、硒和锰水平，以及ASD结局，包括ASD相关 定量神经发育表型;（2）将母亲和儿童的遗传易感性纳入 评估这种风险的分析;（3）检查DNA甲基化（DNAm）在任何检测到的金属中的作用 相关性，无论是作为产前暴露的出生生物标志物，或作为风险效应的中介。本研究 可能会影响自闭症领域，并有助于人类公共卫生的进步，因为它将： 建立产前金属暴露与ASD风险的相关性; B）确定产前金属暴露是否 暴露敏感性因母体或儿童的遗传结构而异; c）潜在信息 与疾病和/或产前暴露有关的途径和生物学机制，即表观遗传学 过程;以及d）在美国两大城市生成统一的GWAS、表观遗传和金属测量数据 纵向妊娠自闭症队列，可用于未来的健康结果调查和/或 额外的暴露领域。

Autism Spectrum Disorder (ASD) is a major public health burden in the US, with current prevalence estimates of 1 in 68 children and economic costs exceed $60 billion per year. Identification of causes that can inform prevention and policy is the most efficient way to stem the tide of this rising prevalence. Most research to date has focused on identifying genetic causes of autism, however, recent twin and population-scale studies have shown that both genes and environmental exposures contribute equally to ASD risk and etiology. Evidence suggests the critical exposure window is most likely during in utero development, and thus focus on prenatal risk factors is extremely important. Environmental epidemiology has long recognized the neurotoxic effects of exposure to heavy metals, and some air pollution studies have specifically implicated exposure to metals during pregnancy as a risk factor for ASD. However, further assessment of risk due to prenatal metals exposure has been limited by (1) lack of prospective data from pregnancy; (2) lack of direct measures of biologically effective dose; (3) lack of consideration of maternal or child genetic susceptibility; (4) lack of fully characterized ASD phenotypes. Here we propose the first prospective, longitudinal study examining the contribution of prenatal exposure to lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn) on ASD risk, while accounting for potential genetic modification of metal exposure-ASD associations, using data from 456 mother-child dyads from the two largest enriched risk, prospective, longitudinal pregnancy autism cohorts in the US: Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Bablies Learning the Early Signs (MARBLES). Our aims are to: (1) estimate prospective associations between direct measures of perinatal Pb, Cd, Hg, Se, and Mn levels, and ASD outcomes, including ASD-related quantitative neurodevelopmental phenotypes; (2) Incorporate maternal and child genetic susceptibility into analyses that estimate this risk; (3) Examine the role of DNA methylation (DNAm) in any detected metals associations, either as a birth biomarker of prenatal exposure, or as a mediator of risk effects. This study is likely to impact the field of autism and contribute to the advancement of human public health because it will: a) establish the relevance of prenatal metal exposures to ASD risk; b) determine whether prenatal metal exposure susceptibility differs based on underlying maternal or child genetic structure; c) potentially inform pathways and biological mechanisms, i.e. epigenetics, involved in disease and/or prenatal exposure processes; and d) generate unified GWAS, epigenetic, and metal measurement data across the 2 largest US longitudinal pregnancy autism cohorts that can be used in future investigations of health outcomes and/or additional exposure domains.