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

MARBLES 和 EARLI 产前接触金属和患自闭症谱系障碍的风险

• 批准号: 10013202
• 负责人: HEATHER E VOLK
• 金额: $ 59.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013202
• 关键词: Accounting; Adult; Affect; Age; Air Pollution; Biological; Biological Markers; Birth; Blood; Cadmium; Categories; Child; Child Support; Collaborations; Collection; Communities; DNA Methylation; Data; Development; Disease; Dose; Ensure; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiologist; Epidemiology; Epigenetic Process; Etiology; Exposure to; Family; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Structures; Genotype; Health; Heavy Metals; Human; Individual; Infant; Investigation; Investments; Lead; Learning; Life; Longitudinal Studies; Manganese; Marble; Maternal Exposure; Measurement; Measures; Mediating; Mediation; Mediator of activation protein; Mercury; Metal exposure; Metals; Modification; Molecular; Mothers; Outcome; Pathway interactions; Perinatal; Permeability; Phenotype; Play; Policies; Population; Predisposition; Pregnancy; Prevalence; Prevention; Process; Public Health; Recording of previous events; Research; Resources; Risk; Risk Assessment; Risk Estimate; Risk Factors; Role; Sampling; Selenium; Statistical Models; Testing; Twin Multiple Birth; Umbilical Cord Blood; United States National Institutes of Health; Work; autism spectrum disorder; autistic children; base; boys; cohort; cost; design; disorder risk; economic cost; experience; fetal; fetal lead exposure; follow-up; genome wide association study; in utero; insight; neurotoxic; policy implication; prenatal; prenatal exposure; prenatal risk factor; prospective; social; stem

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.

自闭症谱系障碍(ASD)是美国主要的公共卫生负担，目前患病率 据估计，每68名儿童中就有一名儿童，每年的经济成本超过600亿美元。找出可能导致 告知预防和政策是遏制这一不断上升的流行趋势的最有效方式。大多数研究 到目前为止，研究的重点是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风险和病因学的影响是一样的。 有证据表明，关键的暴露窗口最有可能发生在子宫内发育期间，因此集中在 产前的危险因素是极其重要的。环境流行病学早就认识到神经毒性 接触重金属的影响，以及一些空气污染研究特别涉及接触 孕期金属是自闭症的危险因素。然而，对产前金属所致风险的进一步评估 暴露受到以下因素的限制：(1)缺乏怀孕的预期数据；(2)缺乏对 生物有效剂量；(3)缺乏考虑母婴遗传易感性；(4)缺乏充分的 表征了ASD的表型。在这里，我们提出了第一项前瞻性的纵向研究，考察 产前铅(铅)、镉(Cd)、汞(Hg)、硒(Se)和锰的暴露 (MN)关于自闭症风险，同时考虑到金属暴露-自闭症关联的潜在基因修改， 使用来自两个最大的丰富风险的母子二人组的456个数据，即预期的纵向怀孕 美国的自闭症队列：早期自闭症风险纵向调查(EARLI)和自闭症风险的标记物 Bablies学习早期手势(弹珠)。我们的目标是：(1)估计潜在的关联性 围产期铅、镉、汞、硒和锰水平的直接测量以及包括自闭症相关的自闭症结局 量化神经发育表型；(2)将母婴遗传易感性纳入 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 无论是作为产前暴露的出生生物标志物，还是作为风险影响的中介物，都存在相关性。这项研究是 可能影响自闭症领域并促进人类公共健康，因为它将：a) 建立产前金属暴露与自闭症风险的相关性；b)确定产前金属是否 根据潜在的母亲或儿童遗传结构，暴露易感性不同；c)潜在的信息 涉及疾病和/或产前暴露的途径和生物机制，即表观遗传学 流程；以及d)在美国最大的两个地区生成统一的GWAS、表观遗传学和金属测量数据 可用于未来健康结局和/或调查的纵向妊娠自闭症队列 额外的曝光域。