Autism Spectrum Disorder (ASD) is a major public health burden in the US, with current prevalenceestimates of 1 in 68 children and economic costs exceed $60 billion per year. Identification of causes that caninform prevention and policy is the most efficient way to stem the tide of this rising prevalence. Most researchto date has focused on identifying genetic causes of autism, however, recent twin and population-scale studieshave 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 onprenatal risk factors is extremely important. Environmental epidemiology has long recognized the neurotoxiceffects of exposure to heavy metals, and some air pollution studies have specifically implicated exposure tometals during pregnancy as a risk factor for ASD. However, further assessment of risk due to prenatal metalsexposure has been limited by (1) lack of prospective data from pregnancy; (2) lack of direct measures ofbiologically effective dose; (3) lack of consideration of maternal or child genetic susceptibility; (4) lack of fullycharacterized ASD phenotypes. Here we propose the first prospective, longitudinal study examining thecontribution 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 pregnancyautism cohorts in the US: Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk inBablies Learning the Early Signs (MARBLES). Our aims are to: (1) estimate prospective associations betweendirect measures of perinatal Pb, Cd, Hg, Se, and Mn levels, and ASD outcomes, including ASD-relatedquantitative neurodevelopmental phenotypes; (2) Incorporate maternal and child genetic susceptibility intoanalyses that estimate this risk; (3) Examine the role of DNA methylation (DNAm) in any detected metalsassociations, either as a birth biomarker of prenatal exposure, or as a mediator of risk effects. This study islikely 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 metalexposure susceptibility differs based on underlying maternal or child genetic structure; c) potentially informpathways and biological mechanisms, i.e. epigenetics, involved in disease and/or prenatal exposureprocesses; and d) generate unified GWAS, epigenetic, and metal measurement data across the 2 largest USlongitudinal pregnancy autism cohorts that can be used in future investigations of health outcomes and/oradditional exposure domains.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
