ASD, an early onset neuropsychiatric developmental disorder with prevalence estimates of 1.1-2.6%, is etiologically complex and highly heterogeneous. Identifying ASD pathophysiology has been challenging due to the combination of insufficient sample sizes, difficulty collecting clinical samples without biased selection, and the complexity of etiological mechanisms, including the roles of genetics, environmental risks and gene-environmental interactions (GEX). The proposed research designed will overcome these obstacles by using a biorepository and archived data collected from a population-based, representative Korean sample of ASD families and their matched controls from our ongoing epidemiologic study in the PI's parent R01 grant. A growing body of evidence supports the role of maternal immune responses in the development of ASD, including higher levels of Anti-Brain Antibodies (ABAs) and autoimmune diseases in mothers of probands with ASD, relative to controls. CD4+ T-cells play a critical role in transforming B-cells into antibody producing cells by providing cytokines and co-stimulation. While findings from several studies examining the association between mercury (Hg) exposure in children and ASD risk largely weigh toward negative associations, no studies have examined whether maternal Hg exposure increases ASD risk in offspring. This is particularly relevant to ASD risk since Hg has been shown to alter immune function in humans and animals, resulting in autoantibody formation and altered T-lymphocyte activity. Taken together, one plausible mechanism for increased ASD risk is autoimmunity mediated by T-cell activation in mothers exposed to Hg. This is a plausible and important hypothesis because: (1) Environmental Hg exposure is virtually ubiquitous for adults~ (2) Increased ASD risk has been associated with maternal immune system changes similar to those seen in animal models with Hg exposure~ and, (3) Public health interventions can be developed to reduce the environmental Hg exposure. Consistent with the ViCTER RFA, we propose to explore this high risk and potentially high yield hypothesis.
Specific Aim 1 : Establish the Relationship between ABAs in Maternal Blood and Offspring ASD Risk Specific Aim 2: Investigate the Mechanisms for Maternal Autoimmunity in Children with ASD Sub-aim 2.1: Determine Whether Mothers with ABAs Exhibit Evidence for CD4+ T-cell Activation Sub-Aim 2.2: Determine Whether Maternal Exposure to Chronic, Low Dose Hg is a Risk Factor for the Presence of ABAs and/or CD4+ T-cell Activation Specific Aim 3: Examine Whether Chronic Low Dose Maternal Mercury Exposure Increases Risk for ASD in Their Offspring via Alterations in Maternal Immune Function When completed, this study will add to understanding of the pathogenesis of ASD and lead to public health interventions for decreasing ASD risk.
This proposal aims to identify the environmental risk factors that contribute to Autism Spectrum Disorder (ASD) by examining whether an increased risk for ASD is autoimmunity mediated by increased T-cell activation in mothers who were exposed to mercury and this leads to altered fetal brain development. ASD is a common disorder (prevalence of 1.1-2.6%) with no efficacious interventions. Identifying these environmental risk factors offers a clear route to understanding the neuropathology of ASD and ultimately identifying novel therapeutic agents and public health interventions.
