Interactions of Environmental Chemical Mixtures, Genetics, and Immune Pathways in Autism Spectrum Disorder

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ABSTRACT The rising prevalence of Autism Spectrum Disorder (ASD) among children is a public health concern. An expanding landscape of genetic and environmental risk factors has been implicated in ASD’s development, indicating complex, multifactorial origins in early life. Many endocrine-disrupting chemicals (EDCs) have neurotoxic potential, but their role in ASD development needs clarification. EDCs are implicated in maternal immune dysregulation and inflammation, a leading research hypothesis of ASD’s developmental origins. Gene- environment investigations of EDCs, with focus on plausible biological mechanisms, could provide critical insight into whether genetic subgroups of individuals may be more sensitive to environmental chemicals and bring clarity to this inconsistent evidence between ASD and EDCs. The proposed research seeks to combine polygenic and complex environmental mixtures approaches to address gaps in understanding of ASD’s etiology. During the K99 phase of this award, I will pursue didactic and mentored training in autism epidemiology, immunology, and methodologies of analyzing complex environmental mixtures, genome-wide data, and gene-environment interplay. Under the mentorship of a strong multidisciplinary team with a history of collaboration, I will apply this training to studies of the relationships between environmental, immunologic, and genetic data from the Early Markers for Autism study (EMA; R01ES016669, PI: Croen), a population-based case-control study (n=1005). In Aim 1, I will apply training in complex mixtures methods to examine the pathway between joint exposure to multiple EDCs during gestation, biomarkers of maternal and neonatal immune function, and child ASD. In Aim 2, I will apply training in genome-wide analysis to identify maternal and fetal genetic variants associated with mixtures of EDCs in mid-pregnancy circulation. In the K00 phase (Aim 3), I will harness these new analytical skills to conduct a GxE analysis of the association of EDCs and polygenic risk on early life immune function and ASD development. I will conduct Aim 3 in EMA with replication in two larger mother-child cohort studies. The long-term goal of this research is to identify modifiable risk factors and key biological pathways in ASD which can inform not only interventions to lower neurotoxic exposures in pregnant mothers and infants but also pharmacologic interventions targeting the immune and other physiologic intermediates. These training and research activities will serve as the springboard for developing a competitive R01 application and launching my independent career in autism epidemiology.