Environmental epigenetics of diesel particulate matter toxicogenomics

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disruptions in social communication and behavioral flexibility. Both genetic and environmental factors contribute to ASD risk. Epidemiologic studies indicate that roadway vehicle exhaust and in utero exposure to diesel particulate matter (DPM) are associated with ASD. Using the Comparative Toxicogenomics Database (CTD), we identified genes connected to DPM exposure and ASD, extracted the known enhancers/promoters of the identified genes, and integrated this with Assay for Transposase Accessible Chromatin (ATAC-seq) data from DPM-exposed human neural progenitor cells. Enhancer/promoter elements with significantly different chromosome accessibility revealed enriched DNA sequence motifs with transcription factor binding sites for EGR1. Variant extraction for linkage disequilibrium blocks of these regions followed by analysis through Genome Wide Association Studies (GWAS) revealed multiple neurological trait associations including exploratory eye movement and brain volume measurement. This approach highlights the effects of pollution on the regulatory regions of genes implicated in ASD by genetic studies, indicating convergence of genetic and environmental factors on molecular networks that contribute to ASD. Integration of publicly available data from the CTD, cell culture exposure studies, and phenotypic genetics synergize extensive evidence of chemical exposures on gene regulation for altered brain development.