A Systems Toxicology Approach Reveals Biological Pathways Dysregulated by Prenatal Arsenic Exposure

BACKGROUND: Prenatal exposure to inorganic arsenic (iAs) is associated with dysregulated gene and protein expression in the fetus, both evident at birth. Potential epigenetic mechanisms that underlie these changes include but are not limited to the methylation of cytosines (CpG). OBJECTIVE: The aim of the present study was to compile datasets from studies on prenatal arsenic exposure to identify whether key genes, proteins, or both and their associated biological pathways are perturbed. METHODS: We compiled datasets from 12 studies that analyzed the relationship between prenatal iAs exposure and fetal changes to the epigenome (5-methyl cytosine), transcriptome (mRNA expression), and/or proteome (protein expression changes). FINDINGS: Across the 12 studies, a set of 845 unique genes was identified and found to enrich for their role in biological pathways, including those signaled by peroxisome proliferator-activated receptor, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, and the glucocorticoid receptor. Tumor necrosis factor was identified as a putative cellular regulator underlying most (n = 277) of the identified iAs-associated genes or proteins. CONCLUSIONS: Given their common identification across numerous human cohorts and their known toxicologic role in disease, the identified genes and pathways may underlie altered disease susceptibility associated with prenatal exposure to iAs.