Elucidating Gene-by-Environment Interactions Associated with Differential Susceptibility to Chemical Exposure

BACKGROUND: Modern societies are exposed to vast numbers of potentially hazardous chemicals. Despite demonstrated linkages between chemical exposure and severe health effects, there are limited, often conflicting, data on how adverse health effects of exposure differ across individuals. OBJECTIVES: We tested the hypothesis that population variability in response to certain chemicals could elucidate a role for gene–environment interactions (GxE) in differential susceptibility. METHODS: High-throughput screening (HTS) data on thousands of chemicals in genetically heterogeneous zebrafish were leveraged to identify a candidate chemical (Abamectin) with response patterns indicative of population susceptibility differences. We tested the prediction by generating genome-wide sequence data for 276 individual zebrafish displaying susceptible (Affected) vs. resistant (Unaffected) phenotypes following identical chemical exposure. RESULTS: We found GxE associated with differential susceptibility in the sox7 promoter region and then confirmed gene expression differences between phenotypic response classes. CONCLUSIONS: The results for Abamectin in zebrafish demonstrate that GxE associated with naturally occurring, population genetic variation play a significant role in mediating individual response to chemical exposure. https://doi.org/10.1289/EHP2662