Characterizing Gene-Environment Interactions that Affect Individual Susceptibility to an Expanding Chemical Exposome

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ABSTRACT Environmental chemical exposure has been linked to increases in cancer incidence, birth and developmental defects, impaired cognitive development, and neurodegenerative disease. However, even as the number of manufactured chemicals in the environment grows into the hundreds-of-thousands, comprehensive data on the human and environmental health hazards remain sparse to nonexistent. The data are especially sparse regarding questions of differential susceptibility, where gene-environment interaction (GxE) effects stemming from individual genetic variation play an important role in health outcomes. Thus, understanding the role of GxE in differential susceptibility to an expanding chemical exposome is key to protecting public health— particularly that of vulnerable populations. We propose a solution that combines novel analytics with the power of new high-throughput screening technologies to detect GxE underlying differential susceptibility in a diverse population of zebrafish. Our three Specific Aims will (1) Identify environmental chemicals that induce the greatest differences in population disease susceptibility; (2) Identify critical exposure concentrations and confirm genetic heritability of population susceptibility differences; and (3) Identify and experimentally validate genomic regions associated with differential susceptibility to chemical exposure. The immediate impact of this proposal will be novel empirical evidence for the role of GxE in differential population susceptibility. The lasting significance of this proposal will be a scalable, sustainable system to rapidly address questions of differential genetic susceptibility to an expanding chemical exposome. The data-driven, bioinformatic approaches developed here will be extensible to other systems for identifying patterns of phenotypic variation suggesting GxE.