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

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.