The flame retardant triphenyl phosphate induces varying responses in genetically diverse mouse induced pluripotent stem cells

Genetic variation impacts the biological response to chemical and environmental exposures, contributing to differences in resistance or susceptibility. Forward genetic screens of genetically diverse cell populations can be used to identify the precise genetic variants that drive response variation, but such screens are limited by the lack of available genetically diverse human derived cell panels. Cell lines from laboratory mouse genetic reference populations like the Diversity Outbred (DO) population are genetically diverse and powered for genetic mapping but also offer the significant advantage of in vitro / in vivo trait correlation and in vivo validation using genetically matched individuals. These diverse cell panels are especially beneficial for studying early developmental effects of chemical exposures. We created a panel of induced pluripotent stem cells (iPSCs) derived from the Diversity Outbred mouse population to enable genetic analysis of cellular phenotypes. Cells were exposed to triphenyl phosphate (TPHP), an organophosphate flame retardant that has been linked to numerous adverse developmental effects, to identify cellular responses associated with developmental exposure risk. Our analysis characterizes interline variation in gene expression in response to TPHP in over 200 DO iPSC lines by RNA-seq and applied expression quantitative trait loci (eQTL) mapping to identify genomic loci that contribute to variation in gene expression following TPHP exposure.