RNA-sequencing of 14 diverse mouse strains treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor in the PAS superfamily of environmental sensors that is linked to several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Much remains unknown regarding the impact of genetic variation in AHR-driven disease, as past studies have focused on a small number of inbred strains. Recently, the presence of a wide-range of interindividual variability amongst humans was reported in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototypical ligand of the AHR. In this study, a panel of 14 diverse mouse strains were exposed to TCDD for 10 days to characterize the AHR-mediated response across genetic backgrounds. In this study, responses to TCDD are heavily-dependent on genetic background. While mice carry one of four Ahr alleles that impact the AHR-mediated responses, we observed significant intra-allelic variability suggesting the presence of novel genetic modifiers of AHR signaling. A regression-based approach was used to scan for genes regulated by the AHR and/or associated with TCDD-induced phenotypes. The approach identified seven genes, 2 of which are novel, that are likely regulated by the AHR based on association with hepatic TCDD burden (p≤0.05). Finally, we identified a gene, Dio1, which was associated with change in percent body fat across the diverse set of strains (p≤0.05). Overall, the results in this study exemplify the power of genetics-based approaches in identifying novel genes that are putatively regulated by the AHR. Females were checked daily for vaginal plugs. If a plug was present, mice were separated, weighed, and randomly placed into vehicle or TCDD dose groups. TCDD was administered to mice using peanut butter as the vehicle daily for 10 consecutive days . On day 11, mice were anesthetized with avertin, euthanized via CO2 asphyxiation, and tissues were snap frozen in liquid nitrogen. Pregnancy success was assessed by the presence of absorption sites or embryos within the uterus under a dissection microscope; only pregnant mice were included in downstream analysis.