Genetics-Based Approach to Identify Novel Genes Regulated by the Aryl Hydrocarbon Receptor inMouse Liver. Academic Article uri icon


  • The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor in the Per-Arnt-Sim superfamily of environmental sensors that is linked to several metabolic diseases, including nonalcoholic fatty liver disease. 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 was exposed to TCDD for 10days to characterize the AHR-mediated response across genetic backgrounds. Responses to TCDD are heavily dependent on genetic background. Although mice carry 1 of 4 Ahr alleles known to impact the affinity to AHR-ligands, 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 7 genes, 2 of which are novel, that are likely regulated by the AHR based on association with hepatic TCDD burden (p.05). Finally, we identified 1 gene, Dio1, which was associated with change in percent body fat across the diverse set of strains (p.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.

published proceedings

  • Toxicol Sci

altmetric score

  • 3.75

author list (cited authors)

  • Jurgelewicz, A., Dornbos, P., Warren, M., Nault, R., Arkatkar, A., Lin, H., ... LaPres, J. J.

citation count

  • 1

complete list of authors

  • Jurgelewicz, Amanda||Dornbos, Peter||Warren, Melanie||Nault, Rance||Arkatkar, Anooj||Lin, Hui||Threadgill, David W||Zacharewski, Tim||LaPres, John J

publication date

  • May 2021