Genetics-Based Approach to Identify Novel Genes Regulated by the Aryl Hydrocarbon Receptor in Mouse Liver.

Abstract

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 10 days 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.

• Authors: Amanda Jurgelewicz, Peter Dornbos, Melanie Warren, Rance Nault, Anooj Arkatkar, Hui Lin, David W Threadgill, Tim Zacharewski, John J LaPres
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 181 Issue 2 Pg. 285-294 (05 27 2021) ISSN: 1096-0929 [Electronic] United States
• PMID: 33720361 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Polychlorinated Dibenzodioxins
• Receptors, Aryl Hydrocarbon

Topics

• Animals
• Humans
• Liver (metabolism)
• Mice
• Polychlorinated Dibenzodioxins (toxicity)
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Signal Transduction