{"doi":"10.1093/toxsci/kfab032","title":"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.","journal":"Toxicological Sciences","year":2021,"id":185652,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":391597,"name":"Peter Dornbos","orcid":null,"position":1,"is_corresponding":false},{"id":390528,"name":"Melanie Warren","orcid":"0000-0003-2893-9063","position":2,"is_corresponding":false},{"id":163022,"name":"Rance Nault","orcid":"0000-0002-6822-4962","position":3,"is_corresponding":false},{"id":742856,"name":"Anooj Arkatkar","orcid":null,"position":4,"is_corresponding":false},{"id":742285,"name":"Hui Lin","orcid":"0000-0002-3499-5806","position":5,"is_corresponding":false},{"id":262707,"name":"David W. Threadgill","orcid":"0000-0003-3538-1635","position":6,"is_corresponding":false},{"id":299063,"name":"Tim Zacharewski","orcid":"0000-0002-3662-7919","position":7,"is_corresponding":false},{"id":390531,"name":"John J. LaPres","orcid":"0000-0002-0785-4573","position":8,"is_corresponding":false},{"id":742284,"name":"Amanda Jurgelewicz","orcid":"0000-0003-3478-8652","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-18T23:48:38.805613Z","pmid":"33720361","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}