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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\u2009days 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\u2009\u2264\u2009.05). Finally, we identified 1 gene, Dio1, which was associated with change in percent body fat across the diverse set of strains (p\u2009\u2264\u2009.05). Overall, the results in this study exemplify the power of genetics-based approaches in identifying novel genes that are putatively regulated by the AHR.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab032","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T04:12:10Z","timestamp":1615522330000},"page":"285-294","source":"Crossref","is-referenced-by-count":7,"title":["Genetics-Based Approach to Identify Novel Genes Regulated by the Aryl Hydrocarbon Receptor in\u00a0Mouse Liver"],"prefix":"10.1093","volume":"181","author":[{"given":"Amanda","family":"Jurgelewicz","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA"},{"name":"Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dornbos","sequence":"additional","affiliation":[{"name":"Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA"},{"name":"Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Warren","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Toxicology, Texas A&M University, College Station, Texas 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6822-4962","authenticated-orcid":false,"given":"Rance","family":"Nault","sequence":"additional","affiliation":[{"name":"Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA"},{"name":"Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anooj","family":"Arkatkar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Lin","sequence":"additional","affiliation":[{"name":"The Dow Chemical Company, Environmental Technology Center, Midland, Michigan 48674, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W","family":"Threadgill","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Toxicology, Texas A&M University, College Station, Texas 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Zacharewski","sequence":"additional","affiliation":[{"name":"Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA"},{"name":"Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0785-4573","authenticated-orcid":false,"given":"John J","family":"LaPres","sequence":"additional","affiliation":[{"name":"Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA"},{"name":"Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,15]]},"reference":[{"key":"2021111805390983700_kfab032-B1","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1515\/bc.2010.128","article-title":"An introduction to the molecular basics of aryl hydrocarbon receptor biology","volume":"391","author":"Abel","year":"2010","journal-title":"Biol. 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