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Conversely, differential gene and protein expression is first detected in the central region. To further investigate cell-specific and spatially resolved dose-dependent changes in gene expression elicited by TCDD, single-nuclei RNA sequencing and spatial transcriptomics were used for livers of male mice gavaged with TCDD every 4\u2009days for 28\u2009days. The proportion of 11 cell (sub)types across 131 613 nuclei dose-dependently changed with 68% of all portal and central hepatocyte nuclei in control mice being overtaken by macrophages following TCDD treatment. We identified 368 (portal fibroblasts) to 1339 (macrophages) differentially expressed genes. Spatial analyses revealed initial loss of portal identity that eventually spanned the entire liver lobule with increasing dose. Induction of R-spondin 3 (Rspo3) and pericentral Apc, suggested dysregulation of the Wnt\/\u03b2-catenin signaling cascade in zonally resolved steatosis. Collectively, the integrated results suggest disruption of zonation contributes to the pattern of TCDD-elicited NAFLD pathologies.<\/jats:p>","DOI":"10.1093\/toxsci\/kfac109","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T14:19:53Z","timestamp":1665584393000},"page":"135-148","source":"Crossref","is-referenced-by-count":30,"title":["Single-cell transcriptomics shows dose-dependent disruption of hepatic zonation by TCDD in mice"],"prefix":"10.1093","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6822-4962","authenticated-orcid":false,"given":"Rance","family":"Nault","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, 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":"Satabdi","family":"Saha","sequence":"additional","affiliation":[{"name":"Department of Statistics and Probability, Michigan State University , East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2360-1672","authenticated-orcid":false,"given":"Sudin","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Institute for Integrative Toxicology, Michigan State University , East Lansing, Michigan 48824, USA"},{"name":"Biomedical Engineering Department, Pharmacology & Toxicology, Institute for Quantitative Health Science and Engineering, Michigan State University , East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samiran","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Statistics, Texas A&M University , College Station, Texas 77840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tapabrata","family":"Maiti","sequence":"additional","affiliation":[{"name":"Department of Statistics and Probability, Michigan State University , East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Zacharewski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, 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"}]}],"member":"286","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"2023013111360084800_kfac109-B1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1006\/taap.1996.8067","article-title":"Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation","volume":"144","author":"Andersen","year":"1997","journal-title":"Toxicol. 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