{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T09:52:56Z","timestamp":1762249976895,"version":"build-2065373602"},"reference-count":31,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Furan, the basic skeleton of various flavoring agents, induces cholangiocellular tumors with higher incidences in the caudate lobe and hepatocellular tumors without the lobe specificity in rats, but the mechanism is unclear. We investigated the lobe distribution of possible carcinogenic events. Furan caused proliferation\/infiltration of oval and inflammatory cells prominently in the caudate lobe as early as 4\u00a0weeks and cholangiofibrosis in this lobe at 8\u00a0weeks. In vivo mutagenicity assays using DNA extracted from the caudate or left lateral lobe of male <jats:italic>gpt<\/jats:italic> delta rats, the reporter gene\u2010transgenic rats, treated with 8\u00a0mg\/kg furan for 4 or 8\u00a0weeks showed negative outcomes. The distribution of glutathione <jats:italic>S<\/jats:italic>\u2010transferase placental form (GST\u2010P)\u2010positive or sex\u2010determining region Y\u2010box 9 (SOX9)\u2010positive hepatocytes was examined. Significant increases in the number of GST\u2010P\u2010positive hepatocytes were observed in all lobes of furan\u2010treated rats at 8\u00a0weeks. By contrast, SOX9\u2010positive hepatocytes, liver injury\u2010inducible progenitor cells, were also found in all lobes of treated rats, the incidences of which were by far the highest in the caudate lobe. In addition, some of these hepatocytes also co\u2010expressed delta like 1 homolog (DLK1), a hepatoblast marker, particularly in areas with a predominant presence of inflammatory cells. Overall, furan induced liver injury, leading to the appearance of SOX9\u2010positive hepatocytes, some of which were subjected to dedifferentiation in the inflammatory microenvironment of a cholangiocarcinoma\u2010prone lobe. Thus, the appearance of SOX9\u2010positive hepatocytes together with GST\u2010P\u2010positive hepatocytes could be initial events in furan\u2010induced hepatocarcinogenesis via non\u2010genotoxic mechanisms.<\/jats:p>","DOI":"10.1002\/jat.4691","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T15:44:35Z","timestamp":1724341475000},"page":"1976-1985","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Appearance of sex\u2010determining region Y\u2010box 9 (SOX9)\u2010 and glutathione <i>S<\/i>\u2010transferase placental form (GST\u2010P)\u2010positive hepatocytes as possible carcinogenic events in the early stage of furan\u2010induced hepatocarcinogenesis"],"prefix":"10.1002","volume":"44","author":[{"given":"Daisuke","family":"Hibi","sequence":"first","affiliation":[{"name":"Division of Pathology National Institute of Health Sciences  Kawasaki\u2010shi Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meili","family":"Soma","sequence":"additional","affiliation":[{"name":"Division of Pathology National Institute of Health Sciences  Kawasaki\u2010shi Kanagawa Japan"},{"name":"Graduate School of Animal Health Technology Yamazaki University of Animal Health Technology  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuta","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Division of Pathology National Institute of Health Sciences  Kawasaki\u2010shi Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinji","family":"Takasu","sequence":"additional","affiliation":[{"name":"Division of Pathology National Institute of Health Sciences  Kawasaki\u2010shi Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Ishii","sequence":"additional","affiliation":[{"name":"Division of Pathology National Institute of Health Sciences  Kawasaki\u2010shi Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Umemura","sequence":"additional","affiliation":[{"name":"Division of Pathology National Institute of Health Sciences  Kawasaki\u2010shi Kanagawa Japan"},{"name":"Graduate School of Animal Health Technology Yamazaki University of Animal Health Technology  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_10_2_1","DOI":"10.1053\/j.gastro.2009.02.051"},{"doi-asserted-by":"publisher","key":"e_1_2_10_3_1","DOI":"10.1021\/tx050302k"},{"doi-asserted-by":"publisher","key":"e_1_2_10_4_1","DOI":"10.1053\/j.gastro.2011.06.049"},{"doi-asserted-by":"publisher","key":"e_1_2_10_5_1","DOI":"10.1038\/s41598-021-90958-1"},{"doi-asserted-by":"publisher","key":"e_1_2_10_6_1","DOI":"10.1016\/j.fct.2015.08.029"},{"issue":"2","key":"e_1_2_10_7_1","first-page":"5752","article-title":"Phenotypic characterization of metaplastic intestinal glands and ductular hepatocytes in cholangiofibrotic lesions rapidly induced in the caudate liver lobe of rats treated with furan","volume":"53","author":"Elmore L. 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