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Appearance of sex-determining region Y-box 9 (SOX9)- and glutathione S-transferase placental form (GST-P)-positive hepatocytes as possible carcinogenic events in the early stage of furan-induced hepatocarcinogenesis.
Hibi, Daisuke; Soma, Meili; Suzuki, Yuta; Takasu, Shinji; Ishii, Yuji; Umemura, Takashi.
Afiliação
  • Hibi D; Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan.
  • Soma M; Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan.
  • Suzuki Y; Graduate School of Animal Health Technology, Yamazaki University of Animal Health Technology, Tokyo, Japan.
  • Takasu S; Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan.
  • Ishii Y; Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan.
  • Umemura T; Division of Pathology, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan.
J Appl Toxicol ; 2024 Aug 22.
Article em En | MEDLINE | ID: mdl-39171654
ABSTRACT
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 weeks and cholangiofibrosis in this lobe at 8 weeks. In vivo mutagenicity assays using DNA extracted from the caudate or left lateral lobe of male gpt delta rats, the reporter gene-transgenic rats, treated with 8 mg/kg furan for 4 or 8 weeks showed negative outcomes. The distribution of glutathione S-transferase placental form (GST-P)-positive or sex-determining region Y-box 9 (SOX9)-positive hepatocytes was examined. Significant increases in the number of GST-P-positive hepatocytes were observed in all lobes of furan-treated rats at 8 weeks. By contrast, SOX9-positive hepatocytes, liver injury-inducible 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-expressed 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-positive hepatocytes, some of which were subjected to dedifferentiation in the inflammatory microenvironment of a cholangiocarcinoma-prone lobe. Thus, the appearance of SOX9-positive hepatocytes together with GST-P-positive hepatocytes could be initial events in furan-induced hepatocarcinogenesis via non-genotoxic mechanisms.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article