Lack of genotoxic mechanisms in early‐stage furan‐induced hepatocellular tumorigenesis in gpt delta rats. Issue 2 (3rd May 2016)

• Record Type: Journal Article
• Authors: Hibi, Daisuke; Yokoo, Yu; Suzuki, Yuta; Ishii, Yuji; Jin, Meilan; Kijima, Aki; Nohmi, Takehiko; Nishikawa, Akiyoshi; Umemura, Takashi
• Is Part Of: Journal of applied toxicology. Volume 37:Issue 2(2017)
• Page Start: 142
• Page End: 149
• Publication Date: 2016-05-03
• Subjects: furan -- gpt delta rat -- hepatocarcinogensis -- reporter gene mutation -- cell proliferation; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.3331
• Languages: English
• ISSNs: 0260-437X

Abstract

Abstract: Furan has been used as an intermediate in the chemical‐manufacturing industry and has been shown to contaminate various foods. Although furan induces hepatocellular tumors in rodents, equivocal results from in vitro and in vivo mutagenicity tests have caused controversy regarding the involvement of genotoxic mechanisms in furan‐induced carcinogenesis. In the present study, to elucidate the possible mechanisms underlying furan‐induced hepatocarcinogenesis, a comprehensive medium‐term analysis was conducted using gpt delta rats treated with furan at carcinogenic doses for 13 weeks. In the liver, the frequencies of gpt and Spi ‐ mutants derived mainly from point and deletion mutations, respectively, were not changed, and there were no furan‐specific gpt mutations in furan‐treated rats. In contrast, the number and area of glutathione S‐transferase placental form (GST‐P)‐ positive foci were significantly increased in the high‐dose group. Also, the ratio of PCNA‐positive hepatocytes was significantly elevated in the same group, as supported by significant increases in cyclin d1 and cyclin e1 mRNA levels. Thus, it is highly probable that cell proliferation, but not genotoxic mechanisms, contribute to the development of GST‐P foci in furan‐treated rats. Based on the close relationship between GST‐P and neoplastic hepatocytes, these data allowed us to hypothesize that cell proliferation following signal transduction other than the mitogen‐activated protein kinase (MAPK)/ERK pathway may play a crucial role in early‐stage furan‐induced hepatocarcinogenesis. Copyright © 2016 John Wiley & Sons, Ltd. Abstract : Furan is shown to contaminate various foods and hepatocarcinogen in rodents. To elucidate furan‐induced hepatocarcinogenic mechanisms, comprehensive medium‐term analysis was conducted using gpt delta rats treated with furan at carcinogenic doses for 13 weeks. The reporter gene mutant frequencies in the liver were significantly increased. But, the number and area of glutathione S‐transferase placental form‐positive foci, and cell proliferation activity were significantly increased. Thus, it is highly probable that cell proliferation, but not genotoxic mechanisms, contribute to early‐stage furan‐induced hepatocarcinogenesis.