title: Lack of genotoxic mechanisms in early-stage furan-induced hepatocellular tumorigenesis in gpt delta rats.
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.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hibi
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yokoo
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Meilan
authors.initials: M
authors.lastname: Jin
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Kijima
authors.affiliation: Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.affiliation: Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002274:Carcinogens, Environmental / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins / Q000235:genetics*; D005260:Female; D005663:Furans / Q000633:toxicity*; D017930:Genes, Reporter / Q000235:genetics; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D010430:Pentosyltransferases / Q000235:genetics*; D011916:Rats, Inbred F344; D055647:Rats, Transgenic
chemical_list: D002274:Carcinogens, Environmental; D029968:Escherichia coli Proteins; D005663:Furans; D009153:Mutagens; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat; C039281:furan
keywords: cell proliferation; furan; gpt delta rat; hepatocarcinogensis; reporter gene mutation