title: Mutagenicity of furan in female Big Blue B6C3F1 mice.
abstract: Furan is an abundant food and environmental contaminant that is a potent liver carcinogen in rodent models. To determine if furan is genotoxic in vivo, female B6C3F1 Big Blue transgenic mice were treated with 15 mg/kg bw furan by gavage 5 days a week for 6 weeks, or once weekly for 3 weeks. Liver cII transgene mutation-frequency and mutation spectra were determined. Furan did not increase the mutation frequency under either treatment condition. In the 6-week treatment regimen, there was a change in the cII transgene mutation-spectrum, with the fraction of GC to AT transitions significantly reduced. The only other significant change was an increase in GC to CG transversions; these represented a minor contribution to the overall mutation spectrum. A much larger furan-dependent shift was observed in the 3-week study. There was a significant increase in transversion mutations, predominantly GC to TA transversions as well as smaller non-significant changes in GC to CG and AT to TA transversions. To determine if these mutations were caused by cis-2-butene-1,4-dial (BDA), a reactive metabolite of furan, the mutagenic activity and the mutation spectrum of BDA was determined in vitro, in Big Blue mouse embryonic fibroblasts. This compound did not increase the cII gene mutation-frequency but caused a substantial increase in AT to CG transversions. This increase, however, lost statistical significance when adjusted for multiple comparisons. Together, these findings suggest that BDA may not be directly responsible for the in-vivo effects of furan on mutational spectra. Histopathological analysis of livers from furan-treated mice revealed that furan induced multifocal, hepatocellular necrosis admixed with reactive leukocytes and pigment-laden Kupffer cells, enhanced oval-cell hyperplasia, and increased hepatocyte mitoses, some of which were atypical. An indirect mechanism of genotoxicity is proposed in which chronic toxicity followed by inflammation and secondary cell proliferation triggers cancer development in furan-exposed rodents.
authors.affiliation: Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: terre062@umn.edu.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Terrell
authors.affiliation: Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: huynh082@umn.edu.
authors.forename: Mailee
authors.initials: M
authors.lastname: Huynh
authors.affiliation: Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: gril0043@umn.edu.
authors.forename: Alex E
authors.initials: AE
authors.lastname: Grill
authors.affiliation: Masonic Cancer Center Comparative Pathology Shared Resource, University of Minnesota, St. Paul, MN 55108, United States. Electronic address: rckovi@umn.edu.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Kovi
authors.affiliation: Masonic Cancer Center Comparative Pathology Shared Resource, University of Minnesota, St. Paul, MN 55108, United States. Electronic address: gos@umn.edu.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Department of Basic Science and Craniofacial Biology, and Environmental Medicine, New York University Dental and Medical Schools, New York, NY 10010, United States. Electronic address: Joseph.Guttenplan@nyumc.org.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Guttenplan
authors.affiliation: Division of Biostatistics, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: yho@umn.edu.
authors.forename: Yen-Yi
authors.initials: YY
authors.lastname: Ho
authors.affiliation: Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: peter431@umn.edu.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Peterson
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005663:Furans / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008938:Mitosis / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D019076:Transgenes
chemical_list: D002273:Carcinogens; D005663:Furans; D009153:Mutagens; D000410:Alanine Transaminase; C039281:furan
keywords: Aberrant mitosis; Big Blue mouse; Furan; In-vivo mutagenesis