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 trans-gene 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.

Furan-induced hepatotoxic and hematologic changes in diabetic rats: the protective role of lycopene

“…Microscopic findings in the liver were severe with furan treatment and diabetes, similar to the findings in previous reports (2,21,37). Furan induced vascular congestion, mononuclear cell infiltration, dilation of sinusoids, hemorrhage, and degeneration of hepatocytes in this study.…”

“…Humans may be exposed to it through consumption of thermally treated foods (1). Furan is also found in cigarette smoke and engine exhausts (2). It is also hepatotoxic and carcinogenic in animals; high incidence of cancers has been observed in animals, even at the lowest dose treated (1).…”

Risks for public health related to the presence of furan and methylfurans in food

“…No increase in mutation frequency at the cII locus was observed in BDA-treated mouse embryo fibroblasts derived from Big Blue B6C3F1 mice. However, BDA treatment induced a shift in mutational spectrum with a concentration-dependent increase in AT > CG transversions only (Terrell et al, 2014). Terrell et al (2014) BDA: cis-but-2-ene-1,4-dialdehyde; CHO: Chinese hamster ovary; dA: 2'-deoxyadenosine; dC: 2'-deoxycytidine; dG: 2'-deoxyguanosine; SSB: single strand break; ICL: inter-strand crosslink.…”

Industrial furan and its biological effects on the body systems

“…The alteration of enzymes activity, elevated conjugated and total bilirubin levels were observed following the administration of furan via nasogastric gavage for 90 days at different doses to previously furan‐treated rats (Gill et al, ). Increases in total bilirubin can be as a result of cholestasis following impairment of intrahepatic or extrahepatic bile flow induced by releasing of hepatic membrane bound enzymes (Gill et al, ; Terrell et al, ).…”