In vivo genotoxicity of furan in F344 rats at cancer bioassay doses

• Published in: Toxicology and applied pharmacology Vol. 261; no. 2; pp. 164 - 171
• Main Authors: Ding, Wei, Petibone, Dayton M., Latendresse, John R., Pearce, Mason G., Muskhelishvili, Levan, White, Gene A., Chang, Ching-Wei, Mittelstaedt, Roberta A., Shaddock, Joseph G., McDaniel, Lea P., Doerge, Daniel R., Morris, Suzanne M., Bishop, Michelle E., Manjanatha, Mugimane G., Aidoo, Anane, Heflich, Robert H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-06-2012; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Apoptosis; BIOASSAY; Biological and medical sciences; BONE MARROW; Bone Marrow - drug effects; BUTENES; Cancer; Carcinogenicity; Carcinogenicity Tests; Carcinogens; CELL PROLIFERATION; DNA; DNA Damage; DNA glycosylase; Dose-Response Relationship, Drug; DOSES; EXCISION REPAIR; Food; FURANS; Furans - toxicity; Gene expression; Genotoxicity; GLUTATHIONE; In vivo Comet assay; INFLAMMATION; LIVER; Liver - drug effects; Liver - pathology; Male; Medical sciences; Micronuclei, Chromosome-Defective; Mutagenicity Tests; NEOPLASMS; OXIDATION; Oxidative stress; OXYGEN; Peripheral blood; pyrimidines; RATS; Rats, Inbred F344; Statistical analysis; STRAND BREAKS; Toxicity; Toxicology; Cell proliferation; MN; Oxidative stress; EndoIII; Liver; DNA damage; Inflammation; NTP; BER; In vivo Comet assay; MMR; ROS; NER; Fpg; GSH; BDA; MOA; DSBR; Furan; Bioassay; Rat; Digestive system; Toxicity; Rodentia; Genotoxicity; Malignant tumor; Comet assay; In vivo; Vertebrata; Mammalia; Animal; DNA; Lesion; Dose; Cancer; Genotoxity test
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.03.021

Furan, a potent rodent liver carcinogen, is found in many cooked food items and thus represents a human cancer risk. Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays, combined with analysis of histopathological and gene expression changes. In addition, formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III (EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage. Rats were treated by gavage on four consecutive days with 2, 4, and 8mg/kg bw furan, doses that were tumorigenic in 2-year cancer bioassays, and with two higher doses, 12 and 16mg/kg. Rats were killed 3h after the last dose, a time established as producing maximum levels of DNA damage in livers of furan-treated rats. Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion, with statistically significant increases detected at cancer bioassay doses. No DNA damage was detected in bone marrow, a non-target tissue for cancer, and peripheral blood micronucleus assays were negative. Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation, single-cell necrosis, apoptosis, and cell proliferation. In addition, genes related to apoptosis, cell-cycle checkpoints, and DNA-repair were expressed at a slightly lower level in the furan-treated livers. Although a mixed mode of action involving direct DNA binding cannot be ruled out, the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress, accompanied by inflammation, cell proliferation, and toxicity.
► Furan is a potent rodent liver carcinogen and represents a human cancer risk. ► Furan induces DNA damage in rat liver at cancer bioassay doses. ► Furan induces oxidative stress, inflammation and cell proliferation in rat liver. ► Expression of DNA damage repair-related genes is reduced in furan-treated rat livers. ► Furan induces rat liver cancer mainly through a secondary genotoxic mechanism.