title: In vivo genotoxicity of furan in F344 rats at cancer bioassay doses.
abstract: 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.
authors.affiliation: Division of Genetic and Molecular Toxicology, US FDA/National Center for Toxicological Research, Jefferson, AR 72079, USA. Wei.Ding@fda.hhs.gov
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Dayton M
authors.initials: DM
authors.lastname: Petibone
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: Mason G
authors.initials: MG
authors.lastname: Pearce
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.forename: Gene A
authors.initials: GA
authors.lastname: White
authors.forename: Ching-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Mittelstaedt
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Shaddock
authors.forename: Lea P
authors.initials: LP
authors.lastname: McDaniel
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Morris
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bishop
authors.forename: Mugimane G
authors.initials: MG
authors.lastname: Manjanatha
authors.forename: Anane
authors.initials: A
authors.lastname: Aidoo
authors.forename: Robert H
authors.initials: RH
authors.lastname: Heflich
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D015197:Carcinogenicity Tests; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D048629:Micronuclei, Chromosome-Defective; D009152:Mutagenicity Tests; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D005663:Furans; C039281:furan