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.