First Steps Towards an Understanding of a Mode of Carcinogenic Action for Vanadium Pentoxide

Abstract

Inhalation of vanadium pentoxide clearly increases the incidence of alveolar/bronchiolar neoplasms in male and female B6C3F1 mice at all concentrations tested (1, 2 or 4 mg/m3), whereas responses in F344/N rats was, at most, ambiguous. While vanadium pentoxide is mutagenic in vitro and possibly in vivo in mice, this does not explain the species or site specificity of the neoplastic response. A nose-only inhalation study was conducted in female B6C3F1 mice (0, 0.25, 1 and 4 mg/m3, 6 h/day for 16 days) to explore histopathological, biochemical (α-tocopherol, glutathione and F2-isoprostane) and genetic (comet assays and 9 specific DNA-oxo-adducts) changes in the lungs. No treatment related histopathology was observed at 0.25 mg/m3. At 1 and 4 mg/m3, exposure-dependent increases were observed in lung weight, alveolar histiocytosis, sub-acute alveolitis and/or granulocytic infiltration and a generally time-dependent increased cell proliferation rate of histiocytes. Glutathione was slightly increased, whereas there were no consistent changes in α-tocopherol or 8-isoprostane F2α. There was no evidence for DNA strand breakage in lung or BAL cells, but there was an increase in 8-oxodGuo DNA lesions that could have been due to vanadium pentoxide induction of the lesions or inhibition of repair of spontaneous lesions. Thus, earlier reports of histopathological changes in the lungs after inhalation of vanadium pentoxide were confirmed, but no evidence has yet emerged for a genotoxic mode of action. Evidence is weak for oxidative stress playing any role in lung carcinogenesis at the lowest effective concentrations of vanadium pentoxide.

Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks

“…In addition, the statistically significant increase in lung weights provided a measure of toxicity from exposure in the 1 mg/m 3 group. This observation is consistent with the previously conducted Schuler et al [21] study, which reported a concentration-dependent increase in lung weight and histiocytic inflammatory lesions in B 6 C 3 F 1 mice exposed to 1 mg/m 3 or greater concentration of V 2 O 5 for 16 days [21]. Previously it has been reported that such concentrationrelated increases in lung weight are associated with recruitment of inflammatory cells and an accumulation of fluid within the pulmonary tissues leading to histiocytosis [14,21].…”

“…This conclusion is strengthened by the negative Kras mutation response in the left lobe of the same V 2 O 5 -treated BB mice [23]. The negative mutagenic response to V 2 O 5 exposure in BB mice adds to the body of negative results from several previous in vitro and in vivo genotoxicity studies, such as Ames assay with or without S9 enzymes, micronucleus assay in the peripheral blood of mice [14], and the comet assay in mouse lungs [21]. It also calls into question the significance of the recently reported positive micronucleus and comet assay data in the context of the mode of action of V 2 O 5.…”

“…However, recent studies reported a slight increase in 8-oxodGuo DNA lesions in lungs of female B 6 C 3 F 1 mice exposed to 1 or 4 mg/m 3 V 2 O 5 for 16 days by nose-only inhalation [21], and increased micronuclei in peripheral blood in male but not female CD1 mice exposed to 1.4 mg/m 3 V 2 O 5 for 2 h per week for 4 weeks by aerosol inhalation [20]. 8-oxodGuo DNA lesions are likely to be mutagenic, and impaired or defective repair of these lesions can induce mostly G → T and A → C transversions [22,27], which can be detected in lungs of BB mice following exposure to V 2 O 5 .…”

“…A recent 16-day nose only V 2 O 5 inhalation study by Schuler et al [21] showed negative results in the comet assay in lung and bronchiolar-alveolar lavage (BAL) cells from female B 6 C 3 F 1 mice at exposure levels that caused lung tumors from chronic exposures. On the other hand, in the same study there was a slight increase in 8-oxodGuo DNA lesions, which could have been induced by V 2 O 5 or could have been due to inhibition of repair of spontaneous lesions.…”

Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation

“…8-Oxo-2 -deoxyguaninosine (8-oxo-dG), an oxidized form of deoxyguanosine, is a well-known marker of oxidative DNA damage, which causes A:T to C:G or G:C to T:A transversion mutations. Increases in 8-oxo-dG have been shown to occur in VP treated mouse lung [12]. If direct oxidation of Kras codon 12 (WT, GGT) is responsible for its carcinogenic effects, then induction of Kras codon 12 GTT mutation is expected to be an early event in VPinduced lung carcinogenesis, whereas, no early increase in Kras codon 12 GAT mutation would be expected based on this potential MOA.…”