title: Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks.
abstract: Chronic inhalation of vanadium pentoxide (V2O5) increases the incidence of alveolar/bronchiolar tumors in male and female B6C3F1 mice at 1, 2, or 4 mg/m(3). The genotoxicity of V2O5 has been extensively investigated in the literature with mixed results. In general, tests for gene mutations have been negative. Both positive and negative results were reported for clastogenicity in vitro with some reports suggesting aneugenic potential. In vivo, V2O5 was negative in the mouse micronucleus test (erythrocyte) and comet assay (lung). Previously, K-ras mutations have been detected in the lung tumors in mice exposed to V2O5. Recently, a short-term inhalation study in B6C3F1 mice reported slight induction of 8-oxodGuo DNA lesions in lungs. Because 8-oxodGuo DNA lesions can lead to gene mutations if not repaired or if misrepaired, we have used groups of transgenic Big Blue (BB) mice (B6C3F1) to test whether V2O5 has mutagenic potential in vivo in the tumor target tissue under the conditions of the bioassay. Groups of six male BB mice were exposed to particulate aerosols containing 0, 0.1, or 1 mg/m(3) (tumorigenic concentration) V2O5 for 4 or 8 weeks (6h/day, 5 days/week) and cII mutant frequencies (MFs) were evaluated in the right lungs. A significant increase in lung weight was noted in mice exposed to 1 mg/m(3) V2O5 (P ≤ 0.05) compared to sham control, confirming exposure to an inflammatory level of the test material. The mean MFs (× 10(-6)) of mice in the 4-week exposure groups were 30 (sham control), 39 (0.1 mg/m(3)), and 24 (1 mg/m(3)) while the corresponding values in the 8-week exposure groups were 29, 48, and 17, respectively. None of these cII MFs measured at any time point was significantly higher than the corresponding control MFs (P ≥ 0.1). Overall, these results suggest that mutagenicity is not likely to be an initial key event in the lung tumorigenicity of V2O5.
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, USFDA, Jefferson, AR, United States. Electronic address: Mugimane.manjanatha@fda.hhs.gov.
authors.forename: Mugimane G
authors.initials: MG
authors.lastname: Manjanatha
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, USFDA, Jefferson, AR, United States.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Shelton
authors.affiliation: Toxicological Excellence for Risk Assessment, Cincinnati, OH, United States.
authors.forename: Lynne
authors.initials: L
authors.lastname: Haber
authors.affiliation: Center for Toxicology and Mechanistic Biology, Exponent Inc., Midland, MI, United States.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Gollapudi
authors.affiliation: Toxicology Consulting Services, Bonita Springs, FL, United States.
authors.forename: Judith A
authors.initials: JA
authors.lastname: MacGregor
authors.affiliation: IIT Research Institute, Chicago, IL, United States.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Rajendran
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, USFDA, Jefferson, AR, United States.
authors.forename: Martha M
authors.initials: MM
authors.lastname: Moore
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D017968:Vanadium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D017968:Vanadium Compounds; D014764:Viral Proteins; C039000:cII protein, bacteriophage lambda; C066075:vanadium pentoxide
keywords: Mutagenic mode of action for the carcinogenicity of vanadium pentoxide; Vanadium pentoxide mutagenicity in lungs by inhalation study; cII mutagenicity in Big Blue mice