title: Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation.
abstract: This study investigated whether Kras mutation is an early event in the development of lung tumors induced by inhalation of particulate vanadium pentoxide (VP) aerosols. A National Toxicology Program tumor bioassay of inhaled particulate VP aerosols established that VP-induced alveolar/bronchiolar carcinomas of the B6C3F1 mouse lung carried Kras mutations at a higher frequency than observed in spontaneous mouse lung tumors. Therefore, this study sought to: (1) characterize any Kras mutational response with respect to VP exposure concentration, and (2) investigate the possibility that amplification of preexisting Kras mutation is an early event in VP-induced mouse lung tumorigenesis. Male Big Blue B6C3F1 mice (6 mice/group) were exposed to aerosolized particulate VP by inhalation, 6h/day, 5 days/week for 4 or 8 weeks, using VP exposure concentrations of 0, 0.1, and 1 mg/m(3). The levels of two different Kras codon 12 mutations [GGT → GAT (G12D) and GGT → GTT (G12V)] were measured in lung DNAs by Allele-specific Competitive Blocker PCR (ACB-PCR). For both exposure concentrations (0.1 and 1.0mg/m(3)) and both time points (4 and 8 weeks), the mutant fractions observed in VP-exposed mice were not significantly different from the concurrent controls. Given that 8 weeks of inhalation of a tumorigenic concentration of particulate aerosols of VP did not result in a significant change in levels of lung Kras mutation, the data do not support either a direct genotoxic effect of VP on Kras or early amplification of preexisting mutation as being involved in the genesis of VP-induced mouse lung tumors under the exposure conditions used. Rather, the data suggest that accumulation of Kras mutation occurs later with chronic VP exposure and is likely not an early event in VP-induced mouse lung carcinogenesis.
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, AR, United States.
authors.forename: Malathi
authors.initials: M
authors.lastname: Banda
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, AR, United States.
authors.forename: Karen L
authors.initials: KL
authors.lastname: McKim
authors.affiliation: Toxicology Excellence for Risk Assessment, Cincinnati, OH, United States.
authors.forename: Lynne T
authors.initials: LT
authors.lastname: Haber
authors.affiliation: Toxicology Consulting Services, Bonita Springs, FL, United States.
authors.forename: Judith A
authors.initials: JA
authors.lastname: MacGregor
authors.affiliation: Exponent, Midland, MI, United States.
authors.forename: B Bhaskar
authors.initials: BB
authors.lastname: Gollapudi
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, AR, United States. Electronic address: barbara.parsons@fda.hhs.gov.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Parsons
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; 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*; D052638:Particulate Matter / Q000008:administration & dosage / Q000633:toxicity; D016133:Polymerase Chain Reaction / Q000379:methods; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013997:Time Factors; D017968:Vanadium Compounds / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000336:Aerosols; D003062:Codon; D052638:Particulate Matter; D017968:Vanadium Compounds; C066075:vanadium pentoxide; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Carcinogenesis; Mode of action; Mutation; Vanadium pentoxide