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K-Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose
Citation:
MENG, F., G. W. KNAPP, T. B. GREEN, J. A. ROSS, AND B. L. PARSON. K-Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, 51(2):146-155, (2010).
Impact/Purpose:
This research was undertaken to test the default assumption of low dose linearity for a genotoxic environmental carcinogen, benzo[a]pyrene.
Description:
K-Ras mutant fraction (MF) was measured to examine the default assumption of low dose linearity in the benzo[a]pyrene (B[a]P) mutational response. Groups of ten male A/J mice (7-9 weeks-old) received a single i.p. injection of 0, 0.05, 0.5, 5, or 50 mg/kg B[a]P, and were sacrificed 28 days after treatment. K-Ras codon 12 TGT and GAT MFs in lung DNAs were measured using Allele-specific Competitive Blocker-PCR (ACBPCR). The K-Ras codon 12 TGT geometric mean MF was 3.88 X 10-4 in controls, indicating an average of 1 mutation in every ~1,288 lung cells. The K-Ras codon 12 TGT geometric mean MFs were: 3.56 x 10-4; 6.19 x 10-4; 2.02 x 10-3, and 3.50 x 10-3 for the 0.05, 0.5, 5, and 50 mg/kg B[a]P treatment groups, respectively. The 5 and 50 mg/kg dose groups had TGT MFs significantly higher than controls. Although 10-5 is considered the limit of accurate ACB-PCR quantitation, K-Ras codon 12 GAT geometric mean MFs were: 8.38 x 10-7; 1.47 x 10-6; 2.19 x 10-6, 5.71 x 10-6 and 8.99 x 10-6 for the 0, 0.05, 0.5, 5, and 50 mg/kg B[a]P treatment groups, respectively. The K-Ras TGT and GAT MFs increased in a B[a]P-dose-dependent manner, with response approximately linear over the 0.05 to 5 mg/kg dose range. K-Ras MF increased with B[a]P adduct burden measured for identical doses in a separate study. Thus, ACB-PCR may be useful in characterizing the shape of a dose-response curve at low doses and establishing relationships between DNA adducts and tumor-associated mutations.
