Mutagenesis Advance Access originally published online on November 28, 2005
Mutagenesis 2006 21(1):29-34; doi:10.1093/mutage/gei066
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Levels of H-ras codon 61 CAA to AAA mutation: response to 4-ABP-treatment and Pms2-deficiency
1Division of Genetic and Reproductive Toxicology, 2Division of Biometry and Risk Assessment and 3Division of Biochemical Toxicology, National Center for Toxicological Research, USFDA, Jefferson, AR 72079, USA
DNA mismatch repair (MMR) deficiencies result in increased frequencies of spontaneous mutation and tumor formation. In the present study, we tested the hypothesis that a chemically-induced mutational response would be greater in a mouse with an MMR-deficiency than in the MMR-proficient mouse models commonly used to assay for chemical carcinogenicity. To accomplish this, the induction of H-ras codon 61 CAA
AAA mutation was examined in Pms2 knockout mice (Pms2–/–, C57BL/6 background) and sibling wild-type mice (Pms2+/+). Groups of five or six neonatal male mice were treated with 0.3 µmol 4-aminobiphenyl (4-ABP) or the vehicle control, dimethylsulfoxide. Eight months after treatment, liver DNAs were isolated and analysed for levels of H-ras codon 61 CAAAAA mutation using allele-specific competitive blocker-PCR. In Pms2-proficient and Pms2-deficient mice, 4-ABP treatment caused an increase in mutant fraction (MF) from 1.65 x 10–5 to 2.91 x 10–5 and from 3.40 x 10–5 to 4.70 x 10–5, respectively. Pooling data from 4-ABP-treated and control mice, the 
2-fold increase in MF observed in Pms2-deficient as compared with Pms2-proficient mice was statistically significant (P = 0.0207) and consistent with what has been reported previously in terms of induction of G:CT:A mutation in a Pms2-deficient background. Pooling data from both genotypes, the increase in H-ras MF in 4-ABP-treated mice, as compared with control mice, did not reach the 95% confidence level of statistical significance (P = 0.0606). The 4-ABP treatment caused a 1.76-fold and 1.38-fold increase in average H-ras MF in Pms2-proficient and Pms2-deficient mice, respectively. Furthermore, the levels of induced mutation in Pms2-proficient and Pms2-deficient mice were nearly identical (1.26 x 10–5 and 1.30 x 10–5, respectively). We conclude that Pms2-deficiency does not result in an amplification of the H-ras codon 61 CAAAAA mutational response induced by 4-ABP.
* To whom correspondence should be addressed. Barbara Parsons, Division of Genetic and Reproductive Toxicology, HFT-120, 3900 NCTR Road, Jefferson, AR 72079, USA; Tel: 870 543 7946; Fax: 870 543 7393; Email: bparsons{at}nctr.fda.gov