Mutagenesis Advance Access published online on November 28, 2005
Mutagenesis, doi:10.1093/mutage/gei066
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1 Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, USFDA, Jefferson, AR 72079, USA
* To whom correspondence should be addressed. 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
Received June 1, 2005
Revised October 26, 2005
Accepted October 31, 2005
Original article
Levels of H-ras codon 61 CAA to AAA mutation: response to 4-ABP-treatment and Pms2-deficiency
Barbara L. Parsons 1 *,
Robert R. Delongchamp 2,
Frederick A. Beland 3,
and
Robert H. Heflich 1
2 Division of Biometry and Risk Assessment, National Center for Toxicological Research, USFDA, Jefferson, AR 72079, USA
3 Division of Biochemical Toxicology, National Center for Toxicological Research, USFDA, Jefferson, AR 72079, USA
Barbara L. Parsons, E-mail: bparsons{at}nctr.fda.gov
Abstract 
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.
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