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Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon

Oncogene volume 20, pages 6066–6072 (2001)Cite this article

Abstract

Msh2 deficiency and food-borne carcinogen PhIP have been implicated as genetic and environmental factors, respectively, in human colon carcinogenesis. It is not clear whether loss of one or both alleles of Msh2 gene increases the mutational sensitivity in colon when exposed to environmental carcinogens. In the current study, Msh2+/−/lacI and Msh2−/−/lacI double transgenic mice were treated with PhIP and mutations in the lacI gene were studied in the colon. The spontaneous mutation frequency (MF) is approximately eightfold higher in Msh2−/− mice than in Msh2+/+ mice, while Msh2+/− mice display similar levels of spontaneous mutation as the Msh2 wild type mice. PhIP induced a significant increase in MF in all genotypes of mice. However, induced MF is much higher in Msh2−/− mice compared to Msh2+/+ and Msh2+/− mice. Msh2+/− mice displayed an increased level of G:C>T:A transversions and −1 frameshifts upon PhIP treatment. In contrast, loss of both Msh2 alleles mainly results in increased frequency of G:C>A:T transitions when exposed to PhIP. These results suggest that a defect in mismatch repair may result in an enhanced sensitivity from exposure to a dietary carcinogen. It also provides insight into interaction between genetic and environmental factors in human carcinogenesis.

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Acknowledgements

The authors thank Dave Walsh, Ken Sojonky, Jana Kangas, and James Holcroft for their technical help; and Drs Moyra Brackely and Jiangheng He for statistical analysis and Pauline Tymchuk for editorial assistance. We also thank Dr Frank R Jirik, Dr Susan E Andrew, and Agnes Francis for generously providing the experimental animals. This work was supported by NCIC and the Cancer Research Society Inc.

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  1. Department of Biology, Centre for Environmental Health, University of Victoria, Victoria, V8W 3N5, BC, Canada

    Shulin Zhang, Ruth Lloyd, Greg Bowden, Barry W Glickman & Johan G de Boer

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  1. Shulin Zhang
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Correspondence to Johan G de Boer.

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Zhang, S., Lloyd, R., Bowden, G. et al. Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon. Oncogene 20, 6066–6072 (2001). https://doi.org/10.1038/sj.onc.1204730

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