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.
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.
Zhang
S
S
Centre for Environmental Health, Department of Biology, University of Victoria, Victoria, BC, V8W 3N5, Canada.
Lloyd
R
R
Bowden
G
G
Glickman
B W
BW
de Boer
J G
JG
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D020137:Base Pair Mismatch; D003043:Cocarcinogenesis; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004032:Diet; D004777:Environment; D029968:Escherichia coli Proteins; D007093:Imidazoles; D056968:Lac Repressors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein; D016296:Mutagenesis; D009153:Mutagens; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D007093:Imidazoles; D056968:Lac Repressors; D009153:Mutagens; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein