Induction of aberrant crypt foci in DNA mismatch repair-deficient mice by the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP).

TitleInduction of aberrant crypt foci in DNA mismatch repair-deficient mice by the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP).
Publication TypeJournal Article
Year of Publication2006
AuthorsSmith-Roe SL, Löhr CV, Bildfell RJ, Fischer KA, Hegan DC, Glazer PM, Buermeyer AB
JournalCancer letters
Volume244
Issue1
Pagination79-85
Date Published2006 Nov 28
ISSN0304-3835
KeywordsAdaptor Proteins, Signal Transducing, Animals, Carcinogens, Carrier Proteins, Colon, Colonic Neoplasms, DNA Mismatch Repair, DNA, Neoplasm, Hematologic Neoplasms, Imidazoles, Incidence, Mice, Mice, Knockout, Nuclear Proteins, Precancerous Conditions, Survival Rate
Abstract

Disruption of the DNA mismatch repair (MMR) pathway results in elevated mutation rates, inappropriate survival of cells bearing DNA damage, and increased cancer risk. Relatively little is known about the impact of environmentally relevant carcinogens on cancer risk in individuals with MMR-deficiency. We evaluated the effect of MMR status (Mlh1(+/+) versus Mlh1(-/-)) on the carcinogenic potential of the cooked-meat mutagen, 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) in mice. PhIP exposure did not obviously increase lymphoma or small intestinal tumorigenesis in either Mlh1-deficient or -proficient mice. In contrast, the frequency of aberrant crypt foci (ACF), a preneoplastic biomarker for colon tumorigenesis, was increased by PhIP, and the increase due to PhIP was significantly greater in Mlh1(-/-) versus wild-type littermates. This apparent heightened susceptibility to induction of ACF parallels the previously reported hypermutability of Mlh1-deficient mice to PhIP and is consistent with the hypothesis that MMR-deficiency would increase the likelihood of PhIP-induced carcinogenic mutations. Further evaluation of the risk that consumption of heterocyclic amines may impart to MMR-deficient individuals therefore is warranted.

Alternate JournalCancer Lett.