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).
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AuthorsSmith-Roe, Stephanie L.
Löhr, Christiane V.
Bildfell, Robert J.
Fischer, Kay A.
Hegan, Denise Campisi
Glazer, Peter M.
Buermeyer, Andrew B.
MetadataShow full item record
AbstractDisruption 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.
CitationCancer Lett. 2006, 244 (1):79-85
DescriptionBiomarkers of exposure & effect:: validationBiomarker: PhIPExposure/effect represented: PhIP/ G/C-T/A transversions Study type (in vitro, animals, humans): C57B1/6 miceMode of exposure (if in vivo) (acute, chronic, root of exposure): i.p. injectionsTissue/biological material/sample size: 4μm of tissuesDose-response: In Mlh1K/K mice, PhIP exposure increased the incidence of ACF from 31% (5/16) to 87% (13/15) (PZ0.003) and the average frequency of ACF from 0.4G0.2 to 2.7G0.6 (P! 0.0001)The PhIP-induced frequency of ACF in wild-type littermates was 0.6 per mouse (0.7G0.3-0.1G0.07; PZ0.04), associated with a corresponding increase in incidence from 7% (1/15) to 45% (5/11) (PZ0.05)The vehicle-treated Mlh1K/K mice also had an observed higher incidence (31 versus 7%; PZ0.17) and average frequency of ACF (0.4G0.2 versus 0.1G0.07; P! 0.08) than vehicle-treated. KEYWORDS CLASSIFICATION: Animals;chemically induced;Carcinogens;Carrier Proteins;Colon;Colonic Neoplasms;drug effects;dietary modulation of cancer & cancer biomarkers;DNA Mismatch Repair;DNA,Neoplasm;genetics;Hematologic Neoplasms;Imidazoles;Incidence;mechanisms of carcinogenesis;Mice;Mice,Knockout;Nuclear Proteins;pathology;physiology;Precancerous Conditions;Proteins;Research;Survival Rate;toxicity;Toxicology.
- Mlh1-dependent suppression of specific mutations induced in vivo by the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP).
- Authors: Smith-Roe SL, Hegan DC, Glazer PM, Buermeyer AB
- Issue date: 2006 Feb 22
- A rat colon cancer model induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP.
- Authors: Nakagama H, Ochiai M, Ubagai T, Tajima R, Fujiwara K, Sugimura T, Nagao M
- Issue date: 2002 Sep 30
- Genetic analysis of the susceptibility in rats to aberrant crypt foci formation by 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine, PhIP.
- Authors: Nakagama H, Souda K, Ochiai M, Ishiguro Y, Sugimura T, Nagao M
- Issue date: 1999 Sep 1
- Characterization of dysplastic aberrant crypt foci in the rat colon induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
- Authors: Ochiai M, Ushigome M, Fujiwara K, Ubagai T, Kawamori T, Sugimura T, Nagao M, Nakagama H
- Issue date: 2003 Oct