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).
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.
Smith-Roe
Stephanie L
SL
Department of Environmental and Molecular Toxicology, Oregon State University, 1007 ALS Building, Corvallis, OR 97331, USA.
Löhr
Christiane V
CV
Bildfell
Robert J
RJ
Fischer
Kay A
KA
Hegan
Denise Campisi
DC
Glazer
Peter M
PM
Buermeyer
Andrew B
AB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002352:Carrier Proteins / Q000502:physiology*; D003106:Colon / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D004273:DNA, Neoplasm / Q000502:physiology*; D019337:Hematologic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D007093:Imidazoles / Q000633:toxicity*; D015994:Incidence; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000502:physiology*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D015996:Survival Rate
D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D007093:Imidazoles; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D000070957:MutL Protein Homolog 1