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).

2.50
Hdl Handle:
http://hdl.handle.net/10146/56955
Title:
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).
Authors:
Smith-Roe, Stephanie L.; Löhr, Christiane V.; Bildfell, Robert J.; Fischer, Kay A.; Hegan, Denise Campisi; Glazer, Peter M.; Buermeyer, Andrew B.
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.
Citation:
Cancer Lett. 2006, 244 (1):79-85
Journal:
Cancer letters
Issue Date:
28-Nov-2006
URI:
http://hdl.handle.net/10146/56955
DOI:
10.1016/j.canlet.2005.12.002
PubMed ID:
16427736
Additional Links:
http://www.cancerletters.info/article/S0304-3835(05)01051-7/abstract
Type:
Article
Language:
en
Description:
Biomarkers 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.
ISSN:
0304-3835
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
dc.contributor.authorSmith-Roe, Stephanie L.-
dc.contributor.authorLöhr, Christiane V.-
dc.contributor.authorBildfell, Robert J.-
dc.contributor.authorFischer, Kay A.-
dc.contributor.authorHegan, Denise Campisi-
dc.contributor.authorGlazer, Peter M.-
dc.contributor.authorBuermeyer, Andrew B.-
dc.date.accessioned2009-03-24T09:41:01Z-
dc.date.available2009-03-24T09:41:01Z-
dc.date.issued2006-11-28-
dc.identifier.citationCancer Lett. 2006, 244 (1):79-85en
dc.identifier.issn0304-3835-
dc.identifier.pmid16427736-
dc.identifier.doi10.1016/j.canlet.2005.12.002-
dc.identifier.urihttp://hdl.handle.net/10146/56955-
dc.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.en
dc.description.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.en
dc.language.isoenen
dc.relation.urlhttp://www.cancerletters.info/article/S0304-3835(05)01051-7/abstracten
dc.subjectDNA mismatch repairen
dc.subjectMlh1en
dc.subjectPhIPen
dc.subjectCarcinogenesisen
dc.subjectColonen
dc.subjectAberrant crypt focien
dc.subjectColorectal canceren
dc.subjectLynch syndromeen
dc.subjectDiet and canceren
dc.subject.meshAdaptor Proteins, Signal Transducing-
dc.subject.meshAnimals-
dc.subject.meshCarcinogens-
dc.subject.meshCarrier Proteins-
dc.subject.meshColon-
dc.subject.meshColonic Neoplasms-
dc.subject.meshDNA Mismatch Repair-
dc.subject.meshDNA, Neoplasm-
dc.subject.meshHematologic Neoplasms-
dc.subject.meshImidazoles-
dc.subject.meshIncidence-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshNuclear Proteins-
dc.subject.meshPrecancerous Conditions-
dc.subject.meshSurvival Rate-
dc.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).en
dc.typeArticleen
dc.identifier.journalCancer lettersen
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