DNA mismatch repair-dependent responses to the food-borne carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the mouse Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/c534fr125

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  • The DNA mismatch repair (MMR) pathway maintains genomic stability and reduces cancer risk (colorectal and other internal cancers) by correcting polymerase errors and activating cell cycle checkpoints and apoptosis in response to DNA damage. Few studies have examined the influence of commonly encountered environmental mutagens/carcinogens on the etiology of MMR-deficient cancers. 2-Amino-1-methyl-6- phenylimidazo [4,5-bJ pyridine (PhIP) is a cooked-meat mutagen implicated in human colorectal carcinogenesis. To determine whether PhIP represents a cancer risk to individuals with MMR-deficiency, I examined the effect of Mlh1-deficiency on PhIP-induced mutagenesis, turnorigenesis, and cell-turnover responses in mice following exposure to eight intraperitoneal (i.p.) injections of 50 mg/kg PhIP. Mlh1⁻/⁻ mice were hypermutable by PhIP in colon and small intestine (as measured using transgene shuttle vectors), demonstrating specific increases in mutations not typically associated with PhIP. In contrast, G/C to T/A transversions, the "signature PhIP mutation" were similarly induced in Mlh1⁻/⁻ and wild-type mice. In cancer studies, Mlh1⁻/⁻ mice showed heightened susceptibility to induction of colonic aberrant crypt foci (a biomarker for colon carcinogenesis), whereas adenomas of the small intestine and colon were not induced. Cell-turnover responses in Mlh1⁺/⁺ and Mlh1⁻/⁻ mouse colon were evaluated following multiple i.p. injections or a single i.p. injection of 50 mg/kg PhIP. These responses were compared to a single i.p. injection of 80 mg/kg 1 ,2-dimethylhydrazine (DMH). Colonic apoptosis in response to PhIP increased, shifted to predominately the stem cell compartment of colon crypts, and was partially Mlh1-dependent. This response was also rapid, occurring at 8 h after treatment and diminishing by 16 h. Similar effects were observed in DMH-exposed animals. The apoptotic response to PhIP was greater after multiple exposures compared to a single exposure. PhIP-exposure did not notably alter cell proliferation, whereas proliferation was consistently reduced in DMH-treated mice. These results suggest that loss of Mlh1 alters homeostatic functions of the colonic crypt that may contribute to suppression of the mutagenic effects of PhIP. These data are consistent with the hypothesis that PhIP exposure increases mutagenesis and carcinogenesis in Mlh1⁻/⁻ mice, and support further evaluation of the risk that consumption of heterocyclic amines may impart to MMR-deficient individuals.
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