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Cell proliferation and global methylation status changes in mouse liver after phenobarbital and/or choline-devoid, methionine-deficient diet administration
Department of Pharmacology and Toxicology, Michigan State University East Lansing. MI 48824
1Hoffmann LaRoche Inc. Nutley. NJ 07110, USA
4To whom correspondence should be addressed
Our laboratory is testing the hypothesis that hypomethylation of DNA [a decreased content of 5-methylcytosine (5MeC) compared with cytosine] facilitates aberrant oncogene expression involved in tumorigenesis, using a model system of mouse strains with differing susceptibilities to liver tumorigenesis. The B6C3F1 (C57BL/6 x C3H/He) mouse serves as the relatively susceptible strain and C57BL/ 6 serves as the relatively resistant strain. Phenobarbital (PB)and/or administration of a choline-devoid, methionine-deficient diet (CMD) were employed as non-genotoxic hepatocarcinogens. We have examined hepatocyte and non-hepatocyte proliferation in conjunction with an assessment of global methylation changes in liver DNA of B6C3F1 and C57BL/6 mice following these promoter treatments. Bromodeoxyuridine incorporation into DNA, used to measure cell proliferation indirectly, was visualized by immunohistochemistry and quantified by aMacintosh-based image analysis system. Increased hepatocyte proliferation was demonstrated following all three treatments.This increase was larger in C57BL/6 (the relatively resistant strain) as compared with B6C3F1. In contrast, global hypomethylation was evident to a larger extent in the B6C3F1 mouse, as compared with C57BL/6. PB led to hypomethylation (>20% decrease as compared with controls) at weeks 1, 2 and 4 in B6C3F1, but not in C57BL/6 at the same time points. CMD diet administration led to hypomethylation in both strains. At week 1, 21 and 9% decreasesin global methylation status were observed in B6C3F1 and C57BL/ 6 respectively. Evaluation of these data suggests that the heightened sensitivity of the B6C3F1 mouse compared with the C57BL/6 is due, in part, to a decreased capacity for, or fidelity of, maintaining normal methylation status. The relatively resistant strain is better able to maintain the normal methylation status of DNA in the face of a higher level of cell proliferation.
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