Genomic hypomethylation is a consistent finding in both human and animal tumors 
and mounting experimental evidence suggests a key role for epigenetic events in 
tumorigenesis. Furthermore, it has been suggested that early changes in DNA 
methylation and histone modifications may serve as sensitive predictive markers 
in animal testing for carcinogenic potency of environmental agents. Alterations 
in metabolism of methyl donors, disturbances in activity and/or expression of 
DNA methyltransferases, and presence of DNA single-strand breaks could 
contribute to the loss of cytosine methylation during carcinogenesis; however, 
the precise mechanisms of genomic hypomethylation induced by chemical 
carcinogens remain largely unknown. This study examined the mechanism of DNA 
hypomethylation during hepatocarcinogenesis induced by peroxisome proliferators 
WY-14,643 (4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid) and DEHP 
(di-(2-ethylhexyl)phthalate), agents acting through non-genotoxic mode of 
action. In the liver of male Fisher 344 rats exposed to WY-14,643 (0.1% (w/w), 5 
months), the level of genomic hypomethylation increased by approximately 2-fold, 
as compared to age-matched controls, while in the DEHP group (1.2% (w/w), 5 
months) DNA methylation did not change. Global DNA hypomethylation in livers 
from WY-14,643 group was accompanied by the accumulation of DNA single-strand 
breaks, increased cell proliferation, and diminished expression of DNA 
methyltransferase 1, while the metabolism of methyl donors was not affected. In 
contrast, none of these parameters changed significantly in rats fed DEHP. Since 
WY-14,643 is much more potent carcinogen than DEHP, we conclude that the extent 
of loss of DNA methylation may be related to the carcinogenic potential of the 
chemical agent, and that accumulation of DNA single-strand breaks coupled to the 
increase in cell proliferation and altered DNA methyltransferase expression may 
explain genomic hypomethylation during peroxisome proliferator-induced 
carcinogenesis.