DNA methylation and hepatocarcinogenesis in rats fed a choline-devoid diet

Groups of male Fischer-344 rats were fed either a choline-supplementedor a choline-devoid (CD) diet, for up to 14 months. In ratsfed the CD diet, hepatic lesions developed and progressed throughtwo distinct stages, the first characterized by severe steatosisand an increase in cell turnover and the second by gradual clearanceof the deposited fat, fibrosis and parenchymal nodularity. Largehepatocellular carcinomas were found in rats killed at 14 months.DNA was purified from the livers of all groups of rats and fromthe tumors, and its level of methylations was analyzed usingthe restriction endonucleases Hpall and Mspl. DNA under-methylationwas detected only in the livers of rats fed the CD diet for14 months, whether bearing tumors or not, and in three of fourhepatocellular carcinomas. Undermethylation of liver total DNAis therefore a late effect of dietary choline deficiency inthe rat.