Effect of trichloroethylene and its metabolites, dichloroacetic acid and trichloroacetic acid, on the methylation and expression of c-jun and c-myc protooncogenes in mouse liver: Prevention by methionine

Trichloroethylene (TCE), dichloroacetic acid (DCA), and trichloroacetic aci d (TCA) are environmental contaminants that are carcinogenic in mouse liver . 5-Methylcytosine (5-MeC) in DNA is a mechanism that controls the transcri ption of mRNA, including the protooncogenes, c-jun and c-myc. We have previ ously reported that TCE decreased methylation of the c-jun and c-myc genes and increased the level of their mRNAs. Decreased methylation of the protoo ncogenes could be a result of a deficiency in S-adenosylmethionine (SAM), s o that methionine, by increasing the level of SAM, would prevent hypomethyl ation of the genes. For 5 days, female B6C3F1 mice were administered, daily by oral gavage, either 1000 mg/kg body weight of TCE or 500 mg/kg DCA or T CA. At 30 min after each dose of carcinogen, the mice received, by ip injec tion, 0-, 30-, 100-, 300-, or 450-mg/kg methionine. Mice were euthanized at 100 min after the last dose of DCA, TCA, or TCE. Decreased methylation in the promoter regions of the c-jun and c-myc genes and increased levels of t heir mRNA and proteins were found in livers of mice exposed to TCE, DCA, an d TCA. Methionine prevented both the decreased methylation and the increase d levels of the mRNA and proteins of the two protooncogenes. The prevention by methionine of DCA- TCA-, and TCE-induced DNA hypomethylation supports t he hypothesis that these carcinogens act by depleting the availability of S AM. Hence, methionine would prevent DNA hypomethylation by maintaining the level of SAM. Furthermore, the results suggest that the dose of DCA, TCA, o r TCE must be sufficient to decrease the level of SAM in order for these ca rcinogens to be active.