Search

Trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane, and bromoform) are regulated organic contaminants in chlorinated drinking water. In female B6C3F1 mouse liver, the 4 trihalomethanes have demonstrated carcinogenic activity when administered by oral gavage; however, chloroform was not carcinogenic when administered in drinking water. Female B6C3F1 mice were administered the trihalomethanes for 11 days by gavage at 2 dose levels or in the drinking water at ∼75% saturation. When administered by gavage, the trihalomethanes were toxic to the liver, increased the liver:body weight (bw) ratio, and increased the proliferating cell nuclear antigen-labeling index (PCNA-LI). Chloroform and bromodichloromethane were the most toxic, and they increased the liver:bw ratio the most, while bromoform and chloroform increased the PCNA-LI the most. When administered in drinking water, the toxicity of the trihalomethanes was similar to their low gavage-dose. Furthermore, only chloroform significantly increased the liver:bw ratio and bromoform and chloroform increased the PCNA-LI. Chloroform and bromodichloromethane decreased the level of 5-methylcytosine in hepatic DNA. Methylation in the promoter region of the c-myc gene was reduced by the trihalomethanes. Chloroform administered by gavage was more efficacious than given in drinking water; the efficacy of the other trihalomethanes did not differ for the 2 routes. Thus, in mouse liver, the trihalomethanes administered by gavage enhanced cell proliferation and decreased the methylation of the c-myc gene, consistent with their carcinogenic activity. Furthermore, the more modest toxicity, enhancement of cell proliferation, and decreased methylation induced by chloroform administered in drinking water correlated with its lack of carcinogenic activity. Hence, the activity of the trihalomethanes was dependent on the rate of delivery, i.e. rapid by oral gavage and more slowly in drinking water. [ABSTRACT FROM PUBLISHER]

Trichloroethylene (TCE), dichloroacetic acid (DCA), and trichloroacetic acid (TCA) are environmental contaminants that are carcinogenic in mouse liver. 5-Methylcytosine (5-MeC) in DNA is a mechanism that controls the transcription of mRNA, including the protooncogenes, c-jun and c-myc. We have previously reported that TCE decreased methylation of the c-jun and c-myc genes and increased the level of their mRNAs. Decreased methylation of the protooncogenes could be a result of a deficiency in S-adenosylmethionine (SAM), so that methionine, by increasing the level of SAM, would prevent hypomethylation 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 TCA. At 30 min after each dose of carcinogen, the mice received, by ip injection, 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 their mRNA and proteins were found in livers of mice exposed to TCE, DCA, and TCA. Methionine prevented both the decreased methylation and the increased levels of the mRNA and proteins of the two protooncogenes. The prevention by methionine of DCA- TCA-, and TCE-induced DNA hypomethylation supports the hypothesis that these carcinogens act by depleting the availability of SAM. Hence, methionine would prevent DNA hypomethylation by maintaining the level of SAM. Furthermore, the results suggest that the dose of DCA, TCA, or TCE must be sufficient to decrease the level of SAM in order for these carcinogens to be active. [ABSTRACT FROM PUBLISHER]