DISSIMILAR CHARACTERISTICS OF N-METHYL-N-NITROSOUREA-INITIATED FOCI AND TUMORS PROMOTED BY DICHLOROACETIC ACID OR TRICHLOROACETIC-ACID IN THE LIVER OF FEMALE B6C3F1 MICE

Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolit es of the industrial solvent and environmental contaminant trichloroet hylene (TCE), as well as contaminants of chlorinated drinking water. H uman exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence in mice. Differences in dose-r esponse curves, progression to cancer, and postexposure regression of lesions suggest that TCA and DCA work through different mechanisms. Th e purpose of this study was to further characterize the proliferative hepatocellular lesions promoted by TCP, and DCA using biomarkers of ce ll growth, differentiation, and metabolism in liver sections to better delineate the distinctions in the mechanism of the two chloroacetates . Fifteen-day-old female mice were initiated with 25 mg/kg N-methyl-N- nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmo l/L) in drinking water from age 49 days until euthanasia at age 413 da ys. The pathologic assessment showed that the foci of altered hepatocy tes and tumors occurring in the animals promoted with DCA were eosinop hilic and positive immunohistochemically for TGF-alpha, c-jun, c-myc, CYP 2E1, CYP 4A1, and glutathione S-transferase-pi (GST-pi). The DCA l esions also were essentially negative for c-fos and TGF-beta, but nont umor hepatocytes were consistently TGF-beta-positive. In contrast, tum ors promoted by TCA were predominantly basophilic, lacked GST-pi, and stained variably; usually, more than 50% of the turner hepatocytes wer e essentially negative for the other biomarkers. This study demonstrat es some striking differences in certain molecular biomarkers of cell g rowth, differentiation, and metabolism between DCA and TCA. The result s also suggest some potential growth signal transduction pathways that may contribute to the DCA promotion of tumors, further support the pr emise that these two chloroacetates promote hepatocarcinogenes is in d ifferent ways, and provide a rational basis for a similar comparison w ith TCE. Such a comparison should give some insight as to whether DCA, TCA, or both are playing a significant role in the murine liver carci nogenesis of the parent compound, TCE.