Differences in Phenotype and Cell Replicative Behavior of Hepatic Tumors Induced by Dichloroacetate (DCA) and Trichloroacetate (TCA)

• Published in: Toxicology and applied pharmacology 1997-06, Vol.144 (2), p.235-246
• Main Authors: Stauber, Anja J, Bull, Richard J
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cell Count; Cell Division - drug effects; Chemical agents; Dichloroacetic Acid - administration & dosage; Dichloroacetic Acid - toxicity; Drinking; Immunohistochemistry; Liver - chemistry; Liver - drug effects; Liver - pathology; Liver Neoplasms - chemically induced; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Medical sciences; Mice; Phenotype; Precancerous Conditions - chemically induced; Precancerous Conditions - chemistry; Trichloroacetic Acid - administration & dosage; Trichloroacetic Acid - toxicity; Tumors
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1997.8159

Dichloroacetate (DCA) and trichloroacetate (TCA) are two hepatocarcinogenic by-products of water chlorination. To compare the effects of DCA and TCA on cell replication in the nodules and tumors they induce, male B6C3F1 mice were administered 2.0 g/L DCA or TCA in their drinking water for 38 or 50 weeks, respectively. The pretreated mice were then given water containing 0, 0.02, 0.5, 1.0, or 2.0 g/L DCA or TCA for two additional weeks to determine whether cell proliferation in the normal liver or tumors that had been induced by DCA or TCA was dependent on continued treatment. Prior to sacrifice the mice were subcutaneously implanted with mini-osmotic pumps to label DNA in dividing cells with 5-bromo-2′-deoxyuridine (BrdU). Serial sections of nodules/tumors and normal liver were stained immunohistochemically for BrdU, the oncoproteins c-Junand c-Fos,and hematoxylin and eosin (H & E); or with Periodic acid-Schiff (PAS) stain, BrdU, and H & E, respectively. DCA and TCA transiently stimulated the division of normal hepatocytes relative to rates observed in the livers of control mice. However, at 40 and 52 weeks of treatment, replication of normal hepatocytes was substantially inhibited by DCA and TCA, respectively. Cell division within DCA-induced lesions that were identified macroscopically was significantly higher with increasing dose of DCA administered in the last 2 weeks of the experiment. DCA-induced lesions were found to display immunoreactivity to anti-c-Junand anti-c-Fosantibodies, were predominantly basophilic, and contained very little glycogen relative to surrounding hepatocytes. In contrast, rates of cell division within TCA-induced altered hepatic foci and tumors were very high and appeared to be independent of continued treatment. TCA-induced lesions did not display immunoreactivity to either c-Junor c-Fosantibodies. Results from this study suggest that the mechanisms by which DCA and TCA induce hepatocarcinogenesis in the male B6C3F1 mouse differ.