DIFFERENCES IN PHENOTYPE AND CELL REPLICATIVE BEHAVIOR OF HEPATIC-TUMORS INDUCED BY DICHLOROACETATE (DCA) AND TRICHLOROACETATE (TCA)

Dichloroacetate (DCA) and trichloroacetate (TCA) are two hepatocarcino genic by-products of water chlorination. To compare the effects of DCA and TCA on cell replication in the nodules and tumors they induce, ma le 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 tw o additional weeks to determine whether cell proliferation in the norm al liver or tumors that had been induced by DCA or TCA was dependent o n 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 oncopro teins c-Jun and c-Fos, and hematoxylin and eosin (H & E); or with Peri odic acid-Schiff (PAS) stain, BrdU, and H & E, respectively. DCA and T CA 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 substantial ly inhibited by DCA and TCA, respectively. Cell division within DCA-in duced lesions that were identified macroscopically was significantly h igher with increasing dose of DCA administered in the last 2 weeks of the experiment, DCA-induced lesions were found to display immunoreacti vity to anti-c-Jun and anti-c-Fos antibodies, were predominantly basop hilic, and contained very little glycogen relative to surrounding hepa tocytes. In contrast, rates of cell division within TCA-induced altere d hepatic foci and tumors were very high and appeared to be independen t of continued treatment. TCA-induced lesions did not display immunore activity to either c-Jun or c-Fos antibodies. Results from this study suggest that the mechanisms by which DCA and TCA induce hepatocarcinog enesis in the male B6C3F1 mouse differ. (C) 1997 Academic Press.