ONCOGENE EXPRESSION IN HEPATOCYTES OF THE FISH RIVULUS-OCELLATUS MARMORATUS DURING THE NECROTIC AND REGENERATIVE PHASES OF DIETHYLNITROSAMINE TOXICITY

Livers of mangrove rivulus (Rivulus ocellatus marmoratus) were examine d after an acutely necrogenic dose of diethylnitrosamine (DEN). Immuno histochemical detection of oncoproteins and bromodeoxyuridine (BrdU), enzyme histochemical detection of gamma-glutamyltranspeptidase, and hi stological stains were used in an attempt to separate changes in proto oncogene expression related to hepatic regeneration from those changes that were putatively preneoplastic. Perivenous hepatocytes were round ed and shrunken within 3 days of the beginning of DEN exposure, and wi despread necrosis and hepatocyte proliferation occurred by 21 days (th e last day of DEN exposure). Twenty-four days after the end of DEN exp osure, livers were primarily composed of nodules of regenerated hepato cytes. Epidermal growth factor receptor expression in hepatocytes incr eased in inflamed areas and then returned to control levels as inflamm ation subsided. Increased expression of Fos, Ras and Myc occurred prio r to necrosis in a zonal and chronological progression consistent with regeneration of hepatocytes. Fos, pas, Myc and p53 expression persist ed in scattered cells and foci for 24 days after the end of DEN exposu re, and this expression was at levels higher than during normal cell-c ycle progression. The spatial pattern and persistence of cells express ing Fos, Ras, Myc and p53 at high levels may have represented preneopl astic changes.