EARLY EFFECTS IN CHEMICAL-INDUCED RAT-LIVER CARCINOGENESIS - AN IMMUNOHISTOCHEMICAL STUDY FOLLOWING EXPOSURE TO 0.04-PERCENT AAF

To investigate effects that distinguish AAF from incomplete carcinogen s, the rate of cell death (apoptosis) and cell proliferation was studi ed at early stages of AAF induced rat liver carcinogenesis, Male Wista r rats were fed 0.04% AAF in the diet for 2, 6 and 16 weeks and immuno histochemical markers were measured in the liver, The formation of ini tiated cells and preneoplastic foci was followed by staining for GST-P (glutathione-S-transferase). GST-P-positive foci were present from 6 weeks on, Apoptosis was increased in the periportal area and in preneo plastic foci at all time points, Cell proliferation was enhanced in th e periportal area in oval cells and in bile duct-like cells particular ly at 2 and 6 weeks and mainly in GST-P positive foci at 16 weeks. Not ably, more cells always proliferated than were eliminated, Other apopt osis-related markers like p53 and FAS/Apo-1 could not be demonstrated in either normal hepatocytes, preneoplastic foci or in hepatocytes fro m treated animals, Scattered bcl-2 positive cells were present in live rs at 16 weeks of treatment, The two cell growth and differentiation r elated proto-oncogenes c-FOS and c-JUN were increased in all treated a nimals at early stages, If feeding was stopped after 6 weeks, livers d id not recover significantly within the following 10 weeks. The result s support the complex effects of AAF in rat liver carcinogenesis, Chro nic toxicity locally impairs the balance between cell proliferation an d cell death and induces morphological alterations that promote the gr owth of initiated cells.