EFFECTS OF 2,3,7,8-TETRACHLORO-P-DIOXIN AND 1,2,3,4,6,7,8-HEPTACHLORODIBENZO-P-DIOXIN ON THE PROLIFERATION OF PRENEOPLASTIC LIVER-CELLS IN THE RAT

Using an initiation - promotion system, enzyme-altered putative preneo plastic liver foci were induced in female Wistar rats by application o f diethylnitrosamine (10 mg/kg/day) for 5 days, followed by bi-weekly treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; correspondin g to 100 ng/kg/day) or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HCDD ; corresponding to 5 mu g/kg/day) for up to 17 weeks. Groups of animal s were killed at various time intervals after start of promoter treatm ent. For evaluation of DNA synthesis, 5-bromo-2'-deoxyuridine was admi nistered 24 h prior to killing the animals. Quantitative analysis of t he number and volume fraction of adenosine-triphosphatase-deficient li ver foci revealed that the promoting activity of both dioxins was roug hly comparable under the experimental conditions employed. Nuclear lab elling indices (LIs) of normal hepatocytes were not altered by TCDD or HCDD treatment, while a slight increase in LIs of non-parenchymal liv er cells was observed. Using an immunohistochemical double-staining te chnique, hepatocytes within glutathione-transferase P-positive liver f oci were found to show an approximately 5-to 10-fold higher LI than no rmal hepatocytes throughout all periods of investigation. During the t ime course of the experiment, LIs of foci from all treatment groups de creased with time. However, in TCDD-treated rats, and less pronounced in HCDD-treated rats, the initially high rate of proliferation persist ed for a greater length of time than in non-dioxin-treated control ani mals. Assignment of liver foci into four transection size classes reve aled that LIs in larger size classes varied considerably, indicating h eterogeneity ire the growth behaviour of individual liver lesions. Ove rall, both dioxins had no effects on the proliferation of normal hepat ocytes, while LIs of enzyme-altered liver lesions were slightly enhanc ed by treatment with TCDD or HCDD. Whether the selective, albeit moder ate increase in the proliferation of enzyme-altered liver cells is suf ficient to explain the promoting activity of dioxins, or if additional factors (e.g. decrease in death rates of foci cells) are equally impo rtant, remains to be determined in further experiments.