DIFFERENCES IN KINETICS OF INDUCTION AND REVERSIBILITY OF TCDD-INDUCED CHANGES IN CELL-PROLIFERATION AND CYP1A1 EXPRESSION IN FEMALE SPRAGUE-DAWLEY RAT-LIVER

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent tumor promoter in two-stage initiation-promotion models and induces cell proliferatio n and development of enzyme-altered hepatic foci, It is believed that increased cell proliferation is a necessary step in carcinogenesis, Th erefore, the analysis of the effect of TCDD on cell proliferation in r at liver may aid in the understanding of the mechanism of hepatocarcin ogenesis induced by TCDD, The aim of this study was to investigate the time course and reversibility of cell proliferation in non-initiated and diethylnitrosamine-initiated female rats exposed biweekly to a dai ly averaged dose of 125 ng TCDD/kg/day for up to 60 weeks. In addition we evaluated the suitability of different dose metrics for the evalua tion of TCDD-induced changes in cell proliferation and CYP1A1 enzyme i nduction. Cell proliferation was measured as the incorporation of 5-br omo-2' -deoxyuridine (BrdU) into hepatocytes undergoing replicative DN A synthesis. Mean BrdU labeling indices in TCDD-treated animals were n ot increased over controls after 14 weeks exposure, but were increased 8- and 2-fold after 30 and 60 weeks) treatment respectively, despite similar liver levels of TCDD at all these times (23-30 p.p.b.). In com parison, CYP1A1 activity, as measured by ethoxyresorufin deethylase ac tivity, was significantly induced at all times points analyzed. Sixtee n weeks following cessation of TCDD treatment, labeling indices were s till significantly elevated over controls, but after 30 weeks of withd rawal, labeling indices were no different from controls, indicating th at TCDD-induced changes in cell proliferation were reversible. Dosimet ric analysis indicated that rat liver tissue burden was suitable for p rediction of CYP1A1 expression but not cell proliferation and that the area under the curve was unsuitable for prediction of both TCDD-induc ed changes in CYP1A1 expression and cell proliferation.