Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced tumor promotion by 17 beta-estradiol in female Sprague-Dawley rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatocarcinogen in female but not in male rats. In an initiation-promotion model, ovariectomy inhibits TCDD-induced cell replication and reduces both TCDD-induced tumor formation and the promotion of enzyme-altered hepatocellular foci (AHF). Th e aim of this study was to determine the involvement of the ovarian hormone 17 beta -estradiol in the induction of cell proliferation and development of putative preneoplastic AHF following chronic exposure to TCDD. Diethylni trosamine (DEN)-initiated ovariectomized (OVX) female rats were treated wit h TCDD for 20 or 30 weeks in the presence and absence of 17 beta -estradiol administered continuously by implanted 90-day release pellets. Following 2 0 weeks of treatment, cell proliferation in TCDD-treated rats was decreased regardless of ovarian hormones. Following 30 weeks of exposureTCDD, only s ignificantly induced cell proliferation in OVX rats receiving supplemental 17 beta -estradiol, These data demonstrate that the the transitory mitoinhi bition of cell replication by TCDD is not hormonally responsive, but that i nduction of cell replication at later time paints is. TCDD exposure resulte d in elevated AHF expressing gamma -glutamyltranspeptidase (GGT) in intact, but not OVX rats at both time points. TCDD also induced GGT-positive AHF i n 17 beta -estradiol-supplemented OVX rats. TCDD induced AHF expressing the placental form of glutathione-S-transferase (PGST) in both intact and OVX rats regardless of 17 beta -estradiol exposure, indicating that the modulat ing effect of 17 beta -estradiol on AHF was specific to the GGT-positive ph enotype. (C) 2001 Academic Press diethylnitrosamine; BrdU; 5-bromo-2'-deoxy uridine.