Regulation of 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Tumor Promotion by 17β-Estradiol in Female Sprague–Dawley Rats
详细信息 查看全文
文摘
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). The aim of this study was to determine the involvement of the ovarian hormone 17β-estradiol in the induction of cell proliferation and development of putative preneoplastic AHF following chronic exposure to TCDD. Diethylnitrosamine (DEN)-initiated ovariectomized (OVX) female rats were treated with TCDD for 20 or 30 weeks in the presence and absence of 17β-estradiol administered continuously by implanted 90-day release pellets. Following 20 weeks of treatment, cell proliferation in TCDD-treated rats was decreased regardless of ovarian hormones. Following 30 weeks of exposureTCDD, only significantly induced cell proliferation in OVX rats receiving supplemental 17β-estradiol. These data demonstrate that the the transitory mitoinhibition of cell replication by TCDD is not hormonally responsive, but that induction of cell replication at later time points is. TCDD exposure resulted in elevated AHF expressing γ-glutamyltranspeptidase (GGT) in intact, but not OVX rats at both time points. TCDD also induced GGT-positive AHF in 17β-estradiol-supplemented OVX rats. TCDD induced AHF expressing the placental form of glutathione-S-transferase (PGST) in both intact and OVX rats regardless of 17β-estradiol exposure, indicating that the modulating effect of 17β-estradiol on AHF was specific to the GGT-positive phenotype.