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). The 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. Diethylnitrosamine (DEN)-initiated ovariectomized (OVX) female rats were treated with TCDD for 20 or 30 weeks in the presence and absence of 17 beta-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 17 beta-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 gamma-glutamyltranspeptidase (GGT) in intact, but not OVX rats at both time points. TCDD also induced GGT-positive AHF in 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 modulating effect of 17 beta-estradiol on AHF was specific to the GGT-positive phenotype.
Wyde
M E
ME
National Institute of Environmental Health Sciences, Environmental Toxicology Program, Research Triangle Park, North Carolina 22709, USA.
Eldridge
S R
SR
Lucier
G W
GW
Walker
N J
NJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004052:Diethylnitrosamine / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D010052:Ovariectomy; D010920:Placenta / Q000201:enzymology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000032:analysis
D000072317:Polychlorinated Dibenzodioxins; D004052:Diethylnitrosamine; D004958:Estradiol; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase