Toxicity of chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in diethylnitrosamine-initiated ovariectomized rats implanted with subcutaneous 17 beta-estradiol pellets

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatocarcinogen in female but not in male rats. Several lines of evidence suggest a key role o f ovarian hormones, presumably estrogen, in the mechanism of TCDD-induced h epatocarcinogenesis. The aim of this current study was to determine the tox icity of co-treatment with TCDD and 17 beta-estradiol and assess the effica cy of 90-day subcutaneous constant release 17 beta-estradiol pellets. Ovari ectomized (OVX) female Sprague-Dawley rats were initiated with diethylnitro samine (DEN) and treated with TCDD for 20 or 30 weeks in the presence and a bsence of 17 beta-estradiol, TCDD concentrations were equivalent in livers of TCDD-treated sham operated and OVX rats following 20 weeks of treatment. Following 30 weeks of TCDD treatment, liver TCDD concentrations were highe r in OVX rats than in intact rats. TCDD concentrations in livers of TCDD-tr eated OVX rats receiving supplemental 17 beta-estradiol were similar to int act rats following either 20 or 30 weeks of treatment. Mean hepatic backgro und TCDD concentrations in untreated rats were 2-fold higher in intact rats compared to OVX rats, regardless of 17 beta-estradiol exposure following 2 0, but not 30 weeks of treatment. Serum indicators of hepatocellular and he patobiliary toxicity indicated transient hepatotoxicity in TCDD-treated OVX rats receiving 17 beta-estradiol. Histopathological alterations indicated hepatotoxicity induced by exposure to TCDD following either 20 or 30 weeks of exposure. No excess hepatotoxicity was associated with 17 beta-estradiol -supplementation in TCDD-exposed OVX female Sprague-Dawley rats. Serum 17 b eta-estradiol concentrations were not constant and resulted in supra-physio logical levels that decreased over time, resulting in target physiological serum 17 beta-estradiol concentrations following several weeks of release. Treatment with 17 beta-estradiol resulted in uterine weights and total body weights comparable to sham-operated female rats. These data confirm the ef ficacy of supplemental subcutaneous 17 beta-estradiol pellets on the induct ion of estrogenic responses in TCDD-treated rats and indicate no increased hepatotoxicity associated with 17 beta-estradiol exposure in TCDD-treated r ats.