Wyde M E, Seely J, Lucier G W, Walker N J
Curriculum in Toxicology, University of North Carolina, Chapel Hill, USA.
Toxicol Sci. 2000 Apr;54(2):493-9. doi: 10.1093/toxsci/54.2.493.
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 of ovarian hormones, presumably estrogen, in the mechanism of TCDD-induced hepatocarcinogenesis. The aim of this current study was to determine the toxicity of co-treatment with TCDD and 17 beta-estradiol and assess the efficacy of 90-day subcutaneous constant release 17 beta-estradiol pellets. Ovariectomized (OVX) female Sprague-Dawley rats were initiated with diethylnitrosamine (DEN) and treated with TCDD for 20 or 30 weeks in the presence and absence 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 higher in OVX rats than in intact rats. TCDD concentrations in livers of TCDD-treated OVX rats receiving supplemental 17 beta-estradiol were similar to intact rats following either 20 or 30 weeks of treatment. Mean hepatic background TCDD concentrations in untreated rats were 2-fold higher in intact rats compared to OVX rats, regardless of 17-estradiol exposure following 20, but not 30 weeks of treatment. Serum indicators of hepatocellular and hepatobiliary 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 beta-estradiol concentrations were not constant and resulted in supra-physiological 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 efficacy of supplemental subcutaneous 17 beta-estradiol pellets on the induction of estrogenic responses in TCDD-treated rats and indicate no increased hepatotoxicity associated with 17 beta-estradiol exposure in TCDD-treated rats.
2,3,7,8-四氯二苯并对二恶英（TCDD）对雌性大鼠是一种强效肝致癌物，而对雄性大鼠则不然。多条证据表明，卵巢激素（可能是雌激素）在TCDD诱导的肝癌发生机制中起关键作用。本研究的目的是确定TCDD与17β-雌二醇联合处理的毒性，并评估90天皮下持续释放17β-雌二醇微丸的效果。对去卵巢（OVX）的雌性斯普拉格-道利大鼠先用二乙基亚硝胺（DEN）启动，然后在有或无17β-雌二醇的情况下用TCDD处理20或30周。处理20周后，TCDD处理的假手术大鼠和OVX大鼠肝脏中的TCDD浓度相当。TCDD处理30周后，OVX大鼠肝脏中的TCDD浓度高于完整大鼠。接受补充17β-雌二醇的TCDD处理的OVX大鼠肝脏中的TCDD浓度在处理20周或30周后与完整大鼠相似。无论在处理20周（而非30周）后是否暴露于17-雌二醇，未处理大鼠肝脏中TCDD的平均背景浓度完整大鼠比OVX大鼠高2倍。肝细胞和肝胆毒性的血清指标表明，接受17β-雌二醇的TCDD处理的OVX大鼠存在短暂肝毒性。组织病理学改变表明，暴露于TCDD 20周或30周后会诱导肝毒性。在暴露于TCDD的OVX雌性斯普拉格-道利大鼠中，补充17β-雌二醇未导致额外的肝毒性。血清17β-雌二醇浓度不稳定，导致超生理水平，且随时间下降，在释放几周后达到目标生理血清17β-雌二醇浓度。用17β-雌二醇处理导致子宫重量和总体重与假手术雌性大鼠相当。这些数据证实了补充皮下17β-雌二醇微丸在TCDD处理大鼠中诱导雌激素反应的效果，并表明在TCDD处理大鼠中，暴露于17β-雌二醇不会增加肝毒性。
