Role of the Ah receptor in mediating the down regulation of uterine and hepatic estrogen receptor levels in rats

Administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to 21 day old female Long Evans rats resulted in a dose-dependent decrease in uterine and hepatic estrogen receptor (ER) levels. At a dose level of 80 ug/kg of 2,3,7,8-TCDD, uterine and hepatic ER levels were 54 and 41% of values observed in untreated animals. 2,3,7,8-TCDD also antagonized the estrogenicity of estradiol in the 21 day old rat. For example, administration of estradiol (15 ug/kg) resulted in a 194 and 155% increase in cytosolic and uterine ER levels and a 42% increase in uterine wet weight 48 hours after treatment. Pretreatment of the rats with 2,3,7,8-TCDD (80 ug/kg) prior to administration of estradiol (15 ug/kg) completely blocked the estrogenic effects of estradiol. In fact after cotreatment the uterine and hepatic ER levels were 51 and 54% lower than observed in the controls and the uterine wet weight was 20% lower than in the control animals. The comparative effects of 2,3,7,8-TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 1,3,7,8-TCDD and 1,2,4,7,8-PeCDD on the down regulation of uterine and hepatic ER levels were structure-dependent. There was an excellent correlation between the binding affinities of these congeners for the Ah receptor and their activity as antiestrogens and the results support a role for the Ah receptor in the down regulation of uterine and hepatic ER levels in the rat. (Supported by the Texas Agricultural Experiment Station.).