Administration of a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 20 or 80 μg/kg) resulted in significantly decreased hepatic and uterine estrogen receptor (ER) levels in 25-day-old female Long-Evans rats. By contrast, estradiol (5 and 15 μg/kg) administration increased hepatic and uterine ER levels, while a combination of 2,3,7,8-TCDD plus estradiol resulted in uterine and hepatic ER levels which were similar or lower than those observed after treatment with only 2,3,7,8-TCDD. In addition, 2,3,7,8-TCDD significantly decreased the effects of estradiol on uterine wet weight increase. Competitive binding studies showed that estradiol did not bind to the aryl hydrocarbon (Ah) receptor and that 2,3,7,8-TCDD did not bind to the ER. The effects of structure on the activity of polychlorinated dibenzo-p-dioxin congeners on their activity to down-regulate hepatic and uterine ER levels were determined by using 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. Both 2,3,7,8-TCDD and 1,2,3,7,8-PeCDD exhibit high affinities for the Ah receptor and at dose levels of 80 μg/kg the hepatic ER levels were decreased 42 and 41%, respectively, and uterine ER levels were decreased 53 and 49%, respectively. 1,3,7,8-TCDD and 1,2,4,7,8-PeCDD bind less avidly to the Ah receptor and at dose levels of 400 μg/kg these compounds decreased hepatic ER levels 36 and 40%, respectively, and uterine ER levels 21 and 24%, respectively. These results support a role for the Ah receptor in the down-regulation of uterine and hepatic ER levels in the female rat by 2,3,7,8-TCDD and this effect may be associated with the decrease in spontaneous mammary and uterine tumors observed in female rats treated with 2,3,7,8-TCDD.
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