Comparative activities of 2,3,7,8-tetrachlorodibenzo- p-dioxin and progesterone as antiestrogens in the female rat uterus

Abstract

The comparative antiestrogenic effects of progesterone and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) on cytosolic and nuclear estrogen (ER c and ER n, respectively) and progesterone (PR c and PR n, respectively) receptor levels were determined in female Long Evans rats. Estradiol treatment typically increases ER and PR levels in target cells or tissues and these proteins have been proposed as markers of estrogen action. 2,3,7,8-TCDD causes a dose-dependent decrease in uterine ER c, ER n, PR c, and PR n levels which persist up to 7 days. Progesterone treatment caused significant decreases in uterine ER c, ER n, and PR n levels; however, after 7 days, the effects of the hormone on receptor levels were diminished. The effects of 2,3,7,8-TCDD and progesterone on hepatic ER and PR levels were comparable to those observed in the uterus. Treatment of the rats with estradiol (5 μg/kg), estradiol (5 μg/kg) plus progesterone (1 mg/animal), or 2,3,7,8-TCDD (80 μg/kg) showed that both progesterone and 2,3,7,8-TCDD significantly antagonized the estradiol-mediated increases in uterine (and hepatic) ER c, ER n, PR c, and PR n levels and for 2,3,7,8-TCDD the decreased receptor levels persisted for up to 7 days. In vitro studies with freshly isolated uterine strips demonstrated that both 2,3,7,8-TCDD and progesterone antagonized the estradiol-mediated increases in ER and PR levels. Previous studies suggest that the antiestrogenic activity of progesterone is due, in part, to the induction of proteins which are involved in decreasing ER n levels in target cells. Moreover in the uterine strip assay procedure, it was previously shown and reproduced in this study that the decrease in uterine ER n by progesterone was inhibited by both protein and RNA synthesis inhibitors over a 4-hr incubation period. In contrast, the 2,3,7,8-TCDD-mediated decrease in uterine ER n was inhibited only by actinomycin D and not by cycloheximide or puromycin. These in vitro studies thus confirm that both progesterone and 2,3,7,8-TCDD exhibit comparable antiestrogenic effects invivo and in vitro; however, the results suggest that these effects are expressed through different mechanisms.