Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on estrogenic responses

Abstract

The competitive receptor binding affinities of thirteen 2- substituted-3,7,8-trichlorodibenzo-p-dioxins to hepatic cytosol from rat, mouse, guinea pig and hamster were determined using [3H]- 2,3,7,8-tetrachlorodibenzo-p-dioxin (2 ,3 ,7 ,8 -TCDD) as the radio-ligand. Significant species-dependent structural differences in the Ah receptor ligand binding site were observed and support the heterologous nature of the receptor protein. The interactions of 2,3,7,8-TCDD and estrogenic responses in the female rat and human breast cancer cells were also investigated. Cotreatment of 25-day-old female Long Evans rats with 20 or 80 ug/kg of 2,3,7,8-TCDD resulted in a dose-dependent decrease in both uterine and hepatic estrogen receptor (ER) levels. Moreover, these levels are decreased for at least ten days and appear to be related to the tissue persistence of 2,3,7,8-TCDD. In contrast, estradiol (15 ug/kg) elevated uterine and hepatic ER levels and increased uterine wet weights. Cotreatment of the rats with 2 ,3 ,7 ,8 -TCDD and estradiol resulted in hepatic and uterine ER levels which were comparable to those observed in the control rats; in addition, 2 ,3 ,7 ,8-TCDD also antagonized the effects of estradiol-induced uterine wet weights. Subsequent studies showed that 2,3,7,8-TCDD causes a persistent and dose-dependent decrease in cytosolic and nuclear ER and progesterone receptor (PR) levels. Similar results were obtained when examining the effects of 2,3,7,8-TCDD on ERn in MCF-7 human breast cancer cells. Like progesterone, 2,3,7,8-TCDD also decreased ER[n] levels in estrogen-treated rat uterine strips in vitro : however this decrease was inhibited by actinomycin D but not by cycloheximide or puromycin. The specificity of this inhibition by the RNA polymerase inhibitor, actinomycin D, is not understood. These results indicate some similarities and differences in the antiestrogenic activities of progesterone and 2,3,7,8-TCDD; data from the in vitro studies suggest that the activities of the non-steroidal and steroidal antiestrogens are expressed through different mechanisms. Evidence supporting the role of the Ah receptor in mediating these antiestrogenic effects was obtained with quantitative structure activity relationship (QSAR) studies and experiments utilizing 6- m ethyl-1,3,8-trichlorodibenzofuran (MCDF). Induced estradiol metabolism does not appear to significantly contribute to the antiestrogenicity of 2,3,7,8-TCDD.