title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds as antioestrogens: characterization and mechanism of action.
abstract: In the female Sprague-Dawley rat uterus 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds exhibited a broad spectrum of antioestrogenic responses. For example 2,3,7,8-TCDD inhibited the 17 beta-oestradiol-induced uterine wet weight increase, peroxidase activity, oestrogen and progesterone receptor levels, epidermal growth factor (EGF) receptor binding, and EGF receptor and c-fos protooncogene mRNA levels. The aryl hydrocarbon (Ah) receptor was identified in the rat uterus and the antioestrogenic activities of TCDD and related compounds were structure-dependent. In parallel studies, the effects of TCDD as an antioestrogen in MCF-7 human breast cancer cells was also investigated. TCDD inhibited the 17 beta-oestradiol-induced proliferation of these cells and the secretion of the 34-, 52- and 160-kDa proteins. Treatment of MCF-7 cells with 1 nM [3H]-17 beta-oestradiol resulted in a rapid accumulation of nuclear oestrogen receptor (ER) complexes. Pretreatment of the cells with TCDD caused a rapid decrease in nuclear ER binding activity and immunoreactive protein; moreover, the structure-dependent potencies of TCDD and related compounds as antioestrogens were similar to their Ah receptor binding affinities. TCDD also caused a decrease in nuclear ER levels in wild-type Ah-responsive Hepa 1c1c7 cells but was inactive in Ah non-responsive mutant Hepa 1c1c7 cells. Moreover, in the wild-type cells, both actinomycin D and cycloheximide blocked the effects of TCDD. 6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) has previously been characterized as a TCDD antagonist in rodents and in transformed rodent cell lines. However, like TCDD, MCDF also exhibited a broad spectrum of antioestrogenic activities in both the female Sprague-Dawley rat uterus and MCF-7 cells. MCDF is relatively non-toxic compared to TCDD and is being investigated as a compound which may be clinically useful for the treatment of mammary cancer.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A & M University, College Station 77843-4466.
authors.forename: S
authors.initials: S
authors.lastname: Safe
authors.forename: B
authors.initials: B
authors.lastname: Astroff
authors.forename: M
authors.initials: M
authors.lastname: Harris
authors.forename: T
authors.initials: T
authors.lastname: Zacharewski
authors.forename: R
authors.initials: R
authors.lastname: Dickerson
authors.forename: M
authors.initials: M
authors.lastname: Romkes
authors.forename: L
authors.initials: L
authors.lastname: Biegel
mesh_terms: D000818:Animals; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured
chemical_list: D004965:Estrogen Antagonists; D000072317:Polychlorinated Dibenzodioxins