ANTIESTROGENIC EFFECTS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ARE MEDIATED BY DIRECT TRANSCRIPTIONAL INTERFERENCE WITH THE LIGANDED ESTROGEN-RECEPTOR - CROSS-TALK BETWEEN ARYL HYDROCARBON-MEDIATED AND ESTROGEN-MEDIATED SIGNALING

Aryl hydrocarbon receptor (AhR) ligands have diverse biological effect s including striking antiestrogenic activity. We have investigated at the molecular level the antiestrogenic activity of 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD). We show that the previously documented TCDD-m ediated decrease in estradiol-inducible gene products such as cathepsi n D (cat D) is due to a sharp decline in mRNA accumulation despite any change in estrogen receptor (ER) mRNA levels. The decline in cat D mR NA level is most likely due to a decrease in transcription of the cat D gene since TCDD blocks the ability of ER to transactivate from an es trogen response element. AhR is required for this activity as TCDD is no longer antiestrogenic in a mutant cell line that is deficient in fu nctional AhR. We provide evidence that the loss of transactivation pot ential by ER in the presence of TCDD is due to a sharp decrease in its ability to bind to an estrogen response element. Reciprocally, estrad iol treatment blocked TCDD-induced accumulation of CYP1A1 mRNA and AhR -mediated activation of the CYP1A1 promoter. This is due to the abilit y of liganded ER to interfere with the binding of AhR to the xenobioti c response element. These results provide a molecular mechanism for th e antiestrogenic effects of TCDD and demonstrate the presence of a two -way crosstalk between the intracellular signaling pathways involving estrogens and aryl hydrocarbons.