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- and estrogen-mediated signaling.
Aryl hydrocarbon receptor (AhR) ligands have diverse biological effects including striking antiestrogenic activity. We have investigated at the molecular level the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We show that the previously documented TCDD-mediated decrease in estradiol-inducible gene products such as cathepsin 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 mRNA 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 estrogen response element. AhR is required for this activity as TCDD is no longer antiestrogenic in a mutant cell line that is deficient in functional AhR. We provide evidence that the loss of transactivation potential by ER in the presence of TCDD is due to a sharp decrease in its ability to bind to an estrogen response element. Reciprocally, estradiol treatment blocked TCDD-induced accumulation of CYP1A1 mRNA and AhR-mediated activation of the CYP1A1 promoter. This is due to the ability of liganded ER to interfere with the binding of AhR to the xenobiotic response element. These results provide a molecular mechanism for the antiestrogenic effects of TCDD and demonstrate the presence of a two-way crosstalk between the intracellular signaling pathways involving estrogens and aryl hydrocarbons.
Kharat
I
I
Molecular Biology Laboratory, Maharishi International University, Fairfield, Iowa 52557, USA.
Saatcioglu
F
F
D002402:Cathepsin D / Q000235:genetics; D002460:Cell Line; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism; D006838:Hydrocarbons / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004965:Estrogen Antagonists; D004967:Estrogens; D006838:Hydrocarbons; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D002402:Cathepsin D