MODULATION OF GENE-EXPRESSION AND ENDOCRINE RESPONSE PATHWAYS BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN AND RELATED-COMPOUNDS

The aryl hydrocarbon (Ah) receptor binds several different structural classes of chemicals, including halogenated aromatics, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polynuclear aromatic and heteropolynuclear aromatic hydrocarbons. TCDD induces expression of several genes including CYP1A1, and molecular biology studies show that the Ah receptor acts as a nuclear ligand-induced transcription factor that interacts with xenobiotic or dioxin responsive elements located in 5'-flanking regions of responsive genes. TCDD also elicits diverse toxic effects, modulates endocrine pathways and inhibits a broad spectrum of estrogen (17 beta-estradiol)-induced responses in rodents and human breast cancer cell lines. Molecular biology studies show that TCDD inhibited 17 beta-estradiol-induced cathepsin D gene expression by targeted interaction of the nuclear Ah receptor with imperfect dioxin responsive elements strategically located within the estrogen receptor- Spl enhancer sequence of this gene.