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-Sp1 enhancer sequence of this gene.
D000444:Aldehyde Dehydrogenase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology; D002402:Cathepsin D / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D005982:Glutathione Transferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D002402:Cathepsin D