title: Dioxin toxicity in vivo results from an increase in the dioxin-independent transcriptional activity of the aryl hydrocarbon receptor.
abstract: The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins--widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function.
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, East Sussex, United Kingdom.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Céspedes
authors.forename: Maximo Ibo
authors.initials: MI
authors.lastname: Galindo
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Couso
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity; D005123:Eye / Q000378:metabolism / Q000648:ultrastructure; D005124:Eye Abnormalities / Q000139:chemically induced / Q000235:genetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D009154:Mutation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic
chemical_list: D004147:Dioxins; D029721:Drosophila Proteins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C112211:ss protein, Drosophila; C109766:tgo protein, Drosophila; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D049452:Green Fluorescent Proteins