title: Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin.
abstract: The contribution of environmental pollutants to liver fibrosis is an important and poorly explored issue. In vitro studies suggest that the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands induce several genes that are known to be upregulated during liver fibrosis. Our aim was to determine whether exposure to such pollutants can lead to liver fibrosis and to characterize the mechanisms of action. Mice were treated for 2, 14, or 42 days, once a week with 25 µg/kg of TCDD. Gene and protein expression, in vitro and in vivo, as well as liver histology were investigated for each treatment. Treatment of mice with TCDD for 2 weeks modified the hepatic expression of markers of fibrosis such as collagen 1A1 and α-smooth muscle actin. This is not observed in AhR knockout mice. Following 6 weeks of treatment, histological features of murine hepatic fibrosis became apparent. In parallel, the levels of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor α) and of markers of activated fibroblasts(fibroblast-specific protein 1) were found to be upregulated. Interestingly, we also found increased expression of genes of the TGF-β pathway and a concomitant decrease of miR-200a levels. Because the transcription factors of the Snail family were shown to be involved in liver fibrosis, we studied their regulation by TCDD. Two members of the Snail family were increased, whereas their negative targets, the epithelial marker E-cadherin and Claudin 1, were decreased. Further, the expression of mesenchymal markers was increased. Finally, we confirmed that Snai2 is a direct transcriptional target of TCDD in the human hepatocarcinoma cell line, HepG2. The AhR ligand, TCDD, induces hepatic fibrosis by directly regulating profibrotic pathways.
authors.affiliation: * INSERM UMR-S 747, Toxicologie Pharmacologie et Signalisation Cellulaire, Paris, France;
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pierre
authors.forename: Aline
authors.initials: A
authors.lastname: Chevallier
authors.forename: Fatima
authors.initials: F
authors.lastname: Teixeira-Clerc
authors.forename: Ariane
authors.initials: A
authors.lastname: Ambolet-Camoit
authors.forename: Linh-Chi
authors.initials: LC
authors.lastname: Bui
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Bats
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Fournet
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernandez-Salguero
authors.forename: Martine
authors.initials: M
authors.lastname: Aggerbeck
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
authors.forename: Robert
authors.initials: R
authors.lastname: Barouki
authors.forename: Xavier
authors.initials: X
authors.lastname: Coumoul
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004785:Environmental Pollutants; D018836:Inflammation Mediators; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C111235:AHR protein, human; C484722:Ahr protein, mouse; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse
keywords: AhR; dioxin; inflammation.; liver diseases; mice