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Article Dans Une Revue Toxicological Sciences Année : 2013

Aryl Hydrocarbon Receptor-Dependent Induction of Liver Fibrosis by Dioxin

Résumé

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 up-regulated 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 25µg/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-1α1 and α-smooth-muscle-actin. Following 6-weeks of treatment, histological features of murine hepatic fibrosis became apparent. In parallel, the levels of inflammatory cytokines(interleurkin-1-beta, tumor-necrosis-factor-α) and of markers of activated fibroblasts(Fibroblast-Specific-Protein1) were found to be up-regulated. Interestingly, we also found increased expression of genes of the TGFß pathway and a concomitant decrease of miR-200a levels. Since 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 Claudin1, were decreased. Further, the expression of mesenchymal markers were 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 pro-fibrotic pathways.

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Dates et versions

hal-02195641 , version 1 (26-07-2019)

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Stéphane Pierre, Aline Chevallier, Fatima Teixeira-Cler, Ariane Ambolet-Camoit, Linh-Chi Bui, et al.. Aryl Hydrocarbon Receptor-Dependent Induction of Liver Fibrosis by Dioxin. Toxicological Sciences, 2013, 137 (1), pp.114-124. ⟨10.1093/toxsci/kft236⟩. ⟨hal-02195641⟩
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