期刊
TOXICOLOGICAL SCIENCES
卷 137, 期 1, 页码 114-124出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kft236
关键词
dioxin; mice; AhR; liver diseases; inflammation
类别
资金
- Agence Nationale de Securite Sanitaire, de l'alimentation, de l'environnement et du travail
- Agence Nationale de la Recherche [06SEST26]
- Association pour la Recherche sur le Cancer [3927, SFI20101201842]
- Centre National de la recherche scientifique
- Fondation pour la Recherche Medicale
- Institut National du Cancer (Hepatodiox)
- Institut National de la Sante et de la Recherche Medicale
- Ligue contre le Cancer
- Ministere de l'enseignement superieur et de la recherche
- Region Ile de France
- Universite Paris Descartes - Paris Sorbonne Cite
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 g/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 -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 ) 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- 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.
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