Anchoring Hepatic Gene Expression with Development of Fibrosis and Neoplasia in a Toxicant-induced Fish Model of Liver Injury. (July 2013)

• Record Type: Journal Article
• Authors: Van Wettere, Arnaud J.; Law, J. Mac; Hinton, David E.; Kullman, Seth W.
• Is Part Of: Toxicologic pathology. Volume 41:Number 5(2013)
• Page Start: 744
• Page End: 760
• Publication Date: 2013-07
• Subjects: dimethylnitrosamine -- liver -- fibrosis -- neoplasia -- medaka -- Oryzias latipes -- gene expression.; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623312464308
• Languages: English
• ISSNs: 0192-6233

Abstract

Fish have been used as laboratory models to study hepatic development and carcinogenesis but not for pathogenesis of hepatic fibrosis. In this study, a dimethylnitrosamine-induced fish model of hepatic injury was developed in Japanese medaka ( Oryzias latipes ) and gene expression was anchored with the development of hepatic fibrosis and neoplasia. Exposed livers exhibited mild hepatocellular degenerative changes 2 weeks' postexposure. Within 6 weeks, hepatic fibrosis/cirrhosis was evident with development of neoplasia by 10 weeks. Stellate cell activation and development of fibrosis was associated with upregulation of transforming growth factor beta 1 ( tgfb1 ), tgfb receptor 2, mothers against decapentaplegic homolog 3 ( smad3a ), smad3b, beta-catenin ( ctnnb1 ), myc, matrix metalloproteinase ( mmp2 ), mmp14a, mmp14b, tissue inhibitors of metalloproteinase ( timp ) 2a, timp2b, timp3, collagen type I alpha 1a ( col1a1a ), and col1a1b and a less pronounced increase in mmp13 and col4a1 expression. Tgfb receptor I expression was unchanged. Immunohistochemistry suggested that biliary epithelial cells and stellate cells were the main producers of TGF-β1. This study identified a group of candidate genes likely to be involved in the development of hepatic fibrosis and demonstrated that the TGF-β pathway likely plays a major role in the pathogenesis. These results support the medaka as a viable fish model of hepatic fibrosis.