Anchoring Hepatic Gene Expression with Development of Fibrosis and Neoplasia in a Toxicant-induced Fish Model of Liver Injury

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.