title: Neoplastic and nonneoplastic liver lesions induced by dimethylnitrosamine in Japanese medaka fish.
abstract: Small fish models have been used for decades in carcinogenicity testing. Demonstration of common morphological changes associated with specific mechanisms is a clear avenue by which data can be compared across divergent phyletic levels. Dimethylnitrosamine, used in rats to model human alcoholic cirrhosis and hepatic neoplasia, is also a potent hepatotoxin and carcinogen in fish. We recently reported some striking differences in the mutagenicity of DMN in lambda cII transgenic medaka fish vs. Big Blue(®) rats, but the pre-neoplastic and neoplastic commonalities between the two models are largely unknown. Here, we focus on these commonalities, with special emphasis on the TGF-β pathway and its corresponding role in DMN-induced hepatic neoplasia. Similar to mammals, hepatocellular necrosis, regeneration, and dysplasia; hepatic stellate cell and "spindle cell" proliferation; hepatocellular and biliary carcinomas; and TGF-β1 expression by dysplastic hepatocytes all occurred in DMN-exposed medaka. Positive TGF-β1 staining increased with increasing DMN exposure in bile preductular epithelial cells, intermediate cells, immature hepatocytes and fewer mature hepatocytes. Muscle specific actin identified hepatic stellate cells in DMN-exposed fish. Additional mechanistic comparisons between animal models at different phyletic levels will continue to facilitate the interspecies extrapolations that are so critical to toxicological risk assessments.
authors: Integrated Laboratory Systems, Research Triangle Park, NC, USA.
authors: K R
authors: KR
authors: Hobbie
authors: A B
authors: AB
authors: DeAngelo
authors: M H
authors: MH
authors: George
authors: J M
authors: JM
authors: Law
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001661:Biliary Tract Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000662:veterinary*; D015415:Biomarkers / Q000378:metabolism; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology / Q000662:veterinary*; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000662:veterinary*; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005393:Fish Diseases / Q000139:chemically induced / Q000473:pathology*; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000662:veterinary*; D008297:Male; D009152:Mutagenicity Tests; D009990:Oryzias; D051381:Rats; D015398:Signal Transduction; D013045:Species Specificity; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D016212:Transforming Growth Factor beta; D004128:Dimethylnitrosamine