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Neoplastic and nonneoplastic liver lesions induced by dimethylinitrosamine in Japanese Medaka fish
Hobbie, K. R., A. B. DEANGELO, AND M. H. George. Neoplastic and nonneoplastic liver lesions induced by dimethylinitrosamine in Japanese Medaka fish. Veterinary Pathology. American College of Veterinary Pathologists, Middleton, WI, 49(2):372-85, (2012).
Small fish models are becoming commonplace in the laboratory, and have been used for decades in chemical toxicity and carcinogenicity testing. However, extrapolation of findings from aquatic models to humans is still a concern in risk assessment. Demonstration of common morphological changes associated with specific biochemical mechanisms is a clear avenue by which data can be compared across divergent phyletic levels for a given chemical. Dimethylnitrosamine (DMN), used in rats to model human alcoholic cirrhosis and hepatic neoplasia is also a potent hepatotoxin and carcinogen in fish, although the progression of morphological changes associated with DMN exposure is less well characterized than other carcinogens such as diethylnitrosamine. We recently reported some striking differences in the mutagenicity of DMN in lambda ell transgenic medaka fish vs. Big Blue®F344 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-B pathway and its corresponding role in DMN-induced hepatic neoplasia. Hepatocellular necrosis, apoptosis, regeneration, and dysplasia; hepatic stellate cell and "spindle cell" proliferation; hepatocellular and biliary carcinomas; and TGF-B1 expression by dysplastic hepatocytes all resulted in DMN-exposed medaka, but with some important morphological differences from the rat. Mechanistic comparisons between animal models at different phyletic levels will help facilitate the interspecies extrapolations that are so critical to toxicological risk assessments.
Demonstration of common morphological changes associated with specific biochemical mechanisms is a clear avenue by which data can be compared across divergent phyletic levels for a given chemical.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION