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MECHANISMS OF DMN-INDUCED HEPATIC PRENEOPLASIA IN MEDAKA
Citation:
HOBBIE, K., A. B. DEANGELO, AND J. M. LAW. MECHANISMS OF DMN-INDUCED HEPATIC PRENEOPLASIA IN MEDAKA. Presented at Aquatic Animal Models of Human Disease, Athens, GA, October 30 - November 02, 2005.
Description:
Dimethylnitrosamine (DMN), a known carcinogen and hepatotoxin, is capable of inducing tumors in a variety of tissues and is used in a rodent model of human alcoholic cirrhosis. DMN's active metabolite, methyldiazonium ion, forms DNA adducts such as O6-methylguanine (O6-meG), to yield GC->AT transition mutations. Transforming growth factor-(ß1(TGF-(ß1), and its cell signaling proteins, SMADs, have been associated with both hepatic neoplasia and fibrosis in humans and rodents. Liver injury induces hepatic stellate cells (HSC) to transdifferentiate to myofibroblast-like cells due to reactive oxygen intermediates and other cellular mediators. Activation of TGF-(ß1 and SMAD proteins stimulate the transdifferentiated hepatic stellate cells to produce collagen, type I. TGF-ßl also has tumor suppressor activity through growth inhibition and induction of apoptosis in hepatocytes. Mutations in TGF-ß1 and/or SMAD(s) have been associated with hepatocellular carcinomas (HCC). The role of TGF-ß1 as a profibrotic cytokine and tumor suppressor protein has been documented in humans and rodents, and DMN-associated hepatic lesions in rodents are TGF-ß1 dependent. DMN is also a potent hepatotoxin and carcinogen in fish and is associated with hepatocellular necrosis and hepatocellular carcinoma. Mutagenesis studies in DMN-exposed medaka have demonstrated lesions in DNA similar to those seen in rodents exposed to DMN, but the mechanisms by which morphologic changes occur in the liver are not known. In the current study, we exposed 3-month-old medaka to 0, 10, 50, 100 or 200 ppm DMN for 28 days in the ambient water, followed by grow-out in clean water with intermittent sacrifices for histopathology and immunohistochemistry. Results in the liver included: necrosis, apoptosis, regeneration, and dysplasia of hepatocytes, as well as proliferation of hepatic stellate cells, proliferation of pluripotential bile preductular cells, and evidence of fibrogenesis. We hypothesize that the DMN ¬associated morphologic changes seen microscopically in the liver of medaka are associated with activation of TGF-ß1.