MOLECULAR MECHANISMS OF CARCINOGENESIS IN FERAL FISH

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Close to 100% of older Hudson River tomcod exhibit histologically defined hepatocellular carcinomas, whereas this condition is absent in tomcod from a clean waterway environment. The etiology of neoplasia in these fishes is unknown. However, the Hudson River has historically been subject to elevated levels of environmental insult with a multitude of known mammalian carcinogens. Increased knowledge of carcinogenesis in fishes has the potential to increase our understanding of the process of cancer induction in all vertebrates, and may result in the description of alternate species suitable for carcinogenesis testing. While other workers have addressed the environmental origin of carcinogenesis in feral fish populations, investigations on the genetic aspects of neoplasia in these organisms are lacking. This study will evaluate molecular genetic mechanisms in the carcinogenic process in Hudson River tomcod. Specifically, we will determine if Hudson River tomcod constitute a separate population with either a genetically programmed predisposition to neoplasia or increased sensitivity to environmental carcinogens. This will be accomplished through the use of mitochondrial DNA analysis and determination of tumor incidence in fish from each population exposed to clean or Hudson River environments. In addition, we will explore the potential activation of both known and novel fish oncogenes in Hudson River tomcod. This approach will involve a series of transfections of tomcod DNA into NIH3T3 cells and use of the nude mouse co-transfection assay. Transformed cells will be assayed for exogenous fish DNA sequences and oncogenes identified by use of Southern blot hybridization. Activated oncogenes will be characterized with respect to their mechanisms of activation and novel oncogenes will be cloned and characterized.