Epizootic hepatic tumors occur in the flatfish winter flounder (Pseudopleuronectes americanus) in Boston Harbor. This disease is associated with locally high levels of carcinogenic polynuclear aromatic hydrocarbons (PAH) suggesting a hypothesis that these compounds are involved in the origin of these tumors. The objective is to examine fundamental aspects of the biochemistry and molecular biology associated with environmental tumorigenesis in these fish. 1). We will examine the regiospecificity and stereospecificity of bioactivation and metabolism of highly prevalent PAR carcinogenes benzo(a)pyrene and fluoranthene in the environment of winter flounder, and establish the nature of the primary catalyst. 2). We will evaluate the function of glutathione S-transferase activity and the levels of glutathione as related to the function of cytochrome P-450 in carcinogen activation and detoxication. 3). We will identify and quantify carcinogen adducts to DNA in target and non-target organs and determine the rates of hepatic DNA repair in vivo by analysis of DNA adduct persistence using and post-labelling methods. 4). We will establish the occurrence and identity of carcinogen adducts to the blood proteins serum albumin and hemoglobin, and to develop methods for the detection of those adducts in feral fish. 5). We will evaluate the occurrence of oncogenes in winter flounder tissues and evaluate ocogene activation by identifying and analyzing sequences in flounder tumor DNA capable of transforming NIH-3T3 fibroblasts, and by analyzing expression of oncogene proteins by immunoblotting. The levels of DNA and protein adducts will be correlated and the influence of environmental and biological variables on the use of these adducts in dosimetry in further studies of the etiology of environmental neoplasms will be evaluated. Subsequent studies will compare experimental results with those in populations afflicted or not afflicted with neoplasms. This combined effort will provide a unified picture of the mechanisms and biological markers associated with initiation and progression of a neoplastic disease of epidemic proportions.
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