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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA044306-01
Application #
3186859
Study Section
(SRC)
Project Start
1986-09-30
Project End
1990-08-31
Budget Start
1986-09-30
Budget End
1987-08-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Woods Hole Oceanographic Institution
Department
Type
Graduate Schools
DUNS #
001766682
City
Woods Hole
State
MA
Country
United States
Zip Code
02543
Kloepper-Sams, P J; Stegeman, J J (1994) Turnover of hepatic microsomal cytochrome P4501A protein and heme in beta-naphthoflavone-induced Fundulus heteroclitus. Mol Mar Biol Biotechnol 3:171-83
Koza, R A; Moore, M J; Stegeman, J J (1993) Elevated ornithine decarboxylase activity, polyamines and cell proliferation in neoplastic and vacuolated liver cells of winter flounder (Pleuronectes americanus) Carcinogenesis 14:399-405
Kloepper-Sams, P J; Stegeman, J J (1992) Effects of temperature acclimation on the expression of hepatic cytochrome P4501A mRNA and protein in the fish Fundulus heteroclitus. Arch Biochem Biophys 299:38-46
Day, B W; Naylor, S; Gan, L S et al. (1991) Gas chromatographic-mass spectrometric analysis of diols and tetrols from reactions of polycyclic aromatic hydrocarbon epoxides with hemoglobin. J Chromatogr 562:563-71
Gray, E S; Woodin, B R; Stegeman, J J (1991) Sex differences in hepatic monooxygenases in winter flounder (Pseudopleuronectes americanus) and scup (Stenotomus chrysops) and regulation of P450 forms by estradiol. J Exp Zool 259:330-42
Stegeman, J J; Smolowitz, R M; Hahn, M E (1991) Immunohistochemical localization of environmentally induced cytochrome P450IA1 in multiple organs of the marine teleost Stenotomus chrysops (Scup). Toxicol Appl Pharmacol 110:486-504
Smolowitz, R M; Hahn, M E; Stegeman, J J (1991) Immunohistochemical localization of cytochrome P-450IA1 induced by 3,3',4,4'-tetrachlorobiphenyl and by 2,3,7,8-tetrachlorodibenzoafuran in liver and extrahepatic tissues of the teleost Stenotomus chrysops (scup). Drug Metab Dispos 19:113-23
Stegeman, J J; Lech, J J (1991) Cytochrome P-450 monooxygenase systems in aquatic species: carcinogen metabolism and biomarkers for carcinogen and pollutant exposure. Environ Health Perspect 90:101-9
Stegeman, J J; Woodin, B R; Smolowitz, R M (1990) Structure, function and regulation of cytochrome P-450 forms in fish. Biochem Soc Trans 18:19-21
McMahon, G; Huber, L J; Moore, M J et al. (1990) Mutations in c-Ki-ras oncogenes in diseased livers of winter flounder from Boston Harbor. Proc Natl Acad Sci U S A 87:841-5

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