Comparative Metabolism of Unsubstituted and Methylated Polynuclear Aromatic Hydrocarbons by FishEPA Grant Number: R823874
Title: Comparative Metabolism of Unsubstituted and Methylated Polynuclear Aromatic Hydrocarbons by Fish
Investigators: Sikka, Harish C. , Kumar, Subodh , Maccubbin, Alexander
Institution: The State University of New York at Buffalo
EPA Project Officer: Manty, Dale
Project Period: October 1, 1995 through September 1, 1998
Project Amount: $400,672
RFA: Exploratory Research - Environmental Biology (1995) RFA Text | Recipients Lists
Research Category: Biology/Life Sciences , Health , Ecosystems
Description:Methylated polynuclear aromatic hydrocarbons (methylated PAHs) are commonly occurring environmental contaminants. They are often more carcinogenic than the parent compound and their carcinogenic activity varies with the position of the methyl substituent in the aromatic nucleus. Fish are capable of converting PAHs to carcinogenic metabolites which may have long-term adverse effects on not only fish but humans if they ingest residues of PAHs and/or their toxic metabolites present in edible tissues of fish from contaminated areas. Thus, information on the metabolism of methylated PAHs in fish is important for assessing: (a) the carcinogenic potential of these chemicals in fish, and (b) the risks to humans who may consume fish captured from contaminated areas.
In order to obtain information on the pathways involved in the metabolic activation and detoxification of methylated PAHs in fish, the highly carcinogenic 5-methylchrysene (5-MeC) has been selected as a model compound. Parallel studies on metabolism of the weakly carcinogenic parent hydrocarbon chrysene are also proposed in order to assess the affect of a non-benzo-ring, bay-region methyl substituent on the various reactions involved in the metabolism of the parent PAH by fish and on the persistence of PAH-DNA adducts.
The specific aims of the proposed research are: (1) To examine the in vitro metabolism of chrysene and 5-MeC and their corresponding 1R,2R-dihydrodiols by liver microsomes of brown bullhead (Ameiurus nebulosus) (a fish species known to be susceptible to the carcinogenic action of PAHs) with regard to the rates of metabolism, metabolite profile, and stereoselectivity; (2) To investigate the metabolism of chrysene 1R,2R-diol and 5-MeC-1R,2R-diol by freshly isolated brown bullhead hepatocytes with special reference to the relative extents of competing activation and detoxification reactions which the two chemicals may undergo; (3) To assess the formation and persistence of chrysene/5-MeC-1R,2S-diol-3S,4R-epoxide-DNA adducts in brown bullhead liver in vivo; and (4) To compare the data on the metabolism of 5-MeC by brown bullhead with those reported for rodents.
The proposed research is expected to provide basic information: (1) on the pathways by which methylated PAHs are metabolized by fish, and (2) on the influence of the non benzo-ring bay region methyl substituent on the metabolism of the parent PAHs by fish. We expect that such information will be useful in predicting the types of biotransformation reactions which may occur in fish with other similarly substituted methylated PAHs. This predictive capability will be useful in assessing the potential hazard that PAHs substituted with a non benzo-region methyl group may present to fish and to humans who consume fish collected from areas contaminated with these chemicals.