Specific Aims: Polynuclear aromatic hydrocarbons (PAHs) are a class of prominent environmental pollutants. Exposure to PAH has been associated with cancers. The carcinogenic effect of PAH is thought to derive from its ability to form DNA adducts following bio-activation. If these adducts persist in cells, they are potentially toxic, mutagenic, and carcinogenic. These DNA adducts are normally removed by DNA repair. Thus, DNA repair constitutes an important defense system against PAH damage. However, under certain circumstances, some DNA damage will be left un-repaired in the genome, leading to toxicity, mutation, or eventual carcinogenic transformation. Extensive studies have yielded considerable information on the metabolic activation of PAHs and the DNA adducts produced by the ultimate carcinogens of PAHs. In contrast, relatively little is known about the repair of PAH adducts in DNA, especially how efficiently various PAIl adducts are repaired. The repair efficiency of a given PAH adduct may be an important contributor to the toxic and carcinogenic potential of the compound. Accordingly, my long-term objectives are to gain some insights into the mechanism of PAIl toxicity and carcinogenicity by studying their repair and to understand how these PAIl adducts in DNA are repaired by human cells. To achieve these long-term goals, my specific aims are the following. I. To examine the ability of human cells to repair DNA damage caused by several PAHs, using a human cell-free DNA repair system.4 II. To determine the repair mechanism responsible for the removal of the PAH adducts. III. To determine the repair efficiencies of various PAIl adducts. IV. To correlate the DNA repair capacity of each PAIl with its toxicity and mutagenicity, such that the hypothesis that DNA repair is an important determinant to PAH toxicity and mutagenicity will be tested. The PAH that will be studied in this proposal are benzo{a}pyrene, benz{a}anthrascene, benzo{b}flouranthene, and chrysene.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31ES005796-02
Application #
2770724
Study Section
Special Emphasis Panel (ZRG2-PSF (02))
Project Start
1998-09-01
Project End
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506