DESCRIPTION (provided by applicant): There are usually no obvious symptoms of early stage ovarian cancer; therefore, the five-year survival rate for ovarian cancer patients is 44%. The etiology of ovarian cancer is multifactorial and remains largely undefined; therefore, the mechanisms by which this disease progresses to more malignant phenotype are poorly understood. Recent studies have shown that tobacco smoking is associated with cancer of the ovary. The mechanisms that can account for the role of tobacco smoking on this disease remain unknown. In this project we seek to uncover the mechanisms that can account for ovarian carcinogenesis in mice treated with dibenzo[a,l]pyrene (DB[a,l]P); an environmental pollutant and a tobacco smoke constituent. Presence of DNA adducts in tissues exposed to environmental carcinogens is crucial to the initiation of the carcinogenic process, and therefore the detection of DNA adducts derived from cigarette smoke constituents in ovaries may indicate increasing the risk of ovarian cancer. Diol-epoxides derived from polycyclic aromatic hydrocarbons (PAH) can covalently bind to DNA of ovarian cells from human exposed to cigarette smoke. There is ample evidence in the literature that DB[a,l]P, an environmental pollutant and a tobacco smoke component, is the most powerful PAH carcinogen (skin, mammary, lung, and ovary) known to date; its remarkable genotoxicity has been attributed to the sterically hindered fjord region diol epoxides (+)-anti- DB[a,l]PDE. In addition, reactive oxygen species (ROS) derived from redox cycling of o-quinone derived from dihydrodiol metabolite of DB[a,l]P can lead to the formation of the mutagenic lesion, 8-hydroxy-2'- deoxyguanosine (8-oxo-dG). Literature reports and our preliminary results, have shown the induction of ovarian cancer by DB[a,l]P. We also detected DB[a,l]PDE-DNA adducts for the first time in the ovaries of mice treated with DB[a,l]P using our newly developed LC-MS/MS method. However, it remains unknown that whether DB[a,l]P is metabolically activated in ovary of mouse and which DB[a,l]P-induced DNA adducts or damage is/are responsible for its carcinogenicity. We hypothesize that the levels and conformations of the DNA adducts formed, and their removal by mammalian DNA repair enzymes are critical factors involved in the initiation stage of carcinogenesis of DB[a,l]P in ovaries of mice (both covalent adducts and those induced by ROS). We further hypothesize that DB[a,l]P-induced DNA adducts will influence the expression of certain proteins that may be critical in the development of ovarian cancer. In this project, we aim to determine 1. the pharmacokinetic parameters and the tissues distribution of DB[a,l]P, and 2. a. the formation and disappearance of various DNA lesions in the ovary of mice treated with DB[a,l]P (covalent adducts and 8-oxo- dG) as a function of time, b. the optimal dose for DB[a,l]P to induce ovarian cancer more specifically, and c. the effect of DB[a,l]P on molecular markers which are important in human ovarian cancer development.
|Effective start/end date||9/15/13 → 8/31/17|
- National Institute of Environmental Health Sciences: $229,500.00