title: Induction of ovarian cancer and DNA adducts by Dibenzo[a,l]pyrene in the mouse.
abstract: Tobacco smoking is an etiological factor of ovarian cacner; however, the mechanisms remain largely undefined. Therefore, as an initial investigation, we examined the carcinogenicity and DNA adducts formation in the ovary of mice treated with DB[a,l]P, a tobacco smoke constituent and environmental pollutant. Ovarian tumors in B6C3F1 mice were induced by direct application of DB[a,l]P (24, 12, 6, and 3 nmol/mouse, three times a week for 38 weeks) into the oral cavity of mice. At 6 nmol, DB[a,l]P induced the highest total ovarian tumor incidence (79%), but the incidence of malignancy was only 15%. However, at the dose of 12 nmol, the total ovarian tumor incidence was 75%, and the incidence of malignancy was 65%. In addition to ovarian tumors, at the dose of 24 nmol, DB[a,l]P induced lesions in sites distal from the ovaries including the skin, mammary, lung, and oral tissues, which were rare at doses lower than 24 nmol. Another bioassay was conducted to detect and quantify DNA adducts induced by DB[a,l]P (24 nmol, three times a week for 5 weeks) in the ovary at 48 h and 1, 2, and 4 weeks after the last administration of DB[a,l]P. DNA was isolated, and the dibenzo[a,l]pyrene-11,12-dihydrodiol-13,14-epoxide (DB[a,l]PDE)-DNA adducts were analyzed by a LC-MS/MS method. DB[a,l]P resulted in the formation of (-)-anti-cis-DB[a,l]PDE-dA and (-)-anti-trans-DB[a,l]PDE-dA adducts, which were 0.8 and 1.6 fmol/10(6) dA, respectively, in ovaries of mice within 48 h, and the level of adducts decreased over a week. Our results indicated that DB[a,l]P can be metabolized to form (-)-anti-DB[a,l]PDE; the latter may, in part, account for DB[a,l]P-induced ovarian cancer. This animal model should assist to better understand the mechanisms, account for the induction of ovarian cancer by tobacco carcinogens, and facilitate the development of chemopreventive agents against ovarian cancer.
authors: Department of Biochemistry and Molecular Biology, Penn State College of Medicine , Hershey, Pennsylvania 17033, United States. kzc3@psu.edu
authors: Kun-Ming
authors: KM
authors: Chen
authors: Shang-Min
authors: SM
authors: Zhang
authors: Cesar
authors: C
authors: Aliaga
authors: Yuan-Wan
authors: YW
authors: Sun
authors: Timothy
authors: T
authors: Cooper
authors: Krishnegowda
authors: K
authors: Gowdahalli
authors: Junjia
authors: J
authors: Zhu
authors: Shantu
authors: S
authors: Amin
authors: Karam
authors: K
authors: El-Bayoumy
mesh_terms: D000818:Animals; D001580:Benzopyrenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism*; D005260:Female; D051379:Mice; D010051:Ovarian Neoplasms / Q000139:chemically induced* / Q000378:metabolism
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; C041517:dibenzo(a,l)pyrene