Abstract 1333: Carcinogenicity and formation of DNA adducts induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and a tobacco smoke component, in the ovary of mouse

Abstract

Abstract Ovarian cancer ranks second among gynecologic cancers, and it is the fifth leading cause of cancer deaths among women; 13,850 deaths are expected in 2010. There is usually no obvious symptoms of early stage ovarian cancer; therefore only 15% of ovarian cancers are diagnosed in the localized stage, and the five-year survival rate for ovarian cancer patients is 46%. A positive relation of mucinous ovarian tumors to tobacco smoking had been reported; furthermore, an association was shown between mucinous ovarian cancer with ex-smokers as well. The mechanisms that can account for the role of tobacco smoking on this disease remain unknown. Currently, there is no preclinical animal model that can accurately reflect the ovarian cancer resulting from chronic exposure to chemical carcinogens present in cigarette smoke. A previous report showed that dibenzo[a,l]pyrene (DB[a,l]P) can induce ovarian cancer in mice. Therefore, in this study we examined the carcinogenicity and DNA adducts formation in the ovary of mice treated with DB[a,l]P. In carcinogenesis study, ovarian tumors in B6C3F1 mice were induced by administering DB[a,l]P into the oral cavity of mice. Several groups of B6C3F1 mice (20/group) received various doses of DB[a,l]P (24, 12, 6, and 3 nmol/mouse), and additional groups received DMSO 3 times a week for 38 weeks or were left untreated as controls. Mice were sacrificed 4 weeks after the last carcinogen administration. A short-term bioassay was also conducted to detect and quantify DNA-adducts induced by DB[a,l]P as a function of time in the ovary; mice were administered orally (24 nmol) 3 times a week for 5 weeks. Ovaries were removed from mice 48 h, 1, 2 and 4 weeks after the last dose. DNA were isolated and hydrolyzed enzymatically, and the DB[a,l]PDE-DNA adducts were analyzed by our newly developed LC-MS/MS method. At the dose of 6 nmol in carcinogenesis study, we observed the highest total ovarian tumor incidence (79%), but the incidence of malignancy was only 15%. However, at the dose of 12 nmol, the total tumor incidence was 75%, and the incidence of malignant granulosa cell tumor was 65%. In addition to ovarian tumors, we also observed lesions in sites distal from the ovaries including the skin, mammary, lung, and oral tissues at the dose of 24 nmol, which were rare in other dosing groups. Treatment of DB[a,l]P in mice resulted in the formation of (−)-anti-cis-DB[a,l]PDE-dA and (−)-anti-trans-DB[a,l]PDE-dA adducts, which were 1.6 and 3.1 fmol/µg DNA respectively in ovaries of mice within 48 hours, and the level of adducts decreased dramatically over a week. Our results indicated that DB[a,l]P can be activated to form (−)-anti-DB[a,l]PDE; the latter may account for DB[a,l]P-induced ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1333. doi:10.1158/1538-7445.AM2011-1333