Genotoxic Mechanism of Equine Estrogen Used in Estrogen Replacement Therapy
Shibutani
| Estrogen replacement therapy (ERT) is widely used to decrease symptoms associated with menopause, and to protect women against the development of osteoporosis. ERT, composed of the estrogens, equilin, and equilenin, is associated with increased risk of breast, ovarian, and endometrial cancers. Estrogens generate oxidative DNA damage and, in some cases react with DNA to form covalent adducts. If such adducts are not fully repaired, DNA lesions will persist in the target tissues and may initiate cancer. Our studies explore the mutagenic potential and rate of repair of equine estrogen-derived DNA adducts and determine the level of covalent DNA adducts and oxidative damage generated in mammary and reproductive tissues of rats treated with equine estrogens or metabolites. In addition, we use ultrasensitive 32P-postlabeling and HPLC/electrochemical detection techniques developed in our laboratory to analyze DNA adducts in endometrial tissues collected from ERT-treated women . This research is designed to establish the molecular mechanisms for the genotoxicity of equine estrogens and to provide biomarkers that can be used to identify those women at high risk of developing ERT-induced cancer. |  |