Abstract
Estrogens are known mutagenic and carcinogenic risk factors. Non-enzymatic oxidation of catechol-estrogens in the presence of copper is reported to generate reactive oxygen species (ROS) that can cause DNA damage. We show that DNA modification in the presence of 4-hydroxyestradiol (4-OHE(2)) and copper (Cu-II) results in single and double strand breaks, base modification, hyperchromicity and change in ellipticity. Modified DNA (4-OHE(2)-Cu(II)-DNA) was highly immunogenic in experimental animals. Induced anti-4-OHE(2)-Cu(II)-DNA antibodies were effectively used as a probe for detecting oxidative lesions in human genomic DNA and for the estimation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the urine of cancer patients. Circulating antibodies from cancer patients showed high binding to 4-OHE(2)-Cu(II)-DNA as compared to native DNA. Our results imply that interaction of catechol-estrogen and copper leads to the production of potent ROS, capable of causing DNA damage, thus playing an important role in carcinogenesis. The modified DNA presents unique epitopes which may be one of the factors for autoantibody induction in cancer.