Oxidative Damage to DNA of Ovarian Surface Epithelial Cells Affected by Ovulation: Carcinogenic Implication and Chemoprevention

Abstract

The majority of cancers of the ovary are thought to originate from a surface epithelial cell perturbed by ovulation. Outgrowth of a follicle destined to ovulate brings it into apposition with the ovarian epithelium. Ovarian surface cells are consequently exposed, within a limited diffusion radius, to inflammatory agents and reactive oxidants generated during periovulatory processes. Cells that overlie the formative site of follicular rupture suffer irreparable damages and undergo apoptosis. Potentially mutagenic 8-oxoguanine modifications were detected in (surviving) cells circumjacent to postovulatory ovine and human follicles. It is conceivable that clonal expansion of a cell with unrepaired DNA, but not committed to death, could be an initiating factor in the etiology of malignancy, insofar as proliferative ovulatory wound-repair responses may propagate mutations. Since the prognosis for ovarian cancer patients with invasive disease is so poor, and early detection has proven elusive, it is imperative that prospective methods of chemoprevention be explored. Ovulation-induced oxidative base damages to the ovarian epithelium of ewes were prevented by vitamin E. Oxoguanine adducts persisted and CA-125 (a phenotype of metaplastic transformation) was expressed in cultures of cells that were distressed by ovulation in which p53 synthesis was inhibited. Vitamin E negated this reaction. Ovarian cyclicity and fertility were not altered in vitamin-treated ewes. A prophylactic benefit of a supplemental antioxidant is suggested in “ovulating” individuals designated at risk (e.g., due to a tumor suppressor malfunction) for the development of ovarian cancer.