Ovulation-induced DNA damage in ovarian surface epithelial cells of ewes: prospective regulatory mechanisms of repair/survival and apoptosis.
Oxidative base (8-oxoguanine) damage, DNA fragmentation, and apoptosis occurred among ovarian surface epithelial cells within the formative site of ovulation in sheep. The incidence of 8-oxoguanine adducts in surviving antiapoptotic Bcl-2/base excision repair polymerase beta-positive cells at the margins of ruptured follicles (which avoid the focal point of the ovulatory assault) was intermediate between apoptotic and outlying healthy epithelium. Cells containing perturbations to DNA expressed the tumor suppressor p53. Localized reactions of DNA injury and programmed cellular death were averted by ovulation blockade with indomethacin. Progesterone enhanced the biosynthesis of polymerase beta in ovarian surface epithelial cells exposed in vitro to a sublethal concentration of H(2)O(2). Ovulation is a putative etiological factor in common epithelial ovarian cancer. A genetically altered progenitor cell, with unrepaired DNA, but not committed to death, could give rise to a transformed phenotype that is hence propagated upon healing of the ovulatory wound; it appears that this incongruity is normally reconciled by up-regulation of the base excision repair pathway during the ensuing luteal phase.
Murdoch
W J
WJ
Department of Animal Science and Reproductive Biology Program, University of Wyoming, Laramie, Wyoming 82071, USA. wmurdoch@uwyo.edu
Townsend
R S
RS
McDonnel
A C
AC
D000818:Animals; D017209:Apoptosis; D018736:DNA Adducts; D004249:DNA Damage; D053938:DNA Fragmentation; D019951:DNA Polymerase beta / Q000032:analysis / Q000378:metabolism; D004260:DNA Repair; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D005260:Female; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D006080:Ovarian Follicle / Q000737:chemistry; D010053:Ovary / Q000737:chemistry* / Q000187:drug effects; D010060:Ovulation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012756:Sheep; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D018736:DNA Adducts; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D011374:Progesterone; C024829:8-hydroxyguanine; D006147:Guanine; D006861:Hydrogen Peroxide; D019951:DNA Polymerase beta; D007213:Indomethacin