The ovary is constantly remodeled by differentiation and involution of substructures. Recent results indicate a unique basis for interaction between parenchymal and other cells of the ovary and reveal novel mediators that appear to regulate the lysis and survival of ovarian structures. The hypothesis is that oxygen radicals serve as mediators of the selective lysis of ovarian structures, and that these reactive species play a fundamental role both in ovulation and in the oocyte. This novel proposition arose directly from recent findings that describe, for the first time, the unique and potent antigonadotropic and lytic actions of oxygen radicals in ovarian cells. Other evidence indicates that production of oxygen radicals, and defensive mechanisms against these reactive species, occurs in the ovary. Both of these processes appear to be under endocrine regulation by gonadotropins, and under paracrine control by cytokines, adenosine, and eicosanoids. The role of antioxidant vitamins (C, E and A), long known to be present in high levels in the ovary, is also predicted by this hypothesis. However, these important and novel aspects of ovarian regulation have not been investigated. This proposal is therefore focused on the identification of the cellular origin of oxygen radicals in the ovary, on their nature of action, and processes which regulate their production, action and degradation. Methods to be used will include cell culture, and in vivo studies, in addition to analysis of oxygen radicals, enzymes, and vitamins. Information gained from these studies has manifold benefits beyond the understanding of interactions between steroidogenic and other cells of the ovary. This information may reveal new insights into the etiology of infertility and open therapeutic avenues. An increased understanding of the etiology of ovarian cancer may also accrue since oxygen radicals are closely linked to carcinogenesis produced by uncontrolled production, by redox-cycling xenobiotics, or by inadequate defenses against these tumor promoters. Finally, we may gain a greater understanding of the role of antioxidant vitamins in reproduction and in immune cell processes in general.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD010718-17
Application #
3311371
Study Section
Reproductive Biology Study Section (REB)
Project Start
1977-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
17
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Pepperell, John R; Porterfield, D Marshall; Keefe, David L et al. (2003) Control of ascorbic acid efflux in rat luteal cells: role of intracellular calcium and oxygen radicals. Am J Physiol Cell Physiol 285:C642-51
Behrman, H R; Kodaman, P H; Preston, S L et al. (2001) Oxidative stress and the ovary. J Soc Gynecol Investig 8:S40-2
Guarnaccia, M M; Takami, M; Jones, E E et al. (2000) Luteinizing hormone depletes ascorbic acid in preovulatory follicles. Fertil Steril 74:959-63
Kodaman, P H; Behrman, H R (1999) Hormone-regulated and glucose-sensitive transport of dehydroascorbic acid in immature rat granulosa cells. Endocrinology 140:3659-65
Zreik, T G; Kodaman, P H; Jones, E E et al. (1999) Identification and characterization of an ascorbic acid transporter in human granulosa-lutein cells. Mol Hum Reprod 5:299-302
Kolodecik, T R; Aten, R F; Behrman, H R (1998) Ascorbic acid-dependent cytoprotection of ovarian cells by leukocyte and nonleukocyte peroxidases. Biochem Pharmacol 55:1497-503
Aten, R F; Kolodecik, T R; Rossi, M J et al. (1998) Prostaglandin f2alpha treatment in vivo, but not in vitro, stimulates protein kinase C-activated superoxide production by nonsteroidogenic cells of the rat corpus luteum. Biol Reprod 59:1069-76
Kodaman, P H; Aten, R F; Behrman, H R (1998) Accumulation of ascorbate by endocrine-regulated and glucose-sensitive transport of dehydroascorbic acid in luteinized rat ovarian cells. Biol Reprod 58:407-13
Musicki, B; Kodaman, P H; Aten, R F et al. (1996) Endocrine regulation of ascorbic acid transport and secretion in luteal cells. Biol Reprod 54:399-406
Behrman, H R; Preston, S L; Aten, R F et al. (1996) Hormone induction of ascorbic acid transport in immature granulosa cells. Endocrinology 137:4316-21

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