The effects of oxidative stress on female reproduction: a review

Reproductive Biology and Endocrinology - Tập 10 - Trang 1-31 - 2012
Ashok Agarwal1, Anamar Aponte-Mellado1, Beena J Premkumar1, Amani Shaman1, Sajal Gupta1
1Center for Reproductive Medicine, Cleveland Clinic, Cleveland, USA

Tóm tắt

Oxidative stress (OS), a state characterized by an imbalance between pro-oxidant molecules including reactive oxygen and nitrogen species, and antioxidant defenses, has been identified to play a key role in the pathogenesis of subfertility in both males and females. The adverse effects of OS on sperm quality and functions have been well documented. In females, on the other hand, the impact of OS on oocytes and reproductive functions remains unclear. This imbalance between pro-oxidants and antioxidants can lead to a number of reproductive diseases such as endometriosis, polycystic ovary syndrome (PCOS), and unexplained infertility. Pregnancy complications such as spontaneous abortion, recurrent pregnancy loss, and preeclampsia, can also develop in response to OS. Studies have shown that extremes of body weight and lifestyle factors such as cigarette smoking, alcohol use, and recreational drug use can promote excess free radical production, which could affect fertility. Exposures to environmental pollutants are of increasing concern, as they too have been found to trigger oxidative states, possibly contributing to female infertility. This article will review the currently available literature on the roles of reactive species and OS in both normal and abnormal reproductive physiological processes. Antioxidant supplementation may be effective in controlling the production of ROS and continues to be explored as a potential strategy to overcome reproductive disorders associated with infertility. However, investigations conducted to date have been through animal or in vitro studies, which have produced largely conflicting results. The impact of OS on assisted reproductive techniques (ART) will be addressed, in addition to the possible benefits of antioxidant supplementation of ART culture media to increase the likelihood for ART success. Future randomized controlled clinical trials on humans are necessary to elucidate the precise mechanisms through which OS affects female reproductive abilities, and will facilitate further explorations of the possible benefits of antioxidants to treat infertility.

Tài liệu tham khảo

Al-Gubory KH, Fowler PA, Garrel C: The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol. 2010, 42: 1634-1650. Burton GJ, Jauniaux E: Oxidative Stress. Best Pract Res Clin Obstet Gynaecol. 2010, 25: 287-299. Cindrova-Davies T, Yung HW, Johns J, Spasic-Boskovic O, Korolchuk S, Jauniaux E, Burton GJ, Charnock-Jones DS: Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am J Pathol. 2007, 171: 1168-1179. Ruder EH, Hartman TJ, Goldman MB: Impact of oxidative stress on female fertility. Curr Opin Obstet Gynecol. 2009, 21: 219-222. Chandra A, Surti N, Kesavan S, Agarwal A: Significance of oxidative stress in human reproduction. Arch Med. 2009, 5: 528-542. Webster RP, Roberts VH, Myatt L: Protein nitration in placenta - functional significance. Placenta. 2008, 29: 985-994. Kovacic P: Unifying mechanism for addiction and toxicity of abused drugs with application to dopamine and glutamate mediators: electron transfer and reactive oxygen species. Med Hypotheses. 2005, 65: 90-96. Hennig B, Hammock BD, Slim R, Toborek M, Saraswathi V, Robertson LW: PCB-induced oxidative stress in endothelial cells: modulation by nutrients. Int J Hyg Environ Health. 2002, 205: 95-102. Jirsova S, Masata J, Jech L, Zvarova J: Effect of polychlorinated biphenyls (PCBs) and 1,1,1-trichloro-2,2,-bis (4-chlorophenyl)-ethane (DDT) in follicular fluid on the results of in vitro fertilization-embryo transfer (IVF-ET) programs. Fertil Steril. 2010, 93: 1831-1836. Samarawickrema N, Pathmeswaran A, Wickremasinghe R, Peiris-John R, Karunaratna M, Buckley N, Dawson A, de Silva J: Fetal effects of environmental exposure of pregnant women to organophosphorus compounds in a rural farming community in Sri Lanka. Clin Toxicol (Phila). 2008, 46: 489-495. Fujii J, Iuchi Y, Okada F: Fundamental roles of reactive oxygen species and protective mechanisms in the female reproductive system. Reprod Biol Endocrinol. 2005, 3: 43- Kehrer JP: The Haber-Weiss reaction and mechanisms of toxicity. Toxicology. 2000, 149: 43-50. Liochev SI: The mechanism of "Fenton-like" reactions and their importance for biological systems. A biologist's view. Met Ions Biol Syst. 1999, 36: 1-39. Halliwell B, Gutteridge JM: Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990, 186: 1-85. Liu L, Keefe DL: Cytoplasm mediates both development and oxidation-induced apoptotic cell death in mouse zygotes. Biol Reprod. 2000, 62: 1828-1834. Liu L, Trimarchi JR, Keefe DL: Involvement of mitochondria in oxidative stress-induced cell death in mouse zygotes. Biol Reprod. 2000, 62: 1745-1753. Agarwal A: Oxidants and antioxidants in human fertility. Middle East Soc Fertil J. 2004, 9: 187-197. Agarwal A, Gupta S, Sekhon L, Shah R: Redox considerations in female reproductive function and assisted reproduction: from molecular mechanisms to health implications. Antioxid Redox Signal. 2008, 10: 1375-1403. Rosselli M, Keller PJ, Dubey RK: Role of nitric oxide in the biology, physiology and pathophysiology of reproduction. Hum Reprod Update. 1998, 4: 3-24. Visioli F, Hagen TM: Antioxidants to enhance fertility: role of eNOS and potential benefits. Pharmacol Res. 2011, 64: 431-437. Gupta S, Agarwal A, Krajcir N, Alvarez JG: Role of oxidative stress in endometriosis. Reprod Biomed Online. 2006, 13: 126-134. Agarwal A, Gupta S, Sharma RK: Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005, 3: 28- Hanafy KA, Krumenacker JS, Murad F: NO, nitrotyrosine, and cyclic GMP in signal transduction. Med Sci Monit. 2001, 7: 801-819. Ignarro LJ: Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol. 2002, 53: 503-514. Goetz RM, Thatte HS, Prabhakar P, Cho MR, Michel T, Golan DE: Estradiol induces the calcium-dependent translocation of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1999, 96: 2788-2793. Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC: Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest. 1997, 100: 3131-3139. Lin S, Fagan KA, Li KX, Shaul PW, Cooper DM, Rodman DM: Sustained endothelial nitric-oxide synthase activation requires capacitative Ca2+ entry. J Biol Chem. 2000, 275: 17979-17985. Sladek SM, Magness RR, Conrad KP: Nitric oxide and pregnancy. Am J Physiol. 1997, 272: R441-R463. Bird IM, Zhang L, Magness RR: Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am J Physiol Regul Integr Comp Physiol. 2003, 284: R245-R258. Boeldt DS, Yi FX, Bird IM: eNOS activation and NO function: pregnancy adaptive programming of capacitative entry responses alters nitric oxide (NO) output in vascular endothelium–new insights into eNOS regulation through adaptive cell signaling. J Endocrinol. 2011, 210: 243-258. Yi FX, Magness RR, Bird IM: Simultaneous imaging of [Ca2+]i and intracellular NO production in freshly isolated uterine artery endothelial cells: effects of ovarian cycle and pregnancy. Am J Physiol Regul Integr Comp Physiol. 2005, 288: R140-R148. Yi FX, Boeldt DS, Gifford SM, Sullivan JA, Grummer MA, Magness RR, Bird IM: Pregnancy enhances sustained Ca2+ bursts and endothelial nitric oxide synthase activation in ovine uterine artery endothelial cells through increased connexin 43 function. Biol Reprod. 2010, 82: 66-75. Sullivan JA, Grummer MA, Yi FX, Bird IM: Pregnancy-enhanced endothelial nitric oxide synthase (eNOS) activation in uterine artery endothelial cells shows altered sensitivity to Ca2+, U0126, and wortmannin but not LY294002–evidence that pregnancy adaptation of eNOS activation occurs at multiple levels of cell signaling. Endocrinology. 2006, 147: 2442-2457. Ducsay CA, Myers DA: eNOS activation and NO function: differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia. J Endocrinol. 2011, 210: 259-269. Xiao D, Bird IM, Magness RR, Longo LD, Zhang L: Upregulation of eNOS in pregnant ovine uterine arteries by chronic hypoxia. Am J Physiol Heart Circ Physiol. 2001, 280: H812-H820. Rees DD, Palmer RM, Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989, 86: 3375-3378. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995, 377: 239-242. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S: Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol. 2009, 157: 527-536. Perkins AV: Endogenous anti-oxidants in pregnancy and preeclampsia. Aust N Z J Obstet Gynaecol. 2006, 46: 77-83. Maiorino M, Bosello V, Ursini F, Foresta C, Garolla A, Scapin M, Sztajer H, Flohe L: Genetic variations of gpx-4 and male infertility in humans. Biol Reprod. 2003, 68: 1134-1141. Sharma RK, Agarwal A: Role of reactive oxygen species in gynecologic diseases. Review article. Reprod Med Biol. 2004, 3: 177-199. Behrman HR, Kodaman PH, Preston SL, Gao S: Oxidative stress and the ovary. J Soc Gynecol Investig. 2001, 8: S40-S42. Guerin P: OS and protection against ROS in the preimplantation embryo and its surroundings. Hum Reprod Update. 2001, 7: 175-189. Orsi NM, Gopichandran N, Leese HJ, Picton HM, Harris SE: Fluctuations in bovine ovarian follicular fluid composition throughout the oestrous cycle. Reproduction. 2005, 129: 219-228. Borchert A, Savaskan NE, Kuhn H: Regulation of expression of the phospholipid hydroperoxide/sperm nucleus glutathione peroxidase gene. Tissue-specific expression pattern and identification of functional cis- and trans-regulatory elements. J Biol Chem. 2003, 278: 2571-2580. Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N: Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci U S A. 2011, 108: 1462-1467. Angelucci S, Ciavardelli D, Di Giuseppe F, Eleuterio E, Sulpizio M, Tiboni GM, Giampietro F, Palumbo P, Di Ilio C: Proteome analysis of human follicular fluid. Biochim Biophys Acta. 2006, 1764: 1775-1785. Irani K: Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res. 2000, 87: 179-183. Droge W: Free radicals in the physiological control of cell function. Physiol Rev. 2002, 82: 47-95. Boutros T, Chevet E, Metrakos P: Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev. 2008, 60: 261-310. Brown MD, Sacks DB: Protein scaffolds in MAP kinase signaling. Cell Signal. 2009, 21: 462-469. Nagai H, Noguchi T, Takeda K, Ichijo H: Pathophysiological roles of ASK1-MAP kinase signaling pathways. J Biochem Mol Biol. 2007, 40: 1-6. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M: Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 2005, 120: 649-661. Matsuzawa A, Ichijo H: Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochim Biophys Acta. 2008, 1780: 1325-1336. Harvey AJ, Kind KL, Thompson JG: REDOX regulation of early embryo development. Reproduction. 2002, 123: 479-486. Dennery PA: Role of redox in fetal development and neonatal diseases. Antioxid Redox Signal. 2004, 6: 147-153. Rowe T: Fertility and a woman's age. J Reprod Med. 2006, 51: 157-163. Desai N, Sharma R, Makker K, Sabanegh E, Agarwal A: Physiologic and pathologic levels of reactive oxygen species in neat semen of infertile men. Fertil Steril. 2009, 92: 1626-1631. Lekamge DN, Lane M, Gilchrist RB, Tremellen KP: Increased gonadotrophin stimulation does not improve IVF outcomes in patients with predicted poor ovarian reserve. J Assist Reprod Genet. 2008, 25: 515-521. Saalu LC: The incriminating role of reactive oxygen species in idiopathic male infertility: an evidence based evaluation. Pak J Biol Sci. 2010, 13: 413-422. Makker K, Agarwal A, Sharma R: Oxidative stress & male infertility. Indian J Med Res. 2009, 129: 357-367. Cummins JM, Jequier AM, Kan R: Molecular biology of human male infertility: links with aging, mitochondrial genetics, and oxidative stress?. Mol Reprod Dev. 1994, 37: 345-362. Sugino N: Roles of reactive oxygen species in the corpus luteum. Anim Sci J. 2006, 77: 556-565. Fait V, Sela S, Ophir E, Khoury S, Nissimov J, Tkach M, Hirsh Y, Khotaba S, Tarasova L, Oettinger M: Hyperemesis gravidarum is associated with oxidative stress. Am J Perinatol. 2002, 19: 93-98. Holthe MR, Staff AC, Berge LN, Lyberg T: Leukocyte adhesion molecules and reactive oxygen species in preeclampsia. Obstet Gynecol. 2004, 103: 913-922. Diamant S, Kissilevitz R, Diamant Y: Lipid peroxidation system in human placental tissue: general properties and the influence of gestational age. Biol Reprod. 1980, 23: 776-781. Little RE, Gladen BC: Levels of lipid peroxides in uncomplicated pregnancy: a review of the literature. Reprod Toxicol. 1999, 13: 347-352. Myatt L, Cui X: Oxidative stress in the placenta. Histochem Cell Biol. 2004, 122: 369-382. Wang YP, Walsh SW, Guo JD, Zhang JY: Maternal levels of prostacyclin, thromboxane, vitamin E, and lipid peroxides throughout normal pregnancy. Am J Obstet Gynecol. 1991, 165: 1690-1694. Salmon AB, Richardson A, Perez VI: Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging?. Free Radic Biol Med. 2010, 48: 642-655. Crist BL, Alekel DL, Ritland LM, Hanson LN, Genschel U, Reddy MB: Association of oxidative stress, iron, and centralized fat mass in healthy postmenopausal women. J Womens Health (Larchmt). 2009, 18: 795-801. Tropea A, Miceli F, Minici F, Tiberi F, Orlando M, Gangale MF, Romani F, Catino S, Mancuso S, Navarra P, et al: Regulation of vascular endothelial growth factor synthesis and release by human luteal cells in vitro. J Clin Endocrinol Metab. 2006, 91: 2303-2309. Giudice LC, Kao LC: Endometriosis. Lancet. 2004, 364: 1789-1799. Carvalho L, Podgaec S, Bellodi-Privato M, Falcone T, Abrao MS: Role of eutopic endometrium in pelvic endometriosis. J Minim Invasive Gynecol. 2011, 18: 419-427. American College of Obstetricians & Gynecologists: Precis: An Update in Obstetrics and Gynecology: Reproductive Endocrinology. 2007, American College of Obstetricians & Gynecologists (US), 3 Wang Y, Sharma RK, Falcone T, Goldberg J, Agarwal A: Importance of reactive oxygen species in the peritoneal fluid of women with endometriosis or idiopathic infertility. Fertil Steril. 1997, 68: 826-830. Ho HN, Wu MY, Chen SU, Chao KH, Chen CD, Yang YS: Total antioxidant status and nitric oxide do not increase in peritoneal fluids from women with endometriosis. Hum Reprod. 1997, 12: 2810-2815. Polak G, Koziol-Montewka M, Gogacz M, Blaszkowska I, Kotarski J: Total antioxidant status of peritoneal fluid in infertile women. Eur J Obstet Gynecol Reprod Biol. 2001, 94: 261-263. Jackson LW, Schisterman EF, Dey-Rao R, Browne R, Armstrong D: Oxidative stress and endometriosis. Hum Reprod. 2005, 20: 2014-2020. Murphy AA, Santanam N, Parthasarathy S: Endometriosis: a disease of oxidative stress?. Semin Reprod Endocrinol. 1998, 16: 263-273. Szczepanska M, Kozlik J, Skrzypczak J, Mikolajczyk M: Oxidative stress may be a piece in the endometriosis puzzle. Fertil Steril. 2003, 79: 1288-1293. Mier-Cabrera M, Jimenez-Zamudio L, Garcia-Latorre E, Cruz-Orozco O, Hernandez-Guerrero C: Quantitative and qualitative peritoneal immune profiles, T-cell apoptosis and oxidative stress-associated characteristics in women with minimal and mild endometriosis. BJOG. 2010, 118: 6-16. Sharma I, Dhaliwal LK, Saha SC, Sangwan S, Dhawan V: Role of 8-iso-prostaglandin F2alpha and 25-hydroxycholesterol in the pathophysiology of endometriosis. Fertil Steril. 2010, 94: 63-70. Rong R, Ramachandran S, Santanam N, Murphy AA, Parthasarathy S: Induction of monocyte chemotactic protein-1 in peritoneal mesothelial and endometrial cells by oxidized low-density lipoprotein and peritoneal fluid from women with endometriosis. Fertil Steril. 2002, 78: 843-848. Kao J, Rosenstein BS, Peters S, Milano MT, Kron SJ: Cellular response to DNA damage. Ann N Y Acad Sci. 2005, 1066: 243-258. Montuschi P, Barnes PJ, Roberts LJ: Isoprostanes: markers and mediators of oxidative stress. FASEB J. 2004, 18: 1791-1800. Morrow JD, Awad JA, Boss HJ, Blair IA, Roberts LJ: Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc Natl Acad Sci U S A. 1992, 89: 10721-10725. Pavlovic D, Dordevic V, Kocic G: A “cross-talk” between oxidative stress and redox cell signaling. Med Biol. 2002, 19: 131-137. Basu S: Isoprostanes: novel bioactive products of lipid peroxidation. Free Radic Res. 2004, 38: 105-122. Seal RL, Gordon SM, Lush MJ, Wright MW, Bruford EA: genenames.org: the HGNC resources in 2011. Nucliec Acids Res. 2011, 39: D514-D519. Uygungil B, Moran LA: Database of Human HSP70 Genes. Database of Human HSP70 Genes. Edited by: Moran LA. 2005 Remakova M, Skoda M, Faustova M, Mann H, Krystufková O, Vencovsky J, Novota P: Gene regulation and signaling: The expression regulation of the HSPA1B gene in patients with myositis is not dependent on the presence of HLA-DRB1*03 risk allele. Ann Rheum Dis. 2011, 70: A19-A20. Rérole A, Gaëtan J, Garrido C: Molecular Chaperones: Methods and Protocols. Edited by: Calderwood SK, Prince TL. 2011, Heidelberg: Springer Science+Business Media, LLC, 205-230.Hsp70: Anti-apoptotic and tumorigenic protein, Methods in Molecular Biology Proctor CJ, Lorimer IA: Modelling the role of the Hsp70/Hsp90 system in the maintenance of protein homeostasis. PLoS One. 2011, 6: e22038- Morishima N: Control of cell fate by Hsp70: more than an evanescent meeting. J Biochem. 2005, 137: 449-453. Arya R, Mallik M, Lakhotia SC: Heat shock genes - integrating cell survival and death. J Biosci. 2007, 32: 595-610. Beere HM: Death versus survival: functional interaction between the apoptotic and stress-inducible heat shock protein pathways. J Clin Invest. 2005, 115: 2633-2639. Ciocca DR, Calderwood SK: Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 2005, 10: 86-103. Khan KN, Kitajima M, Imamura T, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H: Toll-like receptor 4-mediated growth of endometriosis by human heat-shock protein 70. Hum Reprod. 2008, 23: 2210-2219. Noonan EJ, Place RF, Giardina C, Hightower LE: Hsp70B' regulation and function. Cell Stress Chaperones. 2007, 12: 393-402. Lambrinoudaki IV, Augoulea A, Christodoulakos GE, Economou EV, Kaparos G, Kontoravdis A, Papadias C, Creatsas G: Measurable serum markers of oxidative stress response in women with endometriosis. Fertil Steril. 2009, 91: 46-50. Chehna-Patel N, Warty N, Sachdeva G, Khole V: Proteolytic tailoring of the heat shock protein 70 and its implications in the pathogenesis of endometriosis. Fertil Steril. 2011, 95: 1560-1567. Santanam N, Murphy AA, Parthasarathy S: Macrophages, oxidation, and endometriosis. Ann N Y Acad Sci. 2002, 955: 183-198. discussion 119-200, 396-406 Kajihara H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sado T, Oi H, Kobayashi H: New insights into the pathophysiology of endometriosis: from chronic inflammation to danger signal. Gynecol Endocrinol. 2011, 27: 73-79. Foyouzi N, Berkkanoglu M, Arici A, Kwintkiewicz J, Izquierdo D, Duleba AJ: Effects of oxidants and antioxidants on proliferation of endometrial stromal cells. Fertil Steril. 2004, 82 (Suppl 3): 1019-1022. Li YQ, Zhang ZX, Xu YJ, Ni W, Chen SX, Yang Z, Ma D: N-Acetyl-L-cysteine and pyrrolidine dithiocarbamate inhibited nuclear factor-kappaB activation in alveolar macrophages by different mechanisms. Acta Pharmacol Sin. 2006, 27: 339-346. Ngo C, Chereau C, Nicco C, Weill B, Chapron C, Batteux F: Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009, 175: 225-234. McCubrey JA, Lahair MM, Franklin RA: Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal. 2006, 8: 1775-1789. Banu SK, Lee J, Speights VO, Starzinski-Powitz A, Arosh JA: Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. Mol Endocrinol. 2009, 23: 1291-1305. Harada T, Taniguchi F, Izawa M, Ohama Y, Takenaka Y, Tagashira Y, Ikeda A, Watanabe A, Iwabe T, Terakawa N: Apoptosis and endometriosis. Front Biosci. 2007, 12: 3140-3151. Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K, Fujii S: Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clin Cancer Res. 2008, 14: 32-40. Van Langendonckt A, Casanas-Roux F, Donnez J: Oxidative stress and peritoneal endometriosis. Fertil Steril. 2002, 77: 861-870. Byrne JA, Grieve DJ, Cave AC, Shah AM: Oxidative stress and heart failure. Arch Mal Coeur Vaiss. 2003, 96: 214-221. Osborn BH, Haney AF, Misukonis MA, Weinberg JB: Inducible nitric oxide synthase expression by peritoneal macrophages in endometriosis-associated infertility. Fertil Steril. 2002, 77: 46-51. Kobayashi H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sakata M, Sado T, Oi H: The role of iron in the pathogenesis of endometriosis. Gynecol Endocrinol. 2009, 25: 39-52. Pennington JD, Jacobs KM, Sun L, Bar-Sela G, Mishra M, Gius D: Thioredoxin and thioredoxin reductase as redox-sensitive molecular targets for cancer therapy. Curr Pharm Des. 2007, 13: 3368-3377. Savaris AL, do Amaral VF: Nutrient intake, anthropometric data and correlations with the systemic antioxidant capacity of women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol. 2011, 158: 314-318. Augoulea A, Mastorakos G, Lambrinoudaki I, Christodoulakos G, Creatsas G: The role of the oxidative-stress in the endometriosis-related infertility. Gynecol Endocrinol. 2009, 25: 75-81. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC: Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007, 148: 3814-3826. Parazzini F, Chiaffarino F, Surace M, Chatenoud L, Cipriani S, Chiantera V, Benzi G, Fedele L: Selected food intake and risk of endometriosis. Hum Reprod. 2004, 19: 1755-1759. Dragsted LO, Pedersen A, Hermetter A, Basu S, Hansen M, Haren GR, Kall M, Breinholt V, Castenmiller JJ, Stagsted J, et al: The 6-a-day study: effects of fruit and vegetables on markers of oxidative stress and antioxidative defense in healthy nonsmokers. Am J Clin Nutr. 2004, 79: 1060-1072. Huang HY, Appel LJ, Croft KD, Miller ER, Mori TA, Puddey IB: Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial. Am J Clin Nutr. 2002, 76: 549-555. Upritchard JE, Schuurman CR, Wiersma A, Tijburg LB, Coolen SA, Rijken PJ, Wiseman SA: Spread supplemented with moderate doses of vitamin E and carotenoids reduces lipid peroxidation in healthy, nonsmoking adults. Am J Clin Nutr. 2003, 78: 985-992. Sesti F, Capozzolo T, Pietropolli A, Collalti M, Bollea MR, Piccione E: Dietary therapy: a new strategy for management of chronic pelvic pain. Nutr Res Rev. 2011, 25: 1-8. Mier-Cabrera J, Aburto-Soto T, Burrola-Mendez S, Jimenez-Zamudio L, Tolentino M, Casanueva E, Hernandez-Guerrero C: Women with endometriosis improved their peripheral antioxidant markers after the application of a high antioxidant diet. Reprod Biol Endocrinol. 2009, 5: 1-11. Mier-Cabrera J, Genera-Garcia M, De La Jara-Diaz J, Perichart-Perera O, Vadillo-Ortega F, Hernandez-Guerrero C: Effect of vitamins C and E supplementation on peripheral oxidative stress markers and pregnancy rate in women with endometriosis. Int J Gynaecol Obstet. 2008, 100: 252-256. Hernández Guerrero CA, Bujalil Montenegro L, de la Jara Díaz J, Mier Cabrera J, Bouchán Valencia P: Endometriosis and deficient intake of antioxidants molecules related to peripheral and peritoneal oxidative stress. Ginecol Obstet Mex. 2006, 74: 20-28. Ozcelik B, Serin IS, Basbug M, Uludag S, Narin F, Tayyar M: Effect of melatonin in the prevention of post-operative adhesion formation in a rat uterine horn adhesion model. Hum Reprod. 2003, 18: 1703-1706. Guney M, Oral B, Karahan N, Mungan T: Regression of endometrial explants in a rat model of endometriosis treated with melatonin. Fertil Steril. 2008, 89: 934-942. Paul S, Sharma AV, Mahapatra PD, Bhattacharya P, Reiter RJ, Swarnakar S: Role of melatonin in regulating matrix metalloproteinase-9 via tissue inhibitors of metalloproteinase-1 during protection against endometriosis. J Pineal Res. 2008, 44: 439-449. Fauser BCJM: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome: Rotterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2004, 81: 19-25. Setji TL, Holland ND, Sanders LL, Pereira KC, Diehl AM, Brown AJ: Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006, 91: 1741-1747. Hardiman P, Pillay OC, Atiomo W: Polycystic ovary syndrome and endometrial carcinoma. Lancet. 2003, 361: 1810-1812. Creanga AA, Bradley HM, McCormick C, Witkop CT: Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol. 2008, 111: 959-968. Palacio JR, Iborra A, Ulcova-Gallova Z, Badia R, Martinez P: The presence of antibodies to oxidative modified proteins in serum from polycystic ovary syndrome patients. Clin Exp Immunol. 2006, 144: 217-222. Victor VM, Rocha M, Banuls C, Alvarez A, de Pablo C, Sanchez-Serrano M, Gomez M, Hernandez-Mijares A: Induction of oxidative stress and human leukocyte/endothelial cell interactions in polycystic ovary syndrome patients with insulin resistance. J Clin Endocrinol Metab. 2011, 96: 3115-3122. Gonzalez F, Rote NS, Minium J, Kirwan JP: Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006, 91: 336-340. Costello MF, Shrestha B, Eden J, Johnson NP, Sjoblom P: Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Hum Reprod. 2007, 22: 1200-1209. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I, Golan R, Fraser D, Bolotin A, Vardi H, et al: Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008, 359: 229-241. Polak G, Koziol-Montewka M, Tarkowski R, Kotarski J: Peritoneal fluid and plasma 4-hydroxynonenal and malonyldialdehyde concentrations in infertile women. Ginekol Pol. 2001, 72: 1316-1320. Polak G, Rola R, Gogacz M, Koziol-Montewka M, Kotarski J: Malonyldialdehyde and total antioxidant status in the peritoneal fluid of infertile women. Ginekol Pol. 1999, 70: 135-140. Gupta S, Surti N, Metterle L, Chandra A, Agarwal A: Antioxidants and female reproductive pathologies. Arch Med. 2009, 5: 151-173. Badaiwy A, Baker El Nashar A, El Totongy M: Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial. Fertil Steril. 2006, 86: 647-650. Altmae S, Stavreus-Evers A, Ruiz JR, Laanpere M, Syvanen T, Yngve A, Salumets A, Nilsson TK: Variations in folate pathway genes are associated with unexplained female infertility. Fertil Steril. 2010, 94: 130-137. Jauniaux E, Watson A, Burton G: Evaluation of respiratory gases and acid-base gradients in human fetal fluids and uteroplacental tissue between 7 and 16 weeks' gestation. Am J Obstet Gynecol. 2001, 184: 998-1003. Watson AL, Skepper JN, Jauniaux E, Burton GJ: Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab. 1998, 83: 1697-1705. Watson AL, Skepper JN, Jauniaux E, Burton GJ: Changes in concentration, localization and activity of catalase within the human placenta during early gestation. Placenta. 1998, 19: 27-34. Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ: Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol. 2000, 157: 2111-2122. Lunghi L, Ferretti ME, Medici S, Biondi C, Vesce F: Control of human trophoblast function. Reprod Biol Endocrinol. 2007, 5: 6- Nakamura M, Sekizawa A, Purwosunu Y, Okazaki S, Farina A, Wibowo N, Shimizu H, Okai T: Cellular mRNA expressions of anti-oxidant factors in the blood of preeclamptic women. Prenat Diagn. 2009, 29: 691-696. Hempstock J, Jauniaux E, Greenwold N, Burton GJ: The contribution of placental oxidative stress to early pregnancy failure. Hum Pathol. 2003, 34: 1265-1275. Jauniaux E, Gulbis B, Burton GJ: Physiological implications of the materno-fetal oxygen gradient in human early pregnancy. Reprod Biomed Online. 2003, 7: 250-253. Quenby S, Nik H, Innes B, Lash G, Turner M, Drury J, Bulmer J: Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod. 2009, 24: 45-54. Burton GJ, Hempstock J, Jauniaux E: Oxygen, early embryonic metabolism and free radical-mediated embryopathies. Reprod Biomed Online. 2003, 6: 84-96. Gupta S, Agarwal A, Banerjee J, Alvarez JG: The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstet Gynecol Surv. 2007, 62: 335-347. quiz 353-334 Toy H, Camuzcuoglu H, Camuzcuoglu A, Celik H, Aksoy N: Decreased serum prolidase activity and increased oxidative stress in early pregnancy loss. Gynecol Obstet Invest. 2010, 69: 122-127. Toy H, Camuzcuoglu H, Celik H, Erel O, Aksoy N: Assessment of serum paraoxonase and arylesterase activities in early pregnancy failure. Swiss Med Wkly. 2009, 139: 76-81. Liu AX, He WH, Yin LJ, Lv PP, Zhang Y, Sheng JZ, Leung PC, Huang HF: Sustained endoplasmic reticulum stress as a cofactor of oxidative stress in decidual cells from patients with early pregnancy loss. J Clin Endocrinol Metab. 2011, 96: E493-E497. Zachara BA, Dobrzynski W, Trafikowska U, Szymanski W: Blood selenium and glutathione peroxidases in miscarriage. BJOG. 2001, 108: 244-247. Al-Kunani AS, Knight R, Haswell SJ, Thompson JW, Lindow SW: The selenium status of women with a history of recurrent miscarriage. BJOG. 2001, 108: 1094-1097. Rumbold A, Duley L, Crowther C, Haslam R: Antioxidants for preventing pre-eclampsia. Cochrane Database Syst Rev. 2005, 4: CD004227- Quenby SM, Farquharson RG: Predicting recurring miscarriage: what is important?. Obstet Gynecol. 1993, 82: 132-138. Rai R, Regan L: Recurrent miscarriage. Lancet. 2006, 368: 601-611. Poston L, Raijmakers MT: Trophoblast oxidative stress, antioxidants and pregnancy outcome--a review. Placenta. 2004, 25 (Suppl A): S72-S78. Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, Robson SC, Bulmer JN: Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol. 2006, 80: 572-580. Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, Prus D, Cohen-Daniel L, Arnon TI, Manaster I, et al: Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006, 12: 1065-1074. Simsek M, Naziroglu M, Simsek H, Cay M, Aksakal M, Kumru S: Blood plasma levels of lipoperoxides, glutathione peroxidase, beta carotene, vitamin A and E in women with habitual abortion. Cell Biochem Funct. 1998, 16: 227-231. Miller H, Wilson R, Jenkins C, MacLean MA, Roberts J, Walker JJ: Glutathione levels and miscarriage. Fertil Steril. 2000, 74: 1257-1258. El-Far M, El-Sayed IH, El-Motwally Ael G, Hashem IA, Bakry N: Tumor necrosis factor-alpha and oxidant status are essential participating factors in unexplained recurrent spontaneous abortions. Clin Chem Lab Med. 2007, 45: 879-883. Tempfer C, Unfried G, Zeillinger R, Hefler L, Nagele F, Huber JC: Endothelial nitric oxide synthase gene polymorphism in women with idiopathic recurrent miscarriage. Hum Reprod. 2001, 16: 1644-1647. Sata F, Yamada H, Kondo T, Gong Y, Tozaki S, Kobashi G, Kato EH, Fujimoto S, Kishi R: Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent pregnancy loss. Mol Hum Reprod. 2003, 9: 165-169. Sata F, Yamada H, Yamada A, Kato EH, Kataoka S, Saijo Y, Kondo T, Tamaki J, Minakami H, Kishi R: A polymorphism in the CYP17 gene relates to the risk of recurrent pregnancy loss. Mol Hum Reprod. 2003, 9: 725-728. Cotgreave IA: N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol. 1997, 38: 205-227. Kelly GS: Clinical applications of N-acetylcysteine. Altern Med Rev. 1998, 3: 114-127. Xu DX, Chen YH, Wang H, Zhao L, Wang JP, Wei W: Effect of N-acetylcysteine on lipopolysaccharide-induced intra-uterine fetal death and intra-uterine growth retardation in mice. Toxicol Sci. 2005, 88: 525-533. Amin AF, Shaaban OM, Bediawy MA: N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss. Reprod Biomed Online. 2008, 17: 722-726. Lappas M, Permezel M, Rice GE: N-Acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-kappaB deoxyribonucleic acid-binding activity in human fetal membranes in vitro. J Clin Endocrinol Metab. 2003, 88: 1723-1729. Aluigi MG, De Flora S, D'Agostini F, Albini A, Fassina G: Antiapoptotic and antigenotoxic effects of N-acetylcysteine in human cells of endothelial origin. Anticancer Res. 2000, 20: 3183-3187. Gupta S, Aziz N, Sekhon L, Agarwal R, Mansour G, Li J, Agarwal A: Lipid peroxidation and antioxidant status in preeclampsia: a systematic review. Obstet Gynecol Surv. 2009, 64: 750-759. Reslan OM, Khalil RA: Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia. Cardiovasc Hematol Agents Med Chem. 2010, 8: 204-226. Roberts JM, Pearson GD, Cutler JA, Lindheimer MD: Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertens Pregnancy. 2003, 22: 109-127. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy: Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000, 183: S1-S22. American College of Obstetricians and Gynecologists: Practice bulletin No.33: Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol. 2002, 99: 159-167. Khalil RA, Granger JP: Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models. Am J Physiol Regul Integr Comp Physiol. 2002, 283: R29-R45. Burton GJ, Jauniaux E: Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig. 2004, 11: 342-352. Redman CW, Sargent IL: Placental stress and pre-eclampsia: a revised view. Placenta. 2009, 30 (Suppl A): S38-S42. Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS: Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta. 2009, 30 (Suppl A): S43-S48. Kharfi A, Giguere Y, De Grandpre P, Moutquin JM, Forest JC: Human chorionic gonadotropin (hCG) may be a marker of systemic oxidative stress in normotensive and preeclamptic term pregnancies. Clin Biochem. 2005, 38: 717-721. Roberts JM, Cooper DW: Pathogenesis and genetics of pre-eclampsia. Lancet. 2001, 357: 53-56. Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA: Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation. 2002, 9: 147-160. Hung TH, Skepper JN, Burton GJ: In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. Am J Pathol. 2001, 159: 1031-1043. Burton GJ, Yung HW: Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia. Pregnancy Hypertens. 2011, 1: 72-78. Sharp AN, Heazell AE, Crocker IP, Mor G: Placental apoptosis in health and disease. Am J Reprod Immunol. 2010, 64: 159-169. Aris A, Benali S, Ouellet A, Moutquin JM, Leblanc S: Potential biomarkers of preeclampsia: inverse correlation between hydrogen peroxide and nitric oxide early in maternal circulation and at term in placenta of women with preeclampsia. Placenta. 2009, 30: 342-347. Sharma JB, Sharma A, Bahadur A, Vimala N, Satyam A, Mittal S: Oxidative stress markers and antioxidant levels in normal pregnancy and pre-eclampsia. Int J Gynaecol Obstet. 2006, 94: 23-27. Haque SK, Siddiqui MU, Islam N, Moin S: Erythrocyte markers of oxidative stress in higher age-group preeclamptic and normal pregnant mothers. Hypertens Pregnancy. 2010, 29: 69-81. Padmini E, Lavanya S, Uthra V: Preeclamptic placental stress and over expression of mitochondrial HSP70. Clin Chem Lab Med. 2009, 47: 1073-1080. Tsukimori K, Komatsu H, Fukushima K, Kaku T, Nakano H, Wake N: Inhibition of nitric oxide synthetase at mid-gestation in rats is associated with increases in arterial pressure, serum tumor necrosis factor-alpha, and placental apoptosis. Am J Hypertens. 2008, 21: 477-481. Bhatnagar S, Bhattacharjee J, Vaid M, Madan T, Trivedi SS, Sarma PU: Inducible nitric oxide synthase (iNOS) gene polymorphism in pre-eclampsia: a pilot study in North India. Aust N Z J Obstet Gynaecol. 2007, 47: 477-482. Vural P: Nitric oxide/endothelin-1 in preeclampsia. Clin Chim Acta. 2002, 317: 65-70. Shaamash AH, Elsnosy ED, Makhlouf AM, Zakhari MM, Ibrahim OA: HM EL-d: Maternal and fetal serum nitric oxide (NO) concentrations in normal pregnancy, pre-eclampsia and eclampsia. Int J Gynaecol Obstet. 2000, 68: 207-214. Tsukimori K, Fukushima K, Tsushima A, Nakano H: Generation of reactive oxygen species by neutrophils and endothelial cell injury in normal and preeclamptic pregnancies. Hypertension. 2005, 46: 696-700. Cindrova-Davies T: Gabor Than Award Lecture 2008: pre-eclampsia - from placental oxidative stress to maternal endothelial dysfunction. Placenta. 2009, 30 (Suppl A): S55-S65. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, et al: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004, 350: 672-683. Ahmed A, Rahman M, Zhang X, Acevedo CH, Nijjar S, Rushton I, Bussolati B, St John J: Induction of placental heme oxygenase-1 is protective against TNFalpha-induced cytotoxicity and promotes vessel relaxation. Mol Med. 2000, 6: 391-409. De Marco CS, Caniggia I: Mechanisms of oxygen sensing in human trophoblast cells. Placenta. 2002, 23: S58-S68. Li H, Gu B, Zhang Y, Lewis DF, Wang Y: Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta. Placenta. 2005, 26: 210-217. Farina A, Sekizawa A, De Sanctis P, Purwosunu Y, Okai T, Cha DH, Kang JH, Vicenzi C, Tempesta A, Wibowo N, et al: Gene expression in chorionic villous samples at 11 weeks' gestation from women destined to develop preeclampsia. Prenat Diagn. 2008, 28: 956-961. Griendling KK, Sorescu D, Ushio-Fukai M: NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000, 86: 494-501. Wallekut G, Homuth V, Fischer T, Linschau C, Horstkamp B, Jüpner A, VBaur E, Nissen E, Vetter K, Neichel D, et al: Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest. 1999, 103: 945-952. Dechend R, Viedt C, Muller DN, Ugele B, Brandes RP, Wallukat G, Park JK, Janke J, Barta P, Theuer J, et al: AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation. 2003, 107: 1632-1639. Raijmakers MT, Peters WH, Steegers EA, Poston L: NAD(P)H oxidase associated superoxide production in human placenta from normotensive and pre-eclamptic women. Placenta. 2004, 25 (Suppl A): S85-S89. Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M: Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol. 2000, 20: 2175-2183. Costa LG, Vitalone A, Cole TB, Furlong CE: Modulation of paraoxonase (PON1) activity. Biochem Pharmacol. 2005, 69: 541-550. Baker AM, Klein RL, Haeri S, Moss KL, Boggess KA: Association of Midgestational Paraoxonase 1 activity with pregnancies complicated by preeclampsia. Am J Perinatol. 2010, 27: 205-210. Kumru S, Aydin S, Gursu MF, Ozcan Z: Changes of serum paraoxonase (an HDL-cholesterol-associated lipophilic antioxidant) and arylesterase activities in severe preeclamptic women. Eur J Obstet Gynecol Reprod Biol. 2004, 114: 177-181. Uzun H, Benian A, Madazli R, Topcuoglu MA, Aydin S, Albayrak M: Circulating oxidized low-density lipoprotein and paraoxonase activity in preeclampsia. Gynecol Obstet Invest. 2005, 60: 195-200. Walsh SW: Eicosanoids in preeclampsia. Prostaglandins Leukot Essent Fatty Acids. 2004, 70: 223-232. Klemmensen A, Tabor A, Osterdal ML, Knudsen VK, Halldorsson TI, Mikkelsen TB, Olsen SF: Intake of vitamin C and E in pregnancy and risk of pre-eclampsia: prospective study among 57 346 women. BJOG. 2009, 116: 964-974. Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM: Periconceptional multivitamin use reduces the risk of preeclampsia. Am J Epidemiol. 2006, 164: 470-477. Catov JM, Nohr EA, Bodnar LM, Knudson VK, Olsen SF, Olsen J: Association of periconceptional multivitamin use with reduced risk of preeclampsia among normal-weight women in the Danish National Birth Cohort. Am J Epidemiol. 2009, 169: 1304-1311. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH: Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet. 2006, 367: 1145-1154. Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, Pearson GD, Wapner RJ, Varner MW, Thorp JM, et al: Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med. 2010, 362: 1282-1291. Xu H, Perez-Cuevas R, Xiong X, Reyes H, Roy C, Julien P, Smith G, von Dadelszen P, Leduc L, Audibert F, et al: An international trial of antioxidants in the prevention of preeclampsia (INTAPP). Am J Obstet Gynecol. 2010, 202: 239 e231-239 e210. American College of Obstetricians and Gynecologists: Practice Bulletin No. 12: Intrauterine Growth Restriction. Obstet Gynecol. 2000, 95: 1-3. Scifres CM, Nelson DM: Intrauterine growth restriction, human placental development and trophoblast cell death. J Physiol. 2009, 587: 3453-3458. Biri A, Bozkurt N, Turp A, Kavutcu M, Himmetoglu O, Durak I: Role of oxidative stress in intrauterine growth restriction. Gynecol Obstet Invest. 2007, 64: 187-192. Karowicz-Bilinska A: Lipid peroxides concentration in women with intrauterine growth restriction. Ginekol Pol. 2004, 75: 6-9. Potdar N, Singh R, Mistry V, Evans MD, Farmer PB, Konje JC, Cooke MS: First-trimester increase in oxidative stress and risk of small-for-gestational-age fetus. BJOG. 2009, 116: 637-642. Levy R, Smith SD, Chandler K, Sadovsky Y, Nelson DM: Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor. Am J Physiol Cell Physiol. 2000, 278: C982-C988. Levy R, Smith SD, Yusuf K, Huettner PC, Kraus FT, Sadovsky Y, Nelson DM: Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression. Am J Obstet Gynecol. 2002, 186: 1056-1061. Heazell AE, Lacey HA, Jones CJ, Huppertz B, Baker PN, Crocker IP: Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast. Placenta. 2008, 29: 175-186. Hung TH, Burton GJ: Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in preeclampsia. Taiwan J Obstet Gynecol. 2006, 45: 189-200. Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, Charnock-Jones DS, Burton GJ: Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol. 2008, 173: 451-462. Hafner E, Metzenbauer M, Hofinger D, Munkel M, Gassner R, Schuchter K, Dillinger-Paller B, Philipp K: Placental growth from the first to the second trimester of pregnancy in SGA-foetuses and pre-eclamptic pregnancies compared to normal foetuses. Placenta. 2003, 24: 336-342. Arioz DT, Camuzcuoglu H, Toy H, Kurt S, Celik H, Aksoy N: Serum prolidase activity and oxidative status in patients with stage I endometrial cancer. Int J Gynecol Canc. 2009, 19: 1244-1247. Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, Chaiworapongsa T, Mazor M: The preterm parturition syndrome. BJOG. 2006, 113 (Suppl 3): 17-42. Romero R, Gomez R, Mazor M, Ghezzi F, Yoon BH: The preterm labor syndrome. Preterm Labor. Edited by: Elder MG, Romero R, Lamont RF. 1997, New York: Churchill Livingstone, 29-49. Preterm Birth: Causes, Consequences, and Prevention. Edited by: Behrman RE, Bulter AS. 2007, Washington DC: National Academies Press (US) Norman JE, Bollapragada S, Yuan M, Nelson SM: Inflammatory pathways in the mechanism of parturition. BMC Pregnancy Childbirth. 2007, 7 (Suppl 1): S7- Challis JR, Smith SK: Fetal endocrine signals and preterm labor. Biol Neonate. 2001, 79: 163-167. American College of Obstetricians & Gynecologists: Obstetrics. Precis: An Update in Obstetrics and Gynecology. 2010, US: American College of Obstetricians & Gynecologists: American College of Obstetricians & Gynecologists, 84-91. 4 Haddad R, Tromp G, Kuivaniemi H, Chaiworapongsa T, Kim YM, Mazor M, Romero R: Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature. Am J Obstet Gynecol. 2006, 195 (394): e391-324. Khan RN, Matharoo-Ball B, Shaw RW: Antioxidant enzyme expression, lipid peroxidation, and protein oxidation in human myometrium with parturition. Reprod Sci. 2010, 17: 78-84. Mustafa MD, Pathak R, Ahmed T, Ahmed RS, Tripathi AK, Guleria K, Banerjee BD: Association of glutathione S-transferase M1 and T1 gene polymorphisms and oxidative stress markers in preterm labor. Clin Biochem. 2010, 43: 1124-1128. Pathak R, Suke SG, Ahmed T, Ahmed RS, Tripathi AK, Guleria K, Sharma CS, Makhijani SD, Banerjee BD: Organochlorine pesticide residue levels and oxidative stress in preterm delivery cases. Hum Exp Toxicol. 2010, 29: 351-358. Hong YC, Lee KH, Yi CH, Ha EH, Christiani DC: Genetic susceptibility of term pregnant women to oxidative damage. Toxicol Lett. 2002, 129: 255-262. Frosali S, Di Simplicio P, Perrone S, Di Giuseppe D, Longini M, Tanganelli D, Buonocore G: Glutathione recycling and antioxidant enzyme activities in erythrocytes of term and preterm newborns at birth. Biol Neonate. 2004, 85: 188-194. Chadha S, Jain V, Gupta I, Khullar M: Nitric oxide metabolite levels in preterm labor. J Obstet Gynaecol Res. 2007, 33: 710-717. Oberley LW: Mechanism of the tumor suppressive effect of MnSOD overexpression. Biomed Pharmacother. 2005, 59: 143-148. Than NG, Romero R, Tarca AL, Draghici S, Erez O, Chaiworapongsa T, Kim YM, Kim SK, Vaisbuch E, Tromp G: Mitochondrial manganese superoxide dismutase mRNA expression in human chorioamniotic membranes and its association with labor, inflammation, and infection. J Matern Fetal Neonatal Med. 2009, 22: 1000-1013. Keelan JA, Marvin KW, Sato TA, Coleman M, McCowan LM, Mitchell MD: Cytokine abundance in placental tissues: evidence of inflammatory activation in gestational membranes with term and preterm parturition. Am J Obstet Gynecol. 1999, 181: 1530-1536. Cinkaya A, Keskin HL, Buyukkagnici U, Gungor T, Keskin EA, Avsar AF, Bilge U: Maternal plasma total antioxidant status in preterm labor. J Obstet Gynaecol Res. 2010, 36: 1185-1188. Baker AM, Haeri S, Klein RL, Boggess K: Association of midgestation paraoxonase 1 activity and pregnancies complicated by preterm birth. Am J Obstet Gynecol. 2010, 203 (246): e241-e244. Lee JW, Davis JM: Future applications of antioxidants in premature infants. Curr Opin Pediatr. 2011, 23: 161-166. Rayman MP, Wijnen H, Vader H, Kooistra L, Pop V: Maternal selenium status during early gestation and risk for preterm birth. CMAJ. 2011, 183: 549-555. Temma-Asano K, Tskitishvili E, Kanagawa T, Tomimatsu T, Tsutsui T, Kimura T, Chang YS, Nakamura T, Nakai Y, Shimoya K: Effects of 4-hydroxy-2-nonenal, a major lipid peroxidation-derived aldehyde, and N-acetylcysteine on the cyclooxygenase-2 expression in human uterine myometrium. Gynecol Obstet Invest. 2011, 72: 37-42. Hauth JC, Clifton RG, Roberts JM, Spong CY, Myatt L, Leveno KJ, Pearson GD, Varner MW, Thorp JM, Mercer BM, et al: Vitamin C and E supplementation to prevent spontaneous preterm birth: a randomized controlled trial. Obstet Gynecol. 2010, 116: 653-658. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS: Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med. 2006, 354: 1796-1806. Herrero-Mercado M, Waliszewski SM, Caba M, Martinez-Valenzuela C, Gomez Arroyo S, Villalobos Pietrini R, Cantu Martinez PC, Hernandez-Chalate F: Organochlorine pesticide gradient levels among maternal adipose tissue, maternal blood serum and umbilical blood serum. Bull Environ Contam Toxicol. 2011, 86: 289-293. Rotterdam EA-SPcwg: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod (Oxford, England). 2004, 19: 41-47. Metwally M, Li TC, Ledger WL: The impact of obesity on female reproductive function. Obes Rev. 2007, 8: 515-523. Abenhaim HA, Kinch RA, Morin L, Benjamin A, Usher R: Effect of prepregnancy body mass index categories on obstetrical and neonatal outcomes. Arch Gynecol Obstet. 2007, 275: 39-43. Igosheva N, Abramov AY, Poston L, Eckert JJ, Fleming TP, Duchen MR, McConnell J: Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS One. 2010, 5: e10074- Bloomer RJ, Fisher-Wellman KH: Systemic oxidative stress is increased to a greater degree in young, obese women following consumption of a high fat meal. Oxid Med Cell Longev. 2009, 2: 19-25. Mistry HD, Williams PJ: The importance of antioxidant micronutrients in pregnancy. Oxid Med Cell Longev. 2011, 2011: 841749- Jarvie E, Hauguel-de-Mouzon S, Nelson SM, Sattar N, Catalano PM, Freeman DJ: Lipotoxicity in obese pregnancy and its potential role in adverse pregnancy outcome and obesity in the offspring. Clin Sci (Lond). 2010, 119: 123-129. Basu S, Haghiac M, Surace P, Challier JC, Guerre-Millo M, Singh K, Waters T, Minium J, Presley L, Catalano PM, et al: Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation. Obesity (Silver Spring). 2011, 19: 476-482. DiBaise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE: Gut microbiota and its possible relationship with obesity. Mayo Clin Proc. 2008, 83: 460-469. Robker RL, Akison LK, Bennett BD, Thrupp PN, Chura LR, Russell DL, Lane M, Norman RJ: Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women. J Clin Endocrinol Metab. 2009, 94: 1533-1540. Higashi Y, Sasaki S, Nakagawa K, Kimura M, Noma K, Hara K, Matsuura H, Goto C, Oshima T, Chayama K, et al: Low body mass index is a risk factor for impaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress. J Am Coll Cardiol. 2003, 42: 256-263. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003, 112: 1796-1808. Anderson K, Nisenblat V, Norman R: Lifestyle factors in people seeking infertility treatment - A review. Aust N Z J Obstet Gynaecol. 2010, 50: 8-20. Franco Mdo C, Dantas AP, Akamine EH, Kawamoto EM, Fortes ZB, Scavone C, Tostes RC, Carvalho MH, Nigro D: Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. J Cardiovasc Pharmacol. 2002, 40: 501-509. Bernal AB, Vickers MH, Hampton MB, Poynton RA, Sloboda DM: Maternal undernutrition significantly impacts ovarian follicle number and increases ovarian oxidative stress in adult rat offspring. PLoS One. 2010, 5: e15558- Fisher-Wellman K, Bell HK, Bloomer RJ: Oxidative stress and antioxidant defense mechanisms linked to exercise during cardiopulmonary and metabolic disorders. Oxid Med Cell Longev. 2009, 2: 43-51. Fisher-Wellman K, Bloomer RJ: Acute exercise and oxidative stress: a 30 year history. Dyn Med. 2009, 8: 1- Leelarungrayub D, Saidee K, Pothongsunun P, Pratanaphon S, YanKai A, Bloomer RJ: Six weeks of aerobic dance exercise improves blood oxidative stress status and increases interleukin-2 in previously sedentary women. J Bodyw Mov Ther. 2011, 15: 355-362. Wells PG, Bhuller Y, Chen CS, Jeng W, Kasapinovic S, Kennedy JC, Kim PM, Laposa RR, McCallum GP, Nicol CJ, et al: Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. Toxicol Appl Pharmacol. 2005, 207: 354-366. Huang J, Okuka M, McLean M, Keefe DL, Liu L: Effects of cigarette smoke on fertilization and embryo development in vivo. Fertil Steril. 2009, 92: 1456-1465. Kumar S: Occupational, environmental and lifestyle factors associated with spontaneous abortion. Reprod Sci. 2011, 18: 915-930. Ornoy A: Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy. Reprod Toxicol. 2007, 24: 31-41. Valavanidis A, Vlachogianni T, Fiotakis K: Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int J Environ Res Publ Health. 2009, 6: 445-462. Werler MM: Teratogen update: smoking and reproductive outcomes. Teratology. 1997, 55: 382-388. American College of Obstetricians and Gynecologists: Smoking and reproductive health. Int J Gynecol Obstet. 1993, 43: 75-81. Chelchowska M, Ambroszkiewicz J, Gajewska J, Laskowska-Klita T, Leibschang J: The effect of tobacco smoking during pregnancy on plasma oxidant and antioxidant status in mother and newborn. Eur J Obstet Gynecol Reprod Biol. 2011, 155: 132-136. Northrop-Clewes CA, Thurnham DI: Monitoring micronutrients in cigarette smokers. Clin Chim Acta. 2007, 377: 14-38. Tiboni GM, Bucciarelli T, Giampietro F, Sulpizio M, Di Ilio C: Influence of cigarette smoking on vitamin E, vitamin A, beta-carotene and lycopene concentrations in human pre-ovulatory follicular fluid. Int J Immunopathol Pharmacol. 2004, 17: 389-393. Deng XS, Deitrich RA: Ethanol metabolism and effects: nitric oxide and its interaction. Curr Clin Pharmacol. 2007, 2: 145-153. Toda N, Ayajiki K: Vascular actions of nitric oxide as affected by exposure to alcohol. Alcohol Alcohol. 2010, 45: 347-355. Gauthier TW, Kable JA, Burwell L, Coles CD, Brown LA: Maternal alcohol use during pregnancy causes systemic oxidation of the glutathione redox system. Alcohol Clin Exp Res. 2010, 34: 123-130. Sun AY, Ingelman-Sundberg M, Neve E, Matsumoto H, Nishitani Y, Minowa Y, Fukui Y, Bailey SM, Patel VB, Cunningham CC, et al: Ethanol and oxidative stress. Alcohol Clin Exp Res. 2001, 25: 237S-243S. Zima T, Fialova L, Mestek O, Janebova M, Crkovska J, Malbohan I, Stipek S, Mikulikova L, Popov P: Oxidative stress, metabolism of ethanol and alcohol-related diseases. J Biomed Sci. 2001, 8: 59-70. Spiteller G: Peroxyl radicals are essential reagents in the oxidation steps of the Maillard reaction leading to generation of advanced glycation end products. Ann N Y Acad Sci. 2008, 1126: 128-133. Manzocco L, Calligaris S, Mastrocola D, Nicoli MC, Lerici CR: Review of non-enzymatic browning and antioxidant capacity in processed foods. Trends Food Sci Technol. 2001, 11: 340-346. Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, Pinsky D, Stern D: Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994, 269: 9889-9897. Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP: AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res. 1998, 37: 586-600. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, et al: N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem. 1999, 274: 31740-31749. Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R: Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation. 2002, 105: 816-822. Haslbeck KM, Neundorfer B, Schlotzer-Schrehardtt U, Bierhaus A, Schleicher E, Pauli E, Haslbeck M, Hecht M, Nawroth P, Heuss D: Activation of the RAGE pathway: a general mechanism in the pathogenesis of polyneuropathies?. Neurol Res. 2007, 29: 103-110. Kovacic P, Somanathan R: Cell signaling and receptors in toxicity of advanced glycation end products (AGEs): alpha-dicarbonyls, radicals, oxidative stress and antioxidants. J Recept Signal Transduct Res. 2011, 31: 332-339. Alikhani M, Maclellan CM, Raptis M, Vora S, Trackman PC, Graves DT: Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor. Am J Physiol Cell Physiol. 2007, 292: C850-C856. Chen BH, Jiang DY, Tang LS: Advanced glycation end-products induce apoptosis involving the signaling pathways of oxidative stress in bovine retinal pericytes. Life Sci. 2006, 79: 1040-1048. Kalousova M, Zima T, Popov P, Spacek P, Braun M, Soukupova J, Pelinkova K, Kientsch-Engel R: Advanced glycation end-products in patients with chronic alcohol misuse. Alcohol Alcohol. 2004, 39: 316-320. Khalifah RG, Baynes JW, Hudson BG: Amadorins: novel post-Amadori inhibitors of advanced glycation reactions. Biochem Biophys Res Commun. 1999, 257: 251-258. Stracke H, Hammes HP, Werkmann D, Mavrakis K, Bitsch I, Netzel M, Geyer J, Kopcke W, Sauerland C, Bretzel RG, et al: Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabetes. 2001, 109: 330-336. Miyata T, Kurokawa K, van Ypersele de Strihou C: Relevance of oxidative and carbonyl stress to long-term uremic complications. Kidney Int Suppl. 2000, 76: S120-S125. Al-Abed Y, Mitsuhashi T, Li H, Lawson JA, FitzGerald GA, Founds H, Donnelly T, Cerami A, Ulrich P, Bucala R: Inhibition of advanced glycation endproduct formation by acetaldehyde: role in the cardioprotective effect of ethanol. Proc Natl Acad Sci U S A. 1999, 96: 2385-2390. Kotch LE, Chen SY, Sulik KK: Ethanol-induced teratogenesis: free radical damage as a possible mechanism. Teratology. 1995, 52: 128-136. Heaton MB, Paiva M, Mayer J, Miller R: Ethanol-mediated generation of reactive oxygen species in developing rat cerebellum. Neurosci Lett. 2002, 334: 83-86. Wentzel P, Rydberg U, Eriksson UJ: Antioxidative treatment diminishes ethanol-induced congenital malformations in the rat. Alcohol Clin Exp Res. 2006, 30: 1752-1760. Tolstrup JS, Kjaer SK, Holst C, Sharif H, Munk C, Osler M, Schmidt L, Andersen AM, Gronbaek M: Alcohol use as predictor for infertility in a representative population of Danish women. Acta Obstet Gynecol Scand. 2003, 82: 744-749. Kay HH, Grindle KM, Magness RR: Ethanol exposure induces oxidative stress and impairs nitric oxide availability in the human placental villi: a possible mechanism of toxicity. Am J Obstet Gynecol. 2000, 182: 682-688. Cooper RG, Magwere T: Nitric oxide-mediated pathogenesis during nicotine and alcohol consumption. Indian J Physiol Pharmacol. 2008, 52: 11-18. Chan GC, Hinds TR, Impey S, Storm DR: Hippocampal neurotoxicity of Delta9-tetrahydrocannabinol. J Neurosci. 1998, 18: 5322-5332. Battista N, Pasquariello N, Di Tommaso M, Maccarrone M: Interplay between endocannabinoids, steroids and cytokines in the control of human reproduction. J Neuroendocrinol. 2008, 20 (Suppl 1): 82-89. Schuel H, Burkman LJ, Lippes J, Crickard K, Forester E, Piomelli D, Giuffrida A: N-Acylethanolamines in human reproductive fluids. Chem Phys Lipids. 2002, 121: 211-227. Park B, McPartland JM, Glass M: Cannabis, cannabinoids and reproduction. Prostaglandins Leukot Essent Fatty Acids. 2004, 70: 189-197. Fride E: Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development. J Neuroendocrinol. 2008, 20 (Suppl 1): 75-81. Mueller BA, Daling JR, Weiss NS, Moore DE: Recreational drug use and the risk of primary infertility. Epidemiology. 1990, 1: 195-200. Bari M, Battista N, Pirazzi V, Maccarrone M: The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci. 2011, 16: 498-516. Kovacic P, Jacintho JD: Reproductive toxins: pervasive theme of oxidative stress and electron transfer. Curr Med Chem. 2001, 8: 863-892. Kovacic P, Sacman A, Wu-Weis M: Nephrotoxins: widespread role of oxidative stress and electron transfer. Curr Med Chem. 2002, 9: 823-847. Kovacic P, Jacintho JD: Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer. Curr Med Chem. 2001, 8: 773-796. Marimatsu S, Watanabe K, Matsunaga T, Yamamoto I, Imaoka S, Funae Y: Cytochrome P450 isozymes involved in the oxidative metabolism of delta-9-tetrahydrocannabinol by liver microsomes of adult female rats. Drug Metab Dispos. 1992, 20: 79-83. Kovacic P, Osuna JA: Mechanisms of anti-cancer agents: emphasis on oxidative stress and electron transfer. Curr Pharm Des. 2000, 6: 277-309. Sarafian TA, Magallanes JA, Shau H, Tashkin D, Roth MD: Oxidative stress produced by marijuana smoke. An adverse effect enhanced by cannabinoids. Am J Respir Cell Mol Biol. 1999, 20: 1286-1293. Richardson GA, Day NL, McGauhey PJ: The impact of prenatal marijuana and cocaine use on the infant and child. Clin Obstet Gynecol. 1993, 36: 302-318. Zimmerman EF, Potturi RB, Resnick E, Fisher JE: Role of oxygen free radicals in cocaine-induced vascular disruption in mice. Teratology. 1994, 49: 192-201. Hoyme HE, Jones KL, Dixon SD, Jewett T, Hanson JW, Robinson LK, Msall ME, Allanson JE: Prenatal cocaine exposure and fetal vascular disruption. Pediatrics. 1990, 85: 743-747. Lloyd RV, Shuster L, Mason RP: Reexamination of the microsomal transformation of N-hydroxynorcocaine to norcocaine nitroxide. Mol Pharmacol. 1993, 43: 645-648. Kovacic P: Role of oxidative metabolites of cocaine in toxicity and addiction: oxidative stress and electron transfer. Med Hypotheses. 2005, 64: 350-356. Goldstein S, Samuni A, Merenyi G: Reactions of nitric oxide, peroxynitrite, and carbonate radicals with nitroxides and their corresponding oxoammonium cations. Chem Res Toxicol. 2004, 17: 250-257. Lipton JW, Gyawali S, Borys ED, Koprich JB, Ptaszny M, McGuire SO: Prenatal cocaine administration increases glutathione and alpha-tocopherol oxidation in fetal rat brain. Brain Res Dev Brain Res. 2003, 147: 77-84. Lee YW, Hennig B, Fiala M, Kim KS, Toborek M: Cocaine activates redox-regulated transcription factors and induces TNF-alpha expression in human brain endothelial cells. Brain Res. 2001, 920: 125-133. Jacintho JD, Kovacic P: Neurotransmission and neurotoxicity by nitric oxide, catecholamines, and glutamate: unifying themes of reactive oxygen species and electron transfer. Curr Med Chem. 2003, 10: 2693-2703. Sharan N, Chong VZ, Nair VD, Mishra RK, Hayes RJ, Gardner EL: Cocaine treatment increases expression of a 40 kDa catecholamine-regulated protein in discrete brain regions. Synapse. 2003, 47: 33-44. Zhang L, Xiao Y, He J: Cocaine and apoptosis in myocardial cells. Anat Rec. 1999, 257: 208-216. Zaragoza A, Diez-Fernandez C, Alvarez AM, Andres D, Cascales M: Mitochondrial involvement in cocaine-treated rat hepatocytes: effect of N-acetylcysteine and deferoxamine. Br J Pharmacol. 2001, 132: 1063-1070. Woods JR, Plessinger MA, Miller RK: Vitamins C and E: missing links in preventing preterm premature rupture of membranes?. Am J Obstet Gynecol. 2001, 185: 5-10. Slutker L: Risks associated with cocaine use during pregnancy. Obstet Gynecol. 1992, 79: 778-779. Fantel AG, Person RE, Burroughs-Gleim CJ, Mackler B: Direct embryotoxicity of cocaine in rats: effects on mitochondrial activity, cardiac function, and growth and development in vitro. Teratology. 1990, 42: 35-43. Floyd RA, Hensley K, Forster MJ, Kelleher-Andersson JA, Wood PL: Nitrones, their value as therapeutics and probes to understand aging. Mech Ageing Dev. 2002, 123: 1021-1031. Lee JY, Baw CK, Gupta S, Aziz N, Agarwal A: Role of Oxidative Stress in Polycystic Ovary Syndrome. Curr Wom Health Rev. 2010, 6: 96-107. Bagchi M, Hassoun EA, Bagchi D, Stohs SJ: Endrin-induced increases in hepatic lipid peroxidation, membrane microviscosity, and DNA damage in rats. Arch Environ Contam Toxicol. 1992, 23: 1-5. Abdollahi M, Ranjbar A, Shadnia S, Nikfar S, Rezaie A: Pesticides and oxidative stress: a review. Med Sci Monit. 2004, 10: RA141-RA147. Sutton P, Wallinga D, Perron J, Gottlieb M, Sayre L, Woodruff T: Reproductive health and the industrialized food system: a point of intervention for health policy. Health Aff (Millwood). 2011, 30: 888-897. Luo ZC, Liu JM, Fraser WD: Large prospective birth cohort studies on environmental contaminants and child health - goals, challenges, limitations and needs. Med Hypotheses. 2009, 74: 318-324. Organochlorines: http://www.fws.gov/pacific/ecoservices/envicon/pim/reports/contaminantinfo/contaminants.html Pathak R, Mustafa MD, Ahmed T, Ahmed RS, Tripathi AK, Guleria K, Banerjee BD: Intra uterine growth retardation: association with organochlorine pesticide residue levels and oxidative stress markers. Reprod Toxicol. 2011, 31: 534-539. Harley KG, Marks AR, Bradman A, Barr DB, Eskenazi B: DDT exposure, work in agriculture, and time to pregnancy among farmworkers in California. J Occup Environ Med. 2008, 50: 1335-1342. Petrelli G, Figa-Talamanca I, Lauria L, Mantovani A: Spontaneous abortion in spouses of greenhouse workers exposed to pesticides. Environ Health Prev Med. 2003, 8: 77-81. Meeker JD, Maity A, Missmer SA, Williams PL, Mahalingaiah S, Ehrlich S, Berry KF, Altshul L, Perry MJ, Cramer DW, et al: Serum concentrations of polychlorinated biphenyls in relation to in vitro fertilization outcomes. Environ Health Perspect. 2011, 119: 1010-1016. Faroon OM, Keith S, Jones D, de Rosa C: Effects of polychlorinated biphenyls on development and reproduction. Toxicol Ind Health. 2001, 17: 63-93. Foster WG: The reproductive toxicology of Great Lakes contaminants. Environ Health Perspect. 1995, 103 (Suppl 9): 63-69. Kimbrough RD: Polychlorinated biphenyls (PCBs) and human health: an update. Crit Rev Toxicol. 1995, 25: 133-163. Lione A: Polychlorinated biphenyls and reproduction. Reprod Toxicol. 1988, 2: 83-89. Longnecker MP, Klebanoff MA, Dunson DB, Guo X, Chen Z, Zhou H, Brock JW: Maternal serum level of the DDT metabolite DDE in relation to fetal loss in previous pregnancies. Environ Res. 2005, 97: 127-133. Toft G, Hagmar L, Giwercman A, Bonde JP: Epidemiological evidence on reproductive effects of persistent organochlorines in humans. Reprod Toxicol. 2004, 19: 5-26. Meeker JD, Missmer SA, Altshul L, Vitonis AF, Ryan L, Cramer DW, Hauser R: Serum and follicular fluid organochlorine concentrations among women undergoing assisted reproduction technologies. Environ Health. 2009, 8: 32- De Felip E, di Domenico A, Miniero R, Silvestroni L: Polychlorobiphenyls and other organochlorine compounds in human follicular fluid. Chemosphere. 2004, 54: 1445-1449. Younglai EV, Foster WG, Hughes EG, Trim K, Jarrell JF: Levels of environmental contaminants in human follicular fluid, serum, and seminal plasma of couples undergoing in vitro fertilization. Arch Environ Contam Toxicol. 2002, 43: 121-126. Mes J, Marchand L, Davies DJ: Organochlorine residues in adipose tissue of Canadians. Bull Environ Contam Toxicol. 1990, 45: 681-688. Polishuk ZW, Ron M, Wassermann M, Cucos S, Wassermann D, Lemesch C: Organochlorine compounds in human blood plasma and milk. Pestic Monit J. 1977, 10: 121-129. Covaci A, Jorens P, Jacquemyn Y, Schepens P: Distribution of PCBs and organochlorine pesticides in umbilical cord and maternal serum. Sci Total Environ. 2002, 298: 45-53. Nishimura H, Shiota K, Tanimura T, Mizutani T, Matsumoto M, Ueda M: Levels of polychlorinated biphenyls and organochlorine insecticides in human embryos and fetuses. Paediatrician. 1977, 6: 45-67. Toft G, Thulstrup AM, Jonsson BA, Pedersen HS, Ludwicki JK, Zvezday V, Bonde JP: Fetal loss and maternal serum levels of 2,2',4,4',5,5'-hexachlorbiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p, p'-DDE) exposure: a cohort study in Greenland and two European populations. Environ Health. 2010, 9: 22- Hennig B, Slim R, Toborek M, Robertson LW: Linoleic acid amplifies polychlorinated biphenyl-mediated dysfunction of endothelial cells. J Biochem Mol Toxicol. 1999, 13: 83-91. Machala M, Drabek P, Neca J, Kolarova J, Svobodova Z: Biochemical markers for differentiation of exposures to nonplanar polychlorinated biphenyls, organochlorine pesticides, or 2,3,7, 8-tetrachlorodibenzo-p-dioxin in trout liver. Ecotoxicol Environ Saf. 1998, 41: 107-111. Narayanan PK, Carter WO, Ganey PE, Roth RA, Voytik-Harbin SL, Robinson JP: Impairment of human neutrophil oxidative burst by polychlorinated biphenyls: inhibition of superoxide dismutase activity. J Leukoc Biol. 1998, 63: 216-224. Oakley GG, Devanaboyina U, Robertson LW, Gupta RC: Oxidative DNA damage induced by activation of polychlorinated biphenyls (PCBs): implications for PCB-induced oxidative stress in breast cancer. Chem Res Toxicol. 1996, 9: 1285-1292. Smith AG, Carthew P, Clothier B, Constantin D, Francis JE, Madra S: Synergy of iron in the toxicity and carcinogenicity of polychlorinated biphenyls (PCBs) and related chemicals. Toxicol Lett. 1995, 82–83: 945-950. Saito M: Polychlorinated biphenyls-induced lipid peroxidation as measured by thiobarbituric acid-reactive substances in liver subcellular fractions of rats. Biochim Biophys Acta. 1990, 1046: 301-308. Toborek M, Barger SW, Mattson MP, Espandiari P, Robertson LW, Hennig B: Exposure to polychlorinated biphenyls causes endothelial cell dysfunction. J Biochem Toxicol. 1995, 10: 219-226. Bagchi D, Bagchi M, Hassoun EA, Stohs SJ: In vitro and in vivo generation of reactive oxygen species, DNA damage and lactate dehydrogenase leakage by selected pesticides. Toxicology. 1995, 104: 129-140. Banerjee BD, Seth V, Ahmed RS: Pesticide-induced oxidative stress: perspectives and trends. Rev Environ Health. 2001, 16: 1-40. Delescluse C, Ledirac N, Li R, Piechocki MP, Hines RN, Gidrol X, Rahmani R: Induction of cytochrome P450 1A1 gene expression, oxidative stress, and genotoxicity by carbaryl and thiabendazole in transfected human HepG2 and lymphoblastoid cells. Biochem Pharmacol. 2001, 61: 399-407. Flessel P, Quintana PJ, Hooper K: Genetic toxicity of malathion: a review. Environ Mol Mutagen. 1993, 22: 7-17. Halliwell B: Effect of diet on cancer development: is oxidative DNA damage a biomarker?. Free Radic Biol Med. 2002, 32: 968-974. Julka D, Pal R, Gill KD: Neurotoxicity of dichlorvos: effect on antioxidant defense system in the rat central nervous system. Exp Mol Pathol. 1992, 56: 144-152. Gupta S, Sekhon L, Agarwal A: The role of oxidative stress and antioxidants in assisted reproduction. Curr Wom Health Rev. 2010, 6: 227-238. Combelles CM, Gupta S, Agarwal A: Could oxidative stress influence the in-vitro maturation of oocytes?. Reprod Biomed Online. 2009, 18: 864-880. Sikka SC: Role of oxidative stress response elements and antioxidants in prostate cancer pathobiology and chemoprevention–a mechanistic approach. Curr Med Chem. 2003, 10: 2679-2692. Oyawoye O, Abdel Gadir A, Garner A, Constantinovici N, Perrett C, Hardiman P: Antioxidants and reactive oxygen species in follicular fluid of women undergoing IVF: relationship to outcome. Hum Reprod. 2003, 18: 2270-2274. Revelli A, Delle Piane L, Casano S, Molinari E, Massobrio M, Rinaudo P: Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics. Reprod Biol Endocrinol. 2009, 7: 40- Jana SK KNB, Chattopadhyay R, Chakravarty B, Chaudhury K: Upper control limit of reactive oxygen species in follicular fluid beyond which viable embryo formation is not favorable. Reprod Toxicol. 2010, 29: 447-451. Agarwal A, Said TM, Bedaiwy MA, Banerjee J, Alvarez JG: Oxidative stress in an assisted reproductive techniques setting. Fertil Steril. 2006, 86: 503-512. Takenaka M, Horiuchi T, Yanagimachi R: Effects of light on development of mammalian zygotes. Proc Natl Acad Sci U S A. 2007, 104: 14289-14293. Tarozzi N, Bizzaro D, Flamigni C, Borini A: Clinical relevance of sperm DNA damage in assisted reproduction. Reprod Biomed Online. 2007, 14: 746-757. Martin-Romero FJ, Ortiz-de-Galisteo JR, Lara-Laranjeira J, Dominguez-Arroyo JA, Gonzalez-Carrera E, Alvarez IS: Store-operated calcium entry in human oocytes and sensitivity to oxidative stress. Biol Reprod. 2008, 78: 307-315. Tamura H, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, Taketani T, Matsuoka A, Yamagata Y, Shimamura K, et al: Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008, 44: 280-287. Attaran M, Pasqualotto E, Falcone T, Goldberg JM, Miller KF, Agarwal A, Sharma RK: The effect of follicular fluid reactive oxygen species on the outcome of in vitro fertilization. Int J Fertil Womens Med. 2000, 45: 314-320. Martin-Romero FJ, Miguel-Lasobras EM, Dominguez-Arroyo JA, Gonzalez-Carrera E, Alvarez IS: Contribution of culture media to oxidative stress and its effect on human oocytes. Reprod Biomed Online. 2008, 17: 652-661. Kawamura Y, Uchijima Y, Horike N, Tonami K, Nishiyama K, Amano T, Asano T, Kurihara Y, Kurihara H: Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest. J Clin Invest. 2010, 120: 2817-2828. Ozkaya MO, Naziroglu M: Multivitamin and mineral supplementation modulates oxidative stress and antioxidant vitamin levels in serum and follicular fluid of women undergoing in vitro fertilization. Fertil Steril. 2010, 94: 2465-2466.