The ejaculated spermatozoon, as an aerobic cell, must fight against toxic levels of reactive oxygen species (ROS) generated by its own metabolism but also by other sources such as abnormal spermatozoa, chemicals and toxicants, or the presence of leukocytes in semen. Mammalian spermatozoa are extremely sensitive to oxidative stress, a condition occurring when there is a net increase in ROS levels within the cell. Opportunely, this specialized cell has a battery of antioxidant enzymes (superoxide dismutase, peroxiredoxins, thioredoxins, thioredoxins reductases, and glutathione s-transferases) working in concert to assure normal sperm function. Any impairment of the antioxidant enzymatic activities will promote severe oxidative damage which is observed as plasma membrane lipid peroxidation, oxidation of structural proteins and enzymes, and oxidation of DNA bases that lead to abnormal sperm function. Altogether, these damages occurring in spermatozoa are associated with male infertility. The present review contains a description of the enzymatic antioxidant system of the human spermatozoon and a reevaluation of the role of its different components and highlights the necessity of sufficient supply of reducing agents (NADPH and reduced glutathione) to guarantee normal sperm function. 1. Introduction Mammalian and particularly human spermatozoa are sensitive to high levels of reactive oxygen species (ROS) [1, 2]. In the 40s, this toxic effect was first observed independently by different investigators: McLeod working with human and Tosic and Walton working with bull sperm samples; they found that the spermatozoon is very sensitive to high concentrations of hydrogen peroxide (H2O2) [3–5]. These pioneer works opened a new era of research in the biology of reproduction field to understand the mechanisms and players affected by toxic levels of ROS of sperm physiology. The oxidative stress is produced by a net increase of ROS levels because of an increase of their production and/or a decrease of antioxidant defences [6, 7]. It generates substantial damage to all components of the sperm cell; thus, significant levels of lipid peroxidation, protein, and DNA oxidation are seen in this situation [7, 8] and are often associated with infertility [9–12]. This damage is translated to changes in the plasma membrane fluidity, inactivation of key enzymes, and damage of the paternal DNA leading to impairment of sperm motility, mutations in the genomic message, and a variety of reproductive outcomes including, fertilization and embryo development failure, miscarriages, and
References
[1]
B. T. Storey, “Mammalian sperm metabolism: oxygen and sugar, friend and foe,” International Journal of Developmental Biology, vol. 52, no. 5-6, pp. 427–437, 2008.
[2]
R. J. Aitken, K. T. Jones, and S. A. Robertson, “Reactive oxygen species and sperm function—in sickness and in health,” Journal of Andrology, vol. 33, no. 6, pp. 1096–1106, 2012.
[3]
J. MacLeod, “The role of oxygen in the metabolism and motility of human spermatozoa,” American Journal of Physiology, vol. 138, pp. 512–518, 1943.
[4]
J. Tosic and A. Walton, “Formation of hydrogen peroxide by spermatozoa and its inhibitory effect on respiration,” Nature, vol. 158, p. 485, 1946.
[5]
J. Tosic and A. Walton, “Metabolism of spermatozoa. The formation and elimination of hydrogen peroxide by spermatozoa and effects on motility and survival,” The Biochemical Journal, vol. 47, no. 2, pp. 199–212, 1950.
[6]
B. Halliwell, “Oxidative stress and neurodegeneration: where are we now?” Journal of Neurochemistry, vol. 97, no. 6, pp. 1634–1658, 2006.
[7]
B. Halliwell and J. Gutteridge, “Cellular responses to oxidative stress: adaptation, damage, repair, senescence and death,” in Free Radicals in Biology and Medicine, B. Halliwell and J. Gutteridge, Eds., pp. 187–267, Oxford University Press, New York, NY, USA, 2007.
[8]
Y. Li, H. Zhu, K. L. Stansbury, and M. A. Trush, “Role of reactive oxygen species in multistage carcinogenesis,” in Oxygen Radicals and the Disease Process, C. E. Thomas and B. Kalyanaram, Eds., pp. 237–278, Academic Press, Amsterdam, The Netherlands, 1997.
[9]
C. Gagnon, A. Iwasaki, E. De Lamirande, and N. Kovalski, “Reactive oxygen species and human spermatozoa,” Annals of the New York Academy of Sciences, vol. 637, pp. 436–444, 1991.
[10]
E. de Lamirande and C. Gagnon, “Impact of reactive oxygen species on spermatozoa: a balancing act between beneficial and detrimental effects,” Human Reproduction, vol. 10, supplement 1, pp. 15–21, 1995.
[11]
A. Agarwal, S. Gupta, and S. Sikka, “The role of free radicals and antioxidants in reproduction,” Current Opinion in Obstetrics and Gynecology, vol. 18, no. 3, pp. 325–332, 2006.
[12]
R. J. Aitken and M. A. Baker, “Oxidative stress, sperm survival and fertility control,” Molecular and Cellular Endocrinology, vol. 250, no. 1-2, pp. 66–69, 2006.
[13]
E. de Lamirande and C. Gagnon, “Reactive oxygen species and human spermatozoa. I: effects on the motility of intact spermatozoa and on sperm axonemes,” Journal of Andrology, vol. 13, no. 5, pp. 368–378, 1992.
[14]
E. de Lamirande and C. Gagnon, “Reactive oxygen species and human spermatozoa: II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility,” Journal of Andrology, vol. 13, no. 5, pp. 379–386, 1992.
[15]
S. C. Sikka, M. Rajasekaran, and W. J. G. Hellstrom, “Role of oxidative stress and antioxidants in male infertility,” Journal of Andrology, vol. 16, no. 6, pp. 464–468, 1995.
[16]
J. F. Griveau and D. le Lannou, “Reactive oxygen species and human spermatozoa: physiology and pathology,” International Journal of Andrology, vol. 20, no. 2, pp. 61–69, 1997.
[17]
B. T. Storey, “Biochemistry of the induction and prevention of lipoperoxidative damage in human spermatozoa,” Molecular Human Reproduction, vol. 3, no. 3, pp. 203–213, 1997.
[18]
R. J. Aitken, E. Gordon, D. Harkiss et al., “Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa,” Biology of Reproduction, vol. 59, no. 5, pp. 1037–1046, 1998.
[19]
G. Barroso, M. Morshedi, and S. Oehninger, “Analysis of DNA fragmentation, plasma membrane translocation of phosphatidylserine and oxidative stress in human spermatozoa,” Human Reproduction, vol. 15, no. 6, pp. 1338–1344, 2000.
[20]
F. Gallon, C. Marchetti, N. Jouy, and P. Marchetti, “The functionality of mitochondria differentiates human spermatozoa with high and low fertilizing capability,” Fertility and Sterility, vol. 86, no. 5, pp. 1526–1530, 2006.
[21]
A. J. Koppers, G. N. De Iuliis, J. M. Finnie, E. A. McLaughlin, and R. J. Aitken, “Significance of mitochondrial reactive oxygen species in the generation of oxidative stress in spermatozoa,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 8, pp. 3199–3207, 2008.
[22]
J. B. Anderson and R. C. N. Williamson, “Testicular torsion in bristol: a 25-year review,” British Journal of Surgery, vol. 75, no. 10, pp. 988–992, 1988.
[23]
W. Brennemann, B. Stoffel-Wagner, A. Helmers, J. Mezger, N. J？ger, and D. Klingmüller, “Gonadal function of patients treated with cisplatin based chemotherapy for germ cell cancer,” Journal of Urology, vol. 158, no. 3, pp. 844–850, 1997.
[24]
M. Hasegawa, G. Wilson, L. D. Russell, and M. L. Meistrich, “Radiation-induced cell death in the mouse testis: relationship to apoptosis,” Radiation Research, vol. 147, no. 4, pp. 457–467, 1997.
[25]
R. Smith, H. Kaune, D. Parodi et al., “Increased sperm DNA damage in patients with varicocele: relationship with seminal oxidative stress,” Human Reproduction, vol. 21, no. 4, pp. 986–993, 2006.
[26]
R. J. Aitken, D. Harkiss, W. Knox, M. Paterson, and D. S. Irvine, “A novel signal transduction cascade in capacitating human spermatozoa characterised by a redox-regulated, cAMP-mediated induction of tyrosine phosphorylation,” Journal of Cell Science, vol. 111, no. 5, pp. 645–656, 1998.
[27]
C. O'Flaherty and N. Beorlegui, “Role of superoxide anion and hydrogen peroxide in bovine acrosome reaction,” in Andrology in the 21st Century. Proceedings of the 7th International Congress of Andrology, B. Robaire, H. Chemes, and C. Morales, Eds., pp. 103–108, Medimond Publications, 2001.
[28]
E. de Lamirande and C. O'Flaherty, “Sperm activation: role of reactive oxygen species and kinases,” Biochimica et Biophysica Acta—Proteins and Proteomics, vol. 1784, no. 1, pp. 106–115, 2008.
[29]
E. de Lamirande and C. O'Flaherty, “Sperm capacitation as an oxidative event,” in Studies on Men's Health and Fertility, Oxidative Stress in Applied Basic Research and Clinical Practice, J. Aitken, J. Alvarez, and A. Agawarl, Eds., pp. 57–94, Springer Science, New York, NY, USA, 2012.
[30]
P. E. Visconti, J. L. Bailey, G. D. Moore, D. Pan, P. Olds-Clarke, and G. S. Kopf, “Capacitation of mouse spermatozoa. 1. Correlation between the capacitation state and protein tyrosine phosphorylation,” Development, vol. 121, no. 4, pp. 1129–1137, 1995.
[31]
P. E. Visconti and G. S. Kopf, “Regulation of protein phosphorylation during sperm capacitation,” Biology of Reproduction, vol. 59, no. 1, pp. 1–6, 1998.
[32]
C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Phosphorylation of the Arginine-X-X-(Serine/Threonine) motif in human sperm proteins during capacitation: modulation and protein kinase A dependency,” Molecular Human Reproduction, vol. 10, no. 5, pp. 355–363, 2004.
[33]
C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Reactive oxygen species and protein kinases modulate the level of phospho-MEK-like proteins during human sperm capacitation,” Biology of Reproduction, vol. 73, no. 1, pp. 94–105, 2005.
[34]
P. C. Rodriguez, C. M. O'Flaherty, M. T. Beconi, and N. B. Beorlegui, “Nitric oxide induces acrosome reaction in cryopreserved bovine spermatozoa,” Andrologia, vol. 37, no. 5, pp. 166–172, 2005.
[35]
P. C. Rodriguez, C. M. O'Flaherty, M. T. Beconi, and N. B. Beorlegui, “Nitric oxide-induced capacitation of cryopreserved bull spermatozoa and assessment of participating regulatory pathways,” Animal Reproduction Science, vol. 85, no. 3-4, pp. 231–242, 2005.
[36]
C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Positive role of reactive oxygen species in mammalian sperm capacitation: triggering and modulation of phosphorylation events,” Free Radical Biology and Medicine, vol. 41, no. 4, pp. 528–540, 2006.
[37]
C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Reactive oxygen species modulate independent protein phosphorylation pathways during human sperm capacitation,” Free Radical Biology and Medicine, vol. 40, no. 6, pp. 1045–1055, 2006.
[38]
P. C. Rodriguez, L. B. Valdez, T. Zaobornyj, A. Boveris, and M. T. Beconi, “Nitric oxide and superoxide anion production during heparin-induced capacitation in cryopreserved bovine spermatozoa,” Reproduction in Domestic Animals, vol. 46, no. 1, pp. 74–81, 2011.
[39]
K. Tremellen, “Oxidative stress and male infertility—a clinical perspective,” Human Reproduction Update, vol. 14, no. 3, pp. 243–258, 2008.
[40]
J. G. Alvarez, J. C. Touchstone, L. Blasco, and B. T. Storey, “Spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa. Superoxide dismutase as major enzyme protectant against oxygen toxicity,” Journal of Andrology, vol. 8, no. 5, pp. 338–348, 1987.
[41]
R. J. Aitken and B. J. Curry, “Redox regulation of human sperm function: from the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line,” Antioxidants and Redox Signaling, vol. 14, no. 3, pp. 367–381, 2011.
[42]
B. Halliwell and J. Gutteridge, “The chemistry of free radicals and related reactive species,” in Free Radicals in Biology and Medicine, B. Halliwell and J. Gutteridge, Eds., pp. 30–74, Oxford University Press, New York, NY, USA, 2007.
[43]
B. Halliwell, “Free radicals and antioxidants: updating a personal view,” Nutrition Reviews, vol. 70, no. 5, pp. 257–265, 2012.
[44]
A. Iwasaki and C. Gagnon, “Formation of reactive oxygen species in spermatozoa of infertile patients,” Fertility and Sterility, vol. 57, no. 2, pp. 409–416, 1992.
[45]
R. J. Aitken, D. W. Buckingham, A. Carreras, and D. S. Irvine, “Superoxide dismutase in human sperm suspensions: relationship with cellular composition, oxidative stress, and sperm function,” Free Radical Biology and Medicine, vol. 21, no. 4, pp. 495–504, 1996.
[46]
M. R. F. Mennella and R. Jones, “Properties of spermatozoal superoxide dismutase and lack of involvement of superoxides in metal-ion-catalysed lipid-peroxidation reactions in semen,” Biochemical Journal, vol. 191, no. 2, pp. 289–297, 1980.
[47]
J. G. Alvarez and B. T. Storey, “Lipid peroxidation and the reactions of superoxide and hydrogen peroxide in mouse spermatozoa,” Biology of Reproduction, vol. 30, no. 4, pp. 833–841, 1984.
[48]
F. Tramer, F. Rocco, F. Micali, G. Sandri, and E. Panfil, “Antioxidant systems in rat epididymal spermatozoa,” Biology of Reproduction, vol. 59, no. 4, pp. 753–758, 1998.
[49]
P. Cassani, M. T. Beconi, and C. O'Flaherty, “Relationship between total superoxide dismutase activity with lipid peroxidation, dynamics and morphological parameters in canine semen,” Animal Reproduction Science, vol. 86, no. 1-2, pp. 163–173, 2005.
[50]
A. Zini, E. de Lamirande, and C. Gagnon, “Reactive oxygen species in semen of infertile patients: levels of superoxide dismutase- and catalase-like activities in seminal plasma and spermatozoa,” International Journal of Andrology, vol. 16, no. 3, pp. 183–188, 1993.
[51]
J. Aitken, C. Krausz, and D. Buckingham, “Relationships between biochemical markers for residual sperm cytoplasm, reactive oxygen species generation, and the presence of leukocytes and precursor germ cells in human sperm suspensions,” Molecular Reproduction and Development, vol. 39, no. 3, pp. 268–279, 1994.
[52]
R. Peeker, L. Abramsson, and S. L. Marklund, “Superoxide dismutase isoenzymes in human seminal plasma and spermatozoa,” Molecular Human Reproduction, vol. 3, no. 12, pp. 1061–1066, 1997.
[53]
A. Zini, K. Garrels, and D. Phang, “Antioxidant activity in the semen of fertile and infertile men,” Urology, vol. 55, no. 6, pp. 922–926, 2000.
[54]
J. F. Griveau, E. Dumont, P. Renard, J. P. Callegari, and D. Le Lannou, “Reactive oxygen species, lipid peroxidation and enzymatic defence systems in human spermatozoa,” Journal of Reproduction and Fertility, vol. 103, no. 1, pp. 17–26, 1995.
[55]
J. P. Kehrer, “The Haber-Weiss reaction and mechanisms of toxicity,” Toxicology, vol. 149, no. 1, pp. 43–50, 2000.
[56]
J. G. Alvarez and R. J. Aitken, “Lipid peroxidation in human spermatozoa,” in Studies on Men's Health and Fertility, A. Agarwal, R. J. Aitken, and J. G. Alvarez, Eds., pp. 119–130, Humana Press, New York, NY, USA, 2012.
[57]
I. S. Young and J. McEneny, “Lipoprotein oxidation and atherosclerosis,” Biochemical Society Transactions, vol. 29, no. 2, pp. 358–362, 2001.
[58]
B. Chance, H. Sies, and A. Boveris, “Hydroperoxide metabolism in mammalian organs,” Physiological Reviews, vol. 59, no. 3, pp. 527–605, 1979.
[59]
M. Schrader and H. D. Fahimi, “Mammalian peroxisomes and reactive oxygen species,” Histochemistry and Cell Biology, vol. 122, no. 4, pp. 383–393, 2004.
[60]
G. H. Lüers, S. Thiele, A. Schad, A. V？lkl, S. Yokota, and J. Seitz, “Peroxisomes are present in murine spermatogonia and disappear during the course of spermatogenesis,” Histochemistry and Cell Biology, vol. 125, no. 6, pp. 693–703, 2006.
[61]
A. Nenicu, G. H. Lüers, W. Kovacs, M. Bergmann, and E. Baumgart-Vogt, “Peroxisomes in human and mouse testis: differential expression of peroxisomal proteins in germ cells and distinct somatic cell types of the testis,” Biology of Reproduction, vol. 77, no. 6, pp. 1060–1072, 2007.
[62]
S. Lapointe, R. Sullivan, and M. Sirard, “Binding of a bovine oviductal fluid catalase to mammalian spermatozoa,” Biology of Reproduction, vol. 58, no. 3, pp. 747–753, 1998.
[63]
C. O'Flaherty, “Peroxiredoxins, hidden players in the antioxidant defence of human spermatozoa,” Basic and Clinical Andrology, vol. 24, article 4, 2014.
[64]
H. Sies, V. S. Sharov, L. Klotz, and K. Briviba, “Glutathione peroxidase protects against peroxynitrite-mediated oxidations: a new function for selenoproteins as peroxynitrite reductase,” Journal of Biological Chemistry, vol. 272, no. 44, pp. 27812–27817, 1997.
[65]
K. Takahashi, N. Avissar, J. Whitin, and H. Cohen, “Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme,” Archives of Biochemistry and Biophysics, vol. 256, no. 2, pp. 677–686, 1987.
[66]
N. B. Ghyselinck, C. Jimenez, Y. Courty, and J. P. Dufaure, “Androgen-dependent messenger RNA(s) related to secretory proteins in the mouse epididymis,” Journal of Reproduction and Fertility, vol. 85, no. 2, pp. 631–639, 1989.
[67]
F.-. Chu, J. H. Doroshow, and R. S. Esworthy, “Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI,” The Journal of Biological Chemistry, vol. 268, no. 4, pp. 2571–2576, 1993.
[68]
F. Ursini, M. Maiorino, and C. Gregolin, “The selenoenzyme phospholipid hydroperoxide glutathione peroxidase,” Biochimica et Biophysica Acta—General Subjects, vol. 839, no. 1, pp. 62–70, 1985.
[69]
S. Herbette, P. Roeckel-Drevet, and J. R. Drevet, “Seleno-independent glutathione peroxidases: More than simple antioxidant scavengers,” The FEBS Journal, vol. 274, no. 9, pp. 2163–2180, 2007.
[70]
A. Vignini, L. Nanetti, E. Buldreghini et al., “The production of peroxynitrite by human spermatozoa may affect sperm motility through the formation of protein nitrotyrosine,” Fertility and Sterility, vol. 85, no. 4, pp. 947–953, 2006.
[71]
T. Morielli and C. O'Flaherty, “Oxidative stress promotes protein tyrosine nitration and S-glutathionylation impairing motility and capacitation in human spermatozoa,” Free Radical Biology and Medicine, vol. 53, article S137, 2012.
[72]
F. Ursini, S. Heim, M. Kiess et al., “Dual function of the selenoprotein PHGPx during sperm maturation,” Science, vol. 285, no. 5432, pp. 1393–1396, 1999.
[73]
H. Imai, N. Hakkaku, R. Iwamoto et al., “Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice,” Journal of Biological Chemistry, vol. 284, no. 47, pp. 32522–32532, 2009.
[74]
M. Schneider, H. F？rster, A. Boersma et al., “Mitochondrial glutathione peroxidase 4 disruption causes male infertility,” The FASEB Journal, vol. 23, no. 9, pp. 3233–3242, 2009.
[75]
H. Imai, K. Suzuki, K. Ishizaka et al., “Failure of the expression of phospholipid hydroperoxide glutathione peroxidase in the spermatozoa of human infertile males,” Biology of Reproduction, vol. 64, no. 2, pp. 674–683, 2001.
[76]
N. Kaushal and M. P. Bansal, “Diminished reproductive potential of male mice in response to selenium-induced oxidative stress: involvement of HSP70, HSP70-2, and MSJ-1,” Journal of Biochemical and Molecular Toxicology, vol. 23, no. 2, pp. 125–136, 2009.
[77]
L. Flohé, “Selenium in mammalian spermiogenesis,” Biological Chemistry, vol. 388, no. 10, pp. 987–995, 2007.
[78]
M. Conrad, S. G. Moreno, F. Sinowatz et al., “The nuclear form of phospholipid hydroperoxide glutathione peroxidase is a protein thiol peroxidase contributing to sperm chromatin stability,” Molecular and Cellular Biology, vol. 25, no. 17, pp. 7637–7644, 2005.
[79]
K. Williams, J. Frayne, and L. Hall, “Expression of extracellular glutathione peroxidase type 5 (GPX5) in the rat male reproductive tract,” Molecular Human Reproduction, vol. 4, no. 9, pp. 841–848, 1998.
[80]
E. Chabory, C. Damon, A. Lenoir et al., “Mammalian glutathione peroxidases control acquisition and maintenance of spermatozoa integrity,” Journal of Animal Science, vol. 88, no. 4, pp. 1321–1331, 2010.
[81]
C. Foresta, L. Flohé, A. Garolla, A. Roveri, F. Ursini, and M. Maiorino, “Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase,” Biology of Reproduction, vol. 67, no. 3, pp. 967–971, 2002.
[82]
N. Garrido, M. Meseguer, J. Alvarez, C. Simón, A. Pellicer, and J. Remohí, “Relationship among standard semen parameters, glutathione peroxidase/glutathione reductase activity, and mRNA expression and reduced glutathione content in ejaculated spermatozoa from fertile and infertile men,” Fertility and Sterility, vol. 82, supplement 3, pp. 1059–1066, 2004.
[83]
Y. Ho, J. Magnenat, R. T. Bronson et al., “Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia,” Journal of Biological Chemistry, vol. 272, no. 26, pp. 16644–16651, 1997.
[84]
B. Gopalakrishnan, S. Aravinda, C. H. Pawshe et al., “Studies on glutathione S-transferases important for sperm function: evidence of catalytic activity-independent functions,” Biochemical Journal, vol. 329, no. 2, pp. 231–241, 1998.
[85]
T. Hemachand, B. Gopalakrishnan, D. M. Salunke, S. M. Totey, and C. Shaha, “Sperm plasma-membrane-associated glutathione S-transferases as gamete recognition molecules,” Journal of Cell Science, vol. 115, no. 10, pp. 2053–2065, 2002.
[86]
B. Aydemir, I. Onaran, A. R. Kiziler, B. Alici, and M. C. Akyolcu, “Increased oxidative damage of sperm and seminal plasma in men with idiopathic infertility is higher in patients with glutathione S-transferase Mu-1 null genotype,” Asian Journal of Andrology, vol. 9, no. 1, pp. 108–115, 2007.
[87]
M. T. M. Raijmakers, H. M. J. Roelofs, E. A. P. Steegers et al., “Glutathione and glutathione S-transferases A1-1 and P1-1 in seminal plasma may play a role in protecting against oxidative damage to spermatozoa,” Fertility and Sterility, vol. 79, no. 1, pp. 169–172, 2003.
[88]
A. F. Olshan, T. J. Luben, N. M. Hanley et al., “Preliminary examination of polymorphisms of GSTM1, GSTT1, and GSTZ1 in relation to semen quality,” Mutation Research—Fundamental and Molecular Mechanisms of Mutagenesis, vol. 688, no. 1-2, pp. 41–46, 2010.
[89]
J. A. Ross, N. E. Watson Jr., and J. P. Jarow, “The effect of varicoceles on testicular blood flow in man,” Urology, vol. 44, no. 4, pp. 535–539, 1994.
[90]
H. Z. Chae, S. J. Chung, and S. G. Rhee, “Thioredoxin-dependent peroxide reductase from yeast,” Journal of Biological Chemistry, vol. 269, no. 44, pp. 27670–27678, 1994.
[91]
T. Ishii, T. Kawane, S. Taketani, and S. Bannai, “Inhibition of the thiol-specific antioxidant activity of rat liver MSP23 protein by hemin,” Biochemical and Biophysical Research Communications, vol. 216, no. 3, pp. 970–975, 1995.
[92]
D. Jin, H. Z. Chae, S. G. Rhee, and K. Jeang, “Regulatory role for a novel human thioredoxin peroxidase in NF-κB activation,” The Journal of Biological Chemistry, vol. 272, no. 49, pp. 30952–30961, 1997.
[93]
V. Syed and N. B. Hecht, “Rat pachytene spermatocytes down-regulate a pololike kinase and up- regulate a thiol-specific antioxidant protein, whereas sertoli cells down- regulate a phosphodiesterase and up-regulate an oxidative stress protein after exposure to methoxyethanol and methoxyacetic acid,” Endocrinology, vol. 139, no. 8, pp. 3503–3511, 1998.
[94]
S. G. Rhee, S. W. Kang, L. E. Netto, M. S. Seo, and E. R. Stadtman, “A family of novel peroxidases, peroxiredoxins,” BioFactors, vol. 10, no. 2-3, pp. 207–209, 1999.
[95]
S. G. Rhee, S. W. Kang, T.-S. Chang, W. Jeong, and K. Kim, “Peroxiredoxin, a novel family of peroxidases,” IUBMB Life, vol. 52, no. 1-2, pp. 35–41, 2001.
[96]
Z. A. Wood, L. B. Poole, and P. A. Karplus, “Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling,” Science, vol. 300, no. 5619, pp. 650–653, 2003.
[97]
Z. A. Wood, E. Schr？der, J. R. Harris, and L. B. Poole, “Structure, mechanism and regulation of peroxiredoxins,” Trends in Biochemical Sciences, vol. 28, no. 1, pp. 32–40, 2003.
[98]
G. R. Sue, Z. C. Ho, and K. Kim, “Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling,” Free Radical Biology and Medicine, vol. 38, no. 12, pp. 1543–1552, 2005.
[99]
P. Zhang, B. Liu, S. W. Kang, M. S. Seo, S. G. Rhee, and L. M. Obeid, “Thioredoxin peroxidase is a novel inhibitor of apoptosis with a mechanism distinct from that of Bcl-2,” The Journal of Biological Chemistry, vol. 272, no. 49, pp. 30615–30618, 1997.
[100]
I. V. Peshenko and H. Shichi, “Oxidation of active center cysteine of bovine 1-Cys peroxiredoxin to the cysteine sulfenic acid form by peroxide and peroxynitrite,” Free Radical Biology and Medicine, vol. 31, no. 3, pp. 292–303, 2001.
[101]
M. Dubuisson, D. V. Stricht, A. Clippe et al., “Human peroxiredoxin 5 is a peroxynitrite reductase,” FEBS Letters, vol. 571, no. 1-3, pp. 161–165, 2004.
[102]
L. Flohé, S. Toppo, G. Cozza, and F. Ursini, “A comparison of thiol peroxidase mechanisms,” Antioxidants and Redox Signaling, vol. 15, no. 3, pp. 763–780, 2011.
[103]
S. W. Kang, H. Z. Chae, M. S. Seo, K. Kim, I. C. Baines, and S. G. Rhee, “Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generatedin response to growth factors and tumor necrosis factor-α,” Journal of Biological Chemistry, vol. 273, no. 11, pp. 6297–6302, 1998.
[104]
L. A. Ralat, Y. Manevich, A. B. Fisher, and R. F. Colman, “Direct evidence for the formation of a complex between 1-cysteine peroxiredoxin and glutathione S-transferase π with activity changes in both enzymes,” Biochemistry, vol. 45, no. 2, pp. 360–372, 2006.
[105]
L. A. Ralat, S. A. Misquitta, Y. Manevich, A. B. Fisher, and R. F. Colman, “Characterization of the complex of glutathione S-transferase pi and 1-cysteine peroxiredoxin,” Archives of Biochemistry and Biophysics, vol. 474, no. 1, pp. 109–118, 2008.
[106]
J. W. Baty, M. B. Hampton, and C. C. Winterbourn, “Proteomic detection of hydrogen peroxide-sensitive thiol proteins in Jurkat cells,” Biochemical Journal, vol. 389, part 3, pp. 785–795, 2005.
[107]
A. G. Cox and M. B. Hampton, “Bcl-2 over-expression promotes genomic instability by inhibiting apoptosis of cells exposed to hydrogen peroxide,” Carcinogenesis, vol. 28, no. 10, pp. 2166–2171, 2007.
[108]
F. M. Low, M. B. Hampton, A. V. Peskin, and C. C. Winterbourn, “Peroxiredoxin 2 functions as a noncatalytic scavenger of low-level hydrogen peroxide in the erythrocyte,” Blood, vol. 109, no. 6, pp. 2611–2617, 2007.
[109]
A. V. Peskin, F. M. Low, L. N. Paton, G. J. Maghzal, M. B. Hampton, and C. C. Winterbourn, “The high reactivity of peroxiredoxin 2 with H2O2 is not reflected in its reaction with other oxidants and thiol reagents,” Journal of Biological Chemistry, vol. 282, no. 16, pp. 11885–11892, 2007.
[110]
C. O'Flaherty and A. R. De Souza, “Hydrogen peroxide modifies human sperm peroxiredoxins in a dose-dependent manner,” Biology of Reproduction, vol. 84, no. 2, pp. 238–247, 2011.
[111]
S. G. Rhee, S. W. Kang, W. Jeong, T. S. Chang, K. S. Yang, and H. A. Woo, “Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins,” Current Opinion in Cell Biology, vol. 17, no. 2, pp. 183–189, 2005.
[112]
S. G. Rhee, “H2O2, a necessary evil for cell signaling,” Science, vol. 312, no. 5782, pp. 1882–1883, 2006.
[113]
I. Banmeyer, C. Marchand, C. Verhaeghe, B. Vucic, J. Rees, and B. Knoops, “Overexpression of human peroxiredoxin 5 in subcellular compartments of Chinese hamster ovary cells: effects on cytotoxicity and DNA damage caused by peroxides,” Free Radical Biology and Medicine, vol. 36, no. 1, pp. 65–77, 2004.
[114]
S. Immenschuh, E. Baumgart-Vogt, M. Tan, S. Iwahara, G. Ramadori, and H. D. Fahimi, “Differential cellular and subcellular localization of heme-binding protein 23/peroxiredoxin I and heme oxygenase-1 in rat liver,” Journal of Histochemistry & Cytochemistry, vol. 51, no. 12, pp. 1621–1631, 2003.
[115]
M. S. Seo, S. W. Kang, K. Kim, I. C. Baines, T. H. Lee, and S. G. Rhee, “Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate,” Journal of Biological Chemistry, vol. 275, no. 27, pp. 20346–20354, 2000.
[116]
V. J. Thannickal and B. L. Fanburg, “Reactive oxygen species in cell signaling,” American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 279, no. 6, pp. L1005–L1028, 2000.
[117]
T. D. Oberley, E. Verwiebe, W. Zhong, S. W. Kang, and S. G. Rhee, “Localization of the thioredoxin system in normal rat kidney,” Free Radical Biology and Medicine, vol. 30, no. 4, pp. 412–424, 2001.
[118]
R. A. van Gestel, I. A. Brewis, P. R. Ashton, J. F. Brouwers, and B. M. Gadella, “Multiple proteins present in purified porcine sperm apical plasma membranes interact with the zona pellucida of the oocyte,” Molecular Human Reproduction, vol. 13, no. 7, pp. 445–454, 2007.
[119]
K. Park, S. Jeon, Y. Song, and L. S. H. Yi, “Proteomic analysis of boar spermatozoa and quantity changes of superoxide dismutase 1, glutathione peroxidase, and peroxiredoxin 5 during epididymal maturation,” Animal Reproduction Science, vol. 135, no. 1–4, pp. 53–61, 2012.
[120]
S. Gong, M. C. S. Gabriel, A. Zini, P. Chan, and C. O'flaherty, “Low amounts and high thiol oxidation of peroxiredoxins in spermatozoa from infertile men,” Journal of Andrology, vol. 33, no. 6, pp. 1342–1351, 2012.
[121]
Y. Iuchi, F. Okada, S. Tsunoda et al., “Peroxiredoxin 4 knockout results in elevated spermatogenic cell death via oxidative stress,” Biochemical Journal, vol. 419, no. 1, pp. 149–158, 2009.
[122]
B. Ozkosem and C. O'Flaherty, “Detrimental effects of oxidative stress on spermatozoa lacking peroxiredoxin 6,” Free Radical Biology and Medicine, vol. 53, supplement 2, p. S86, 2012.
[123]
C. A. Neumann, D. S. Krause, C. V. Carman et al., “Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression,” Nature, vol. 424, no. 6948, pp. 561–565, 2003.
[124]
R. A. Egler, E. Fernandes, K. Rothermund et al., “Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1,” Oncogene, vol. 24, no. 54, pp. 8038–8050, 2005.
[125]
Y. Han, H. Kim, J. Kim, S. Kim, D. Yu, and E. Moon, “Inhibitory role of peroxiredoxin II (Prx II) on cellular senescence,” FEBS Letters, vol. 579, no. 21, pp. 4897–4902, 2005.
[126]
G. Manandhar, A. Miranda-Vizuete, J. R. Pedrajas et al., “Peroxiredoxin 2 and peroxidase enzymatic activity of mammalian spermatozoa,” Biology of Reproduction, vol. 80, no. 6, pp. 1168–1177, 2009.
[127]
A. G. Cox, C. C. Winterbourn, and M. B. Hampton, “Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling,” Biochemical Journal, vol. 425, no. 2, pp. 313–325, 2010.
[128]
A. J. Koppers, M. L. Garg, and R. J. Aitken, “Stimulation of mitochondrial reactive oxygen species production by unesterified, unsaturated fatty acids in defective human spermatozoa,” Free Radical Biology and Medicine, vol. 48, no. 1, pp. 112–119, 2010.
[129]
R. J. Aitken and G. N. De Iuliis, “On the possible origins of DNA damage in human spermatozoa,” Molecular Human Reproduction, vol. 16, no. 1, pp. 3–13, 2009.
[130]
E. S. J. Arnér and A. Holmgren, “Physiological functions of thioredoxin and thioredoxin reductase,” European Journal of Biochemistry, vol. 267, no. 20, pp. 6102–6109, 2000.
[131]
Y. Meyer, W. Siala, T. Bashandy, C. Riondet, F. Vignols, and J. P. Reichheld, “Glutaredoxins and thioredoxins in plants,” Biochimica et Biophysica Acta—Molecular Cell Research, vol. 1783, no. 4, pp. 589–600, 2008.
[132]
E. M. Hanschmann, J. R. Godoy, C. Berndt, C. Hudemann, and C. H. Lillig, “Thioredoxins, glutaredoxins, and peroxiredoxins-molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling,” Antioxidants & Redox Signaling, vol. 19, pp. 1539–1605, 2013.
[133]
M. Lukosz, S. Jakob, N. Büchner, T. Zschauer, J. Altschmied, and J. Haendeler, “Nuclear redox signaling,” Antioxidants and Redox Signaling, vol. 12, no. 6, pp. 713–742, 2010.
[134]
P. A. Mitozo, L. F. de Souza, G. Loch-Neckel et al., “A study of the relative importance of the peroxiredoxin-, catalase-, and glutathione-dependent systems in neural peroxide metabolism,” Free Radical Biology and Medicine, vol. 51, no. 1, pp. 69–77, 2011.
[135]
A. Miranda-Vizuete, J. Ljung, A. E. Damdimopoulos et al., “Characterization of Sptrx, a novel member of the thioredoxin family specifically expressed in human spermatozoa,” The Journal of Biological Chemistry, vol. 276, no. 34, pp. 31567–31574, 2001.
[136]
A. Miranda-Vizuete, K. Tsang, Y. Yu et al., “Cloning and developmental analysis of murid spermatid-specific thioredoxin-2 (SPTRX-2), a novel sperm fibrous sheath protein and autoantigen,” The Journal of Biological Chemistry, vol. 278, no. 45, pp. 44874–44885, 2003.
[137]
A. Jiménez, C. Johansson, J. Ljung et al., “Human spermatid-specific thioredoxin-1 (Sptrx-1) is a two-domain protein with oxidizing activity,” FEBS Letters, vol. 530, no. 1–3, pp. 79–84, 2002.
[138]
Y. Yu, R. Oko, and A. Miranda-Vizuete, “Developmental expression of spermatid-specific thioredoxin-1 protein: transient association to the longitudinal columns of the fibrous sheath during sperm tail formation,” Biology of Reproduction, vol. 67, no. 5, pp. 1546–1554, 2002.
[139]
A. Miranda-Vizuete, C. M. Sadek, A. Jiménez, W. J. Krause, P. Sutovsky, and R. Oko, “The mammalian testis-specific thioredoxin system,” Antioxidants and Redox Signaling, vol. 6, no. 1, pp. 25–40, 2004.
[140]
C. Buckman, C. Ozanon, J. Qiu et al., “Semen levels of spermatid-specific thioredoxin-3 correlate with pregnancy rates in ART couples,” PLoS ONE, vol. 8, no. 5, Article ID e61000, 2013.
[141]
C. M. Sadek, A. Jiménez, A. E. Damdimopoulos et al., “Characterization of human thioredoxin-like 2: a novel microtubule-binding thioredoxin expressed predominantly in the cilia of lung airway epithelium and spermatid manchette and axoneme,” The Journal of Biological Chemistry, vol. 278, no. 15, pp. 13133–13142, 2003.
[142]
T. B. Smith, M. A. Baker, H. S. Connaughton, U. Habenicht, and R. J. Aitken, “Functional deletion of Txndc2 and Txndc3 increases the susceptibility of spermatozoa to age-related oxidative stress,” Free Radical Biology & Medicine, vol. 65, pp. 872–881, 2013.
[143]
H. H. Jang, K. O. Lee, Y. H. Chi et al., “Two enzymes in one: two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function,” Cell, vol. 117, no. 5, pp. 625–635, 2004.
[144]
J. C. Moon, Y. Hah, W. Y. Kim et al., “Oxidative stress-dependent structural and functional switching of a human 2-Cys peroxiredoxin isotype II that enhances HeLa cell resistance to H2O2-induced cell death,” Journal of Biological Chemistry, vol. 280, no. 31, pp. 28775–28784, 2005.
[145]
C. A. Neumann, J. Cao, and Y. Manevich, “Peroxiredoxin 1 and its role in cell signaling,” Cell Cycle, vol. 8, no. 24, pp. 4072–4078, 2009.
[146]
H. Z. Chae, H. Oubrahim, J. W. Park, S. G. Rhee, and P. B. Chock, “Protein glutathionylation in the regulation of peroxiredoxins: A family of thiol-specific peroxidases that function as antioxidants, molecular chaperones, and signal modulators,” Antioxidants and Redox Signaling, vol. 16, no. 6, pp. 506–523, 2012.
[147]
S. G. Rhee and H. A. Woo, “Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones,” Antioxidants & Redox Signaling, vol. 15, no. 3, pp. 781–794, 2011.
[148]
T. Chang, W. Jeong, A. W. Hyun, M. L. Sun, S. Park, and G. R. Sue, “Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine,” The Journal of Biological Chemistry, vol. 279, no. 49, pp. 50994–51001, 2004.
[149]
T. J. J？nsson and W. T. Lowther, “The peroxiredoxin repair proteins,” Subcellular Biochemistry, vol. 44, pp. 115–141, 2007.
[150]
P. B. Kopnin, L. S. Agapova, B. P. Kopnin, and P. M. Chumakov, “Repression of sestrin family genes contributes to oncogenic Ras-induced reactive oxygen species up-regulation and genetic instability,” Cancer Research, vol. 67, no. 10, pp. 4671–4678, 2007.
[151]
J. Y. Baek, S. H. Han, S. H. Sung et al., “Sulfiredoxin protein is critical for redox balance and survival of cells exposed to low steady-state levels of H2O2,” Journal of Biological Chemistry, vol. 287, no. 1, pp. 81–89, 2012.
[152]
K. Abbas, S. Riquier, and J. Drapier, “Peroxiredoxins and sulfiredoxin at the crossroads of the NO and H2O2 signaling pathways,” Methods in Enzymology, vol. 527, pp. 113–128, 2013.
[153]
Y. Manevich, T. Shuvaeva, C. Dodia, A. Kazi, S. I. Feinstein, and A. B. Fisher, “Binding of peroxiredoxin 6 to substrate determines differential phospholipid hydroperoxide peroxidase and phospholipase A2 activities,” Archives of Biochemistry and Biophysics, vol. 485, no. 2, pp. 139–149, 2009.
[154]
S. Sarkar, A. J. Nelson, and O. W. Jones, “Glucose-6-phosphate dehydrogenase (G6PD) activity of human sperm,” Journal of Medical Genetics, vol. 14, no. 4, pp. 250–255, 1977.
[155]
C. O'Flaherty, N. Beorlegui, and M. T. Beconi, “Heparin- and superoxide anion-dependent capacitation of cryopreserved bovine spermatozoa: Requirement of dehydrogenases and protein kinases,” Free Radical Research, vol. 40, no. 4, pp. 427–432, 2006.
[156]
T. K. Li, “The glutathione and thiol content of mammalian spermatozoa and seminal plasma,” Biology of Reproduction, vol. 12, no. 5, pp. 641–646, 1975.
[157]
B. Halliwell and J. Gutteridge, “Antioxidant defences: endogenous and diet derived,” in Free Radicals in Biology and Medicine, B. Halliwell and J. Gutteridge, Eds., pp. 79–186, Oxford University Press, New York, NY, USA, 2007.
[158]
S. Zhou, Y. Lien, T. Shuvaeva, K. Debolt, S. I. Feinstein, and A. B. Fisher, “Functional interaction of glutathione S-transferase pi and peroxiredoxin 6 in intact cells,” International Journal of Biochemistry and Cell Biology, vol. 45, no. 2, pp. 401–407, 2013.
[159]
I. S. Kil and J. Park, “Regulation of mitochondrial NADP+-dependent isocitrate dehydrogenase activity by glutathionylation,” Journal of Biological Chemistry, vol. 280, no. 11, pp. 10846–10854, 2005.
