The interaction between a genetic variant in the NQO1 gene and environmental influences involving coenzyme Q10 has a significant impact on sperm motility
Keywords:
male infertility, asthenozoospermia, coenzyme Q10, NQO1 geneAbstract
Background and aim: Asthenozoospermia is a condition characterized by reduced sperm motility. Oxidative stress is known to impact sperm parameters, but Coenzyme Q10 (CoQ10), as an antioxidant, protects sperm from such damage. CoQ10 antioxidant activity requires reduction by the NAD(P) oxidoreductase 1(NQO1) enzyme. This study investigated the association between CoQ10 levels in seminal plasma, the NQO1P187S variant of the NQO1 gene, and asthenozoospermia risk.
Research Design and Methods: A case-control study that included 127 asthenozoospermic patients and 55 normozoospermic controls was employed. Levels of CoQ10 in seminal plasma were measured using high-performance liquid chromatography (HPLC). The amplification refractory mutation system (ARMS)-PCR was used to detect the NQO1P187S polymorphism.
Results: Asthenozoospemic patients had significantly lower levels of CoQ10 compared to normozoospermic controls (P=0.02). Additionally, asthenozoospermic patients with the CT/TT genotypes had lower levels of CoQ10 than controls carrying the same genotypes of the NQO1P187S variant. Regression analysis showed that CT/TT genotype was associated with an 8-fold increase in asthenozoospermia risk (OR=8.57, 95%CI: 2.09-3517, P=.003). Furthermore, a 1-unit increase in CoQ10 levels in participants with the CT/TT genotype was associated with a 3% reduction in asthenozoospermia risk.
Conclusion: This study is the first in Jordan to provide evidence that an association between asthenozoospermia and CoQ10 levels in seminal plasma is influenced by the genetic background. CoQ10 protective role is affected by genetic variations of the NQO1P187S. This finding highlights an interaction between genetic and environmental factors in determining the risk of asthenozoospermia.
References
Rajender S, Rahul P, Mahdi AA. Mitochondria, spermatogenesis and male infertility. Mitochondrion. 2010;10(5):419-28. doi: 10.1016/j.mito.2010.05.015.
Agarwal A, Makker K, Sharma R. Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol. 2008;59(1):2-11. doi: 10.1111/j.1600-0897.2007.00559.x.
Moore FL, Reijo-Pera RA. Male sperm motility dictated by mother's mtDNA. Am J Hum Genet. 2000;67(3):543-8. doi: 10.1086/303061.
Okabe M, Ikawa M, Ashkenas J. Male infertility and the genetics of spermatogenesis. Am J Hum Genet. 1998;62(6):1274-81. doi: 10.1086/301895.
O'Flynn O'Brien KL, Varghese AC, Agarwal A. The genetic causes of male factor infertility: a review. Fertil Steril. 2010;93(1):1-12. doi: 10.1016/j.fertnstert.2009.10.045.
Ferlin A, Arredi B, Foresta C. Genetic causes of male infertility. Reprod Toxicol. 2006;22(2):133-41. doi: 10.1016/j.reprotox.2006.04.016.
Pant N, Kumar G, Upadhyay AD, Gupta YK, Chaturvedi PK. Correlation between lead and cadmium concentration and semen quality. Andrologia. 2015;47(8):887-91. doi: 10.1111/and.12342.
World Health Organization. WHO laboratory manual for the examination and processing of human semen. Geneva: World Health Organization; 2021. Report No.: ISBN: 978 92 4 0030787.
Agarwal A, Parekh N, Panner Selvam MK, et al. Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility. World J Mens Health. 2019;37(3):296-312. doi: 10.5534/wjmh.190055.
Agarwal A, Rana M, Qiu E, AlBunni H, Bui AD, Henkel R. Role of oxidative stress, infection and inflammation in male infertility. Andrologia. 2018;50(11):e13126. doi: 10.1111/and.13126.
O'Flaherty C. Reactive Oxygen Species and Male Fertility. Antioxidants (Basel). 2020;9(4). doi: 10.3390/antiox9040287.
Sabeti P, Pourmasumi S, Rahiminia T, Akyash F, Talebi AR. Etiologies of sperm oxidative stress. Int J Reprod Biomed. 2016;14(4):231-40. doi: PMC4918773.
Inupakutika MA, Sengupta S, Devireddy AR, Azad RK, Mittler R. The evolution of reactive oxygen species metabolism. J Exp Bot. 2016;67(21):5933-43. doi: 10.1093/jxb/erw382.
Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014;24(10):R453-62. doi: 10.1016/j.cub.2014.03.034.
Alshahrani S, Agarwal A, Assidi M, et al. Infertile men older than 40 years are at higher risk of sperm DNA damage. Reprod Biol Endocrinol. 2014;12:103. doi: 10.1186/1477-7827-12-103.
Sanocka D, Kurpisz M. Reactive oxygen species and sperm cells. Reprod Biol Endocrinol. 2004;2:12. doi: 10.1186/1477-7827-2-12.
Kemal Duru N, Morshedi M, Oehninger S. Effects of hydrogen peroxide on DNA and plasma membrane integrity of human spermatozoa. Fertil Steril. 2000;74(6):1200-7. doi: 10.1016/s0015-0282(00)01591-0.
Wang X, Sharma RK, Sikka SC, Thomas AJ, Jr., Falcone T, Agarwal A. Oxidative stress is associated with increased apoptosis leading to spermatozoa DNA damage in patients with male factor infertility. Fertil Steril. 2003;80(3):531-5. doi: 10.1016/s0015-0282(03)00756-8.
Bhagavan HN, Chopra RK. Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics. Free Radic Res. 2006;40(5):445-53. doi: 10.1080/10715760600617843.
Doimo M, Desbats MA, Cerqua C, Cassina M, Trevisson E, Salviati L. Genetics of coenzyme q10 deficiency. Mol Syndromol. 2014;5(3-4):156-62. doi: 10.1159/000362826.
Acosta MJ, Vazquez Fonseca L, Desbats MA, et al. Coenzyme Q biosynthesis in health and disease. Biochim Biophys Acta. 2016;1857(8):1079-85. doi: 10.1016/j.bbabio.2016.03.036.
Rodick T, Seibels D, Jeganathan R, Huggins K, Ren G, Mathews S. Potential role of coenzyme Q10 in health and disease conditions. Nutrition and Dietary Supplements. 2018;Volume 10:1-11. doi: 10.2147/NDS.S112119.
Alahmar AT, Sengupta P. Impact of Coenzyme Q10 and Selenium on Seminal Fluid Parameters and Antioxidant Status in Men with Idiopathic Infertility. Biological Trace Element Research. 2021;199(4):1246-52. doi: 10.1007/s12011-020-02251-3.
Gvozdjáková A, Kucharská J, Dubravicky J, Mojto V, Singh RB. Coenzyme Q₁₀, α-tocopherol, and oxidative stress could be important metabolic biomarkers of male infertility. Dis Markers. 2015;2015:827941. doi: 10.1155/2015/827941.
Nadjarzadeh A, Shidfar F, Amirjannati N, et al. Effect of Coenzyme Q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double-blind randomised clinical trial. Andrologia. 2014;46(2):177-83. doi: 10.1111/and.12062.
Barbonetti A, Tienforti D, Castellini C, et al. Effect of antioxidants on semen parameters in men with oligo-astheno-teratozoospermia: a network meta-analysis. Andrology. 2024;12(3):538-52. doi: 10.1111/andr.13498.
Siegel D, Ross D. Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med. 2000;29(3-4):246-53. doi: 10.1016/s0891-5849(00)00310-5.
Traver RD, Siegel D, Beall HD, et al. Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Br J Cancer. 1997;75(1):69-75. doi: 10.1038/bjc.1997.11.
Cadenas E. Antioxidant and prooxidant functions of DT-diaphorase in quinone metabolism. Biochem Pharmacol. 1995;49(2):127-40. doi: 10.1016/s0006-2952(94)00333-5.
Siegel D, Gustafson DL, Dehn DL, et al. NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol. 2004;65(5):1238-47. doi: 10.1124/mol.65.5.1238.
Hyun DH, Hernandez JO, Mattson MP, de Cabo R. The plasma membrane redox system in aging. Ageing Res Rev. 2006;5(2):209-20. doi: 10.1016/j.arr.2006.03.005.
Deller S, Macheroux P, Sollner S. Flavin-dependent quinone reductases. Cell Mol Life Sci. 2008;65(1):141-60. doi: 10.1007/s00018-007-7300-y.
Ross D, Siegel D. Functions of NQO1 in Cellular Protection and CoQ(10) Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. Front Physiol. 2017;8:595. doi: 10.3389/fphys.2017.00595.
Guha N, Chang JS, Chokkalingam AP, Wiemels JL, Smith MT, Buffler PA. NQO1 polymorphisms and de novo childhood leukemia: a HuGE review and meta-analysis. Am J Epidemiol. 2008;168(11):1221-32. doi: 10.1093/aje/kwn246.
Misra V, Grondin A, Klamut HJ, Rauth AM. Assessment of the relationship between genotypic status of a DT-diaphorase point mutation and enzymatic activity. Br J Cancer. 2000;83(8):998-1002. doi: 10.1054/bjoc.2000.1359.
Siegel D, McGuinness SM, Winski SL, Ross D. Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics. 1999;9(1):113-21. doi: 10.1097/00008571-199902000-00015.
Boto RE, Almeida P, Queiroz JA. Thiacarbocyanine as ligand in dye-affinity chromatography for protein purification. Biomed Chromatogr. 2008;22(3):278-88. doi: 10.1002/bmc.925.
Hussain T, Kandeel M, Metwally E, et al. Unraveling the harmful effect of oxidative stress on male fertility: A mechanistic insight. Front Endocrinol (Lausanne). 2023;14:1070692. doi: 10.3389/fendo.2023.1070692.
Balercia G, Mancini A, Paggi F, et al. Coenzyme Q10 and male infertility. J Endocrinol Invest. 2009;32(7):626-32. doi: 10.1007/bf03346521.
Salvio G, Cutini M, Ciarloni A, Giovannini L, Perrone M, Balercia G. Coenzyme Q10 and Male Infertility: A Systematic Review. Antioxidants (Basel). 2021;10(6). doi: 10.3390/antiox10060874.
Alahmar AT, Calogero AE, Singh R, Cannarella R, Sengupta P, Dutta S. Coenzyme Q10, oxidative stress, and male infertility: A review. Clin Exp Reprod Med. 2021;48(2):97-104. doi: 10.5653/cerm.2020.04175.
Alahmar AT, Calogero AE, Sengupta P, Dutta S. Coenzyme Q10 Improves Sperm Parameters, Oxidative Stress Markers and Sperm DNA Fragmentation in Infertile Patients with Idiopathic Oligoasthenozoospermia. World J Mens Health. 2021;39(2):346-51. doi: 10.5534/wjmh.190145.
Lee WS, Ham W, Kim J. Roles of NAD(P)H:quinone Oxidoreductase 1 in Diverse Diseases. Life (Basel). 2021;11(12). doi: 10.3390/life11121301.
Watanabe C, Osaka H, Watanabe M, et al. Total and reduced/oxidized forms of coenzyme Q(10) in fibroblasts of patients with mitochondrial disease. Mol Genet Metab Rep. 2023;34:100951. doi: 10.1016/j.ymgmr.2022.100951.
Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol. 2001;59(2):263-8. doi: 10.1124/mol.59.2.263.
Balercia G, Buldreghini E, Vignini A, et al. Coenzyme Q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo-controlled, double-blind randomized trial. Fertil Steril. 2009;91(5):1785-92. doi: 10.1016/j.fertnstert.2008.02.119.
Agarwal A, Sharma A, Master K, Sharma R, Henkel R. Meta-analysis of double-blind placebo control trials evaluating the role of coenzyme Q10 on semen parameters. Fertility and Sterility. 2018;110(4, Supplement):e167-e8. doi: 10.1016/j.fertnstert.2018.07.497.
Barcelos IP, Haas RH. CoQ10 and Aging. Biology (Basel). 2019;8(2). doi: 10.3390/biology8020028.
Kalén A, Appelkvist EL, Dallner G. Age-related changes in the lipid compositions of rat and human tissues. Lipids. 1989;24(7):579-84. doi: 10.1007/bf02535072.
Hargreaves IP, Duncan AJ, Heales SJ, Land JM. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf. 2005;28(8):659-76. doi: 10.2165/00002018-200528080-00002.
Fischer A, Schmelzer C, Rimbach G, Niklowitz P, Menke T, Döring F. Association between genetic variants in the Coenzyme Q10 metabolism and Coenzyme Q10 status in humans. BMC Res Notes. 2011;4:245. doi: 10.1186/1756-0500-4-245.
Kelsey KT, Ross D, Traver RD, et al. Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. Br J Cancer. 1997;76(7):852-4. doi: 10.1038/bjc.1997.474.
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