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:: Volume 26, Issue 6 (Bimonthly 2022) ::
Feyz 2022, 26(6): 739-749 Back to browse issues page
Importance of 1-carbon cycle antioxidant function in male fertility: A review article
Elham Ghajari , Shaghayegh Kiani , Nushin Naderi , Marziyeh Tvalaee * , Mohammad Hassan Meshkibaf , Mohammad Hossein Nasr-Esfahani
Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, I.R. Iran. , Tavalaee.royan@gmail.com
Abstract:   (609 Views)
Background: Spermatogenesis is a process that leads to the production and differentiation of sperm. During this process, various molecular and metabolic pathways are involved. "1-carbon cycle" is known as one of the most important metabolic cycles, which includes two cycles of folate and methionine and the transsulfuration pathway. This cycle has essential and vital roles in DNA and RNA methylation, DNA condensation and maturation, and maintaining the antioxidant balance in sperm. In this review, the importance of the 1-carbon cycle in the process of spermatogenesis has been considered.
Materials and Methods: Using the keywords of the study, related studies were reviewed from PubMed, Google Scholar and Science Direct databases between 1993 and 2021 in English, and the information of 69 selected articles was extracted.
Result: Disturbance in the 1-carbon cycle metabolism, such as the transsulfuration pathway, the re-methylation process, folate or cobalamin deficiency, and the presence of single nucleotide polymorphism of the MTHFR gene variant C677T, can affect DNA and RNA methylation and sperm DNA integrity. An increase in homocysteine concentration, especially in individuals with folate deficiency, is associated with an increase in oxidative stress and a decrease in antioxidants in the cell, which can affect sperm function and fertility.
Conclusion: Strengthening the 1-carbon cycle with folate and other micronutrients may lead to the improvement of sperm parameters and fertility potential by activating the enzymes involved in the transsulfuration pathway and reducing homocysteine concentration.
Keywords: Male fertility, 1-carbon cycle, Glutathione, Transsulfuration pathway, Sperm
Full-Text [PDF 457 kb]   (368 Downloads)    
Type of Study: Review | Subject: General
Received: 2022/09/24 | Revised: 2023/03/4 | Accepted: 2022/12/19 | Published: 2023/02/22
1. lare CE, Brassington AH, Kwong WY, Sinclair KD. One-Carbon Metabolism: Linking Nutritional Biochemistry to Epigenetic Programming of Long-Term Development. Annu Rev Anim Biosci. 2019; 7: 263-87.
2. Angier RB, Boothe JH, Hutchings BL, Mowat JH, Semb J, Stokstad EL, et al. Synthesis of a compound identical with the l. casei factor isolated from liver. Science 1945; 102(2644): 227-8.
3. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci U S A 2009; 106(36): 15424-9.
4. Ducker GS, Rabinowitz JD. One-Carbon Metabolism in Health and Disease. Cell Metab 2017; 25(1): 27-42.
5. Lyon P, Strippoli V, Fang B, Cimmino L. B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease. Nutrients 2020; 12(9): 2867.
6. Li F, Feng Q, Lee C, Wang S, Pelleymounter LL, Moon I, et al. Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: common gene sequence variation and functional characterization. Mol Genet Metab 2008; 94(3): 326-35.
7. Xu J, Sinclair KD. One-carbon metabolism and epigenetic regulation of embryo development. Reprod Fertil Dev 2015; 27(4): 667-76.
8. Kruman II, Fowler AK. Impaired one carbon metabolism and DNA methylation in alcohol toxicity. J Neurochem 2014; 129(5): 770-80.
9. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28(10): 1057-68.
10. Nunes SC, Serpa J. Glutathione in Ovarian Cancer: A Double-Edged Sword. Int J Mol Sci 2018; 19(7): 1882.
11. Kimura H. Physiological role of hydrogen sulfide and polysulfide in the central nervous system. Neurochem Int 2013; 63(5): 492-7.
12. Kolluru GK, Shen X, Yuan S, Kevil CG. Gasotransmitter Heterocellular Signaling. Antioxid Redox Signal 2017; 26(16): 936-60.
13. Banerjee R, Zou CG. Redox regulation and reaction mechanism of human cystathionine-beta-synthase: a PLP-dependent hemesensor protein. Arch Biochem Biophys 2005; 433(1): 144-56.
14. Miles EW, Kraus JP. Cystathionine beta-synthase: structure, function, regulation, and location of homocystinuria-causing mutations. J Biol Chem 2004; 279(29): 29871-4.
15. Taoka S, Banerjee R. Characterization of NO binding to human cystathionine beta-synthase: possible implications of the effects of CO and NO binding to the human enzyme. J Inorg Biochem 2001; 87(4): 245-51.
16. Gao XH, Krokowski D, Guan BJ, Bederman I, Majumder M, Parisien M, et al. Quantitative H2S-mediated protein sulfhydration reveals metabolic reprogramming during the integrated stress response. Elife 2015; 4: e10067.
17. Dickhout JG, Carlisle RE, Jerome DE, Mohammed-Ali Z, Jiang H, Yang G, et al. Integrated stress response modulates cellular redox state via induction of cystathionine γ-lyase: cross-talk between integrated stress response and thiol metabolism. J Biol Chem 2012; 287(10): 7603-14.
18. Singh K, Jaiswal D. One-carbon metabolism, spermatogenesis, and male infertility. Reprod Sci 2013; 20(6): 622-30.
19. Barati E, Nikzad H, Karimian M. Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management. Cell Mol Life Sci 2020; 77(1): 93-113.
20. Gomez E, Buckingham DW, Brindle J, Lanzafame F, Irvine DS, Aitken RJ. Development of an image analysis system to monitor the retention of residual cytoplasm by human spermatozoa: correlation with biochemical markers of the cytoplasmic space, oxidative stress, and sperm function. J Androl 1996; 17(3): 276-87.
21. Said TM, Agarwal A, Sharma RK, Mascha E, Sikka SC, Thomas AJ Jr. Human sperm superoxide anion generation and correlation with semen quality in patients with male infertility. Fertil Steril 2004; 82(4): 871-7.
22. Agarwal A, Hamada A, Esteves SC. Insight into oxidative stress in varicocele-associated male infertility: part 1. Nat Rev Urol 2012; 9(12): 678-90.
23. Bisht S, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nat Rev Urol 2017; 14(8): 470-85.
24. Persa C, Pierce A, Ma Z, Kabil O, Lou MF. The presence of a transsulfuration pathway in the lens: a new oxidative stress defense system. Exp Eye Res 2004; 79(6): 875-86.
25. Morellato AE, Umansky C, Pontel LB. The toxic side of one-carbon metabolism and epigenetics. Redox Biol 2021; 40: 101850.
26. Xiao W, Loscalzo J. Metabolic Responses to Reductive Stress. Antioxid Redox Signal 2020; 32(18): 1330-47.
27. Pearce K. Nutritional Supplementation for the Treatment of Male Infertility. Nutrition, Fertility, and Human Reproductive Function: CRC Press; 2015. p. 252-73.
28. Adeoye O, Olawumi J, Opeyemi A, Christiania O. Review on the role of glutathione on oxidative stress and infertility. JBRA Assist Reprod 2018; 22(1): 61-6.
29. Kamoun P, Belardinelli MC, Chabli A, Lallouchi K, Chadefaux-Vekemans B. Endogenous hydrogen sulfide overproduction in Down syndrome. Am J Med Genet A 2003; 116A(3): 310-1.
30. Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter?. FASEB J 2002; 16(13): 1792-8.
31. Yonezawa D, Sekiguchi F, Miyamoto M, et al. A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium. Toxicology 2007; 241(1-2): 11-18.
32. Dattilo M. The role of host defences in Covid 19 and treatments thereof. Mol Med. 2020; 26(1): 90.
33. Panagaki T, Randi EB, Augsburger F, Szabo C. Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome. Proc Natl Acad Sci U S A 2019; 116(38): 18769-71.
34. Fu M, Zhang W, Wu L, Yang G, Li H, Wang R. Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proc Natl Acad Sci U S A 2012; 109(8): 2943-8.
35. Cao X, Ding L, Xie ZZ, et al. A Review of Hydrogen Sulfide Synthesis, Metabolism, and Measurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic for Cancer?. Antioxid Redox Signal 2019; 31(1): 1-38.
36. Jha S, Calvert JW, Duranski MR, Ramachandran A, Lefer DJ. Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. Am J Physiol Heart Circ Physiol 2008; 295(2): H801-6.
37. Yang G, Zhao K, Ju Y, et al. Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid Redox Signal 2013; 18(15): 1906-19.
38. Majid AS, Majid AM, Yin ZQ, Ji D. Slow regulated release of H2S inhibits oxidative stress induced cell death by influencing certain key signaling molecules. Neurochem Res 2013; 38(7): 1375-93.
39. Kadlec M, Ros-Santaella JL, Pintus E. The Roles of NO and H2S in Sperm Biology: Recent Advances and New Perspectives. Int J Mol Sci 2020; 21(6): 2174.
40. Sugiura Y, Kashiba M, Maruyama K, Hoshikawa K, Sasaki R, Saito K, et al. Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes. Antioxid Redox Signal 2005; 7(5-6): 781-7.
41. Walport LJ, Hopkinson RJ, Schofield CJ. Mechanisms of human histone and nucleic acid demethylases. Curr Opin Chem Biol 2012; 16(5-6): 525-34.
42. Heck HD, Casanova-Schmitz M, Dodd PB, Schachter EN, Witek TJ, Tosun T. Formaldehyde (CH2O) concentrations in the blood of humans and Fischer-344 rats exposed to CH2O under controlled conditions. Am Ind Hyg Assoc J 1985; 46(1): 1-3.
43. Chippel D, Scrimgeour KG. Oxidative degradation of dihydrofolate and tetrahydrofolate. Can J Biochem 1970; 48(9): 999-1009.
44. Tibbetts AS, Appling DR. Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr 2010; 30: 57-81.
45. De Brouwer V, Zhang GF, Storozhenko S, Straeten DV, Lambert WE. pH stability of individual folates during critical sample preparation steps in prevision of the analysis of plant folates. Phytochem Anal 2007; 18(6): 496-508.
46. Burgos-Barragan G, Wit N, Meiser J, Dingler FA, Pietzke M, Mulderrig L, et al. Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. Nature 2017; 548(7669): 549-54.
47. Zare M, Haghpanah T, Shekari MA, Eftekhar-Vaghefi SH. The prophylactic effect of date palm (Phoenix dactylifera L.) fruit extract on testicular toxicity induced by formaldehyde: An experimental study. Int J Reprod Biomed 2020; 18(4): 275-86.
48. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet 2007; 8(4): 253-62.
49. Azizollahi G, Azizollahi S, Babaei H, Kianinejad M, Baneshi MR, Nematollahi-mahani SN. Effects of supplement therapy on sperm parameters, protamine content and acrosomal integrity of varicocelectomized subjects. J Assist Reprod Genet 2013; 30(4): 593-99.
50. Virtanen HE, Jørgensen N, Toppari J. Semen quality in the 21st century. Nat Rev Urol 2017; 14(2): 120-30.
51. Forges T, Monnier-Barbarino P, Alberto JM, Guéant-Rodriguez RM, Daval JL, Guéant JL. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update 2007; 13(3): 225-38.
52. Aubry F, Habasque C, Satie AP, Jégou B, Samson M. Expression and regulation of the CC-chemokine monocyte chemoattractant protein-1 in rat testicular cells in primary culture. Biol Reprod 2000; 62(5): 1427-35.
53. Miraglia E, De Angelis F, Gazzano E, Hassanpour H, Bertagna AT, Aldieri E, et al. Nitric oxide stimulates human sperm motility via activation of the cyclic GMP/protein kinase G signaling pathway. Reproduction 2011; 141(1): 47-54.
54. Agarwal A, Prabakaran S, Allamaneni S. What an andrologist/urologist should know about free radicals and why. Urology 2006; 67(1): 2-8.
55. Aitken RJ. Reactive oxygen species as mediators of sperm capacitation and pathological damage. Mol Reprod Dev 2017; 84(10): 1039-52.
56. Raigani M, Lakpour N, Soleimani M, Johari B, Sadeghi MR. A Association of MTHFR C677T and MTRR A66G Gene Polymorphisms with Iranian Male Infertility and Its Effect on Seminal Folate and Vitamin B12. Int J Fertil Steril 2021; 15(1): 20-25.
57. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1): 111-3.
58. Kelly TL, Neaga OR, Schwahn BC, Rozen R, Trasler JM. Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation. Biol Reprod 2005; 72(3): 667-77.
59. Dibakar B, Rajeev K, Manoj K, Rima D. Characteristics of MTHFR C677T and A1298C Polymorphisms in Infertile Men and Impact of 3 Weeks of Yoga on MTHFR gene Expression: A Clinical Case Report. Am J Clin Case Rep 2020: 1013.
60. Wang J, Wang W, Li S, et al. Hydrogen Sulfide As a Potential Target in Preventing Spermatogenic Failure and Testicular Dysfunction. Antioxid Redox Signal 2018; 28(16): 1447-62.
61. Bentivoglio G, Melica F, Cristoforoni P. Folinic acid in the treatment of human male infertility. Fertil Steril 1993; 60(4): 698-701.
62. Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis GA, Steegers-Theunissen RP. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil Steril 2002; 77(3): 491-8.
63. Young SS, Eskenazi B, Marchetti FM, Block G, Wyrobek AJ. The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men. Hum Reprod 2008; 23(5): 1014-22.
64. Nassan, Feiby L., and Jorge E. Chavarro. "Diet and Fertility in Men: Are Sperm What Men Eat?." Effects of Lifestyle on Men's Health. Academic Press, 2019. 41-60.
65. Lenzi A, Sgrò P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril 2004; 81(6): 1578-84.
66. Lenzi A, Culasso F, Gandini L, Lombardo F, Dondero F. Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. Hum Reprod 1993; 8(10): 1657-62.
67. Ciftci H, Verit A, Savas M, Yeni E, Erel O. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology. 2009; 74(1): 73-76.
68. Teng H, Wu B, Zhao K, Yang G, Wu L, Wang R. Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease. Proc Natl Acad Sci U S A 2013; 110(31): 12679-84.
69. Li G, Xie ZZ, Chua JM, Wong PC, Bian J. Hydrogen sulfide protects testicular germ cells against heat-induced injury. Nitric Oxide 2015; 46: 165-71.
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Ghajari E, Kiani S, Naderi N, Tvalaee M, Meshkibaf M H, Nasr-Esfahani M H. Importance of 1-carbon cycle antioxidant function in male fertility: A review article. Feyz 2022; 26 (6) :739-749
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