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Baranizadeh, K., Bahmanzadeh, M., Tavilani, H., Ghiasvand, T., Amiri, I., Yavangi, M., & Shafiee, G. (2022). Evaluation of methylenetetrahydrofolate reductase and s-adenosyl-methionine level in male infertility: A case-control study. International Journal of Reproductive BioMedicine (IJRM), 20(4), 299-306. https://doi.org/10.18502/ijrm.v20i4.10902
https://doi.org/10.18502/ijrm.v20i4.10902
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- Cited by 3 articles
authors
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Khadijeh Baranizadeh
Khadijeh Baranizadeh
Department of Clinical Biochemistry, Medicine School, Hamadan University of Medical Sciences, Hamadan, Iran.
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Maryam Bahmanzadeh
Maryam Bahmanzadeh
Department of Anatomical Sciences, School of Medicine, Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
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Heidar Tavilani
Heidar Tavilani
Department of Clinical Biochemistry, Medicine School, Hamadan University of Medical Sciences, Hamadan, Iran.
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Tayebeh Ghiasvand
Tayebeh Ghiasvand
Department of Clinical Biochemistry, Medicine School, Hamadan University of Medical Sciences, Hamadan, Iran.
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Iraj Amiri
Iraj Amiri
Department of Anatomical Sciences, School of Medicine, Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
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Mahnaz Yavangi
Mahnaz Yavangi
Department of Obstetrics and Gynecology, School of Medicine, Endometrium and Endometriosis Research Center, Fatemieh Hospital, Hamadan University of Medical Sciences, Hamadan, Iran.
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Gholamreza Shafiee
Gholamreza Shafiee
Department of Clinical Biochemistry, Medicine School, Nutrition Health Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Published Date
- May 23, 2022
Evaluation of methylenetetrahydrofolate reductase and s-adenosyl-methionine level in male infertility: A case-control study
Abstract
Background: Methylenetetrahydrofolate reductase enzyme (MTHFR) plays a key role in regulating folate balance, converting homocysteine to methionine, and producing s-adenosylmethionine (SAM) that plays a role in the methylation process.
Objective: This study aimed to determine MTHFR activity and SAM level in men with normozoospermia and oligozoospermia.
Materials and Methods: 30 oligozoospermic and 30 normozoospermic men as controls were enrolled in this case-control study. Semen analysis was conducted according to the world health organization criteria. All semen samples were collected after 3-5 days of sexual abstinence. The sperms were evaluated by sperm test video software. All subjects SAM level was measured by enzyme-linked immunosorbent assay kit, and MTHFR were measured manually.
Results: 2 groups had a significant difference in sperm morphology (p = 0.02), concentration (p = 0.02) and motility (p = 0.03). The MTHFR activity in normozoospermic and oligozoospermic groups had significantly differences (p = 0.01). The level of SAM in the semen of oligozoospermic men was statistically lower than normozoospermic men (p = 0.03). Also, there was a positive association between MTHFR enzyme activity and SAM level in the normozoospermia group (p = 0.02, β = 0.67) and oligozoospermia group (p = 0.03, β = 0.54).
Conclusion: MTHFR activity and SAM concentration were statistically lower in oligozoospermia men. It seems they can affect sperm concentration, morphology, and motility.
Key words: Methylenetetrahydrofolate reductase, s-adenosylmethionine, Normozoospermia, Oligozoospermia, Folic acid.
References
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[12] Ali F, Zeb F, Almajwal A, Fatima S, Wu X. Relationship of nutrigenomics and aging: Involvement of DNA methylation. J Nutr Inter Metab 2019; 16; 100098.
[13] Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, et al. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet 2007; 16: 2542–2551.
[14] Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World health organization reference values for human semen characteristics. Hum Reprod Update 2010; 16: 231–245.
[15] Khabour OF, Al-azzam AM, Alfaouri AA, Zayed F. Association of polymorphisms in DAZL gene with male infertility. J Adv Med Med Res 2013; 3: 41–48.
[16] Zalata A, El-Baz A, Othman G, Hassan A, Mostaf T. Seminal plasma S-adenosylmethionine and Sadenosylhomocysteine associations in infertile men. Hum Androl 2011; 1: 103–107.
[17] Rosner B. Fundamentas of biostatistics. 4th ed. Belmont: Duxbury Press; 1995. 283.
[18] Kuo-Kuang Lee R, Tseng HCh, Hwu YM, Fan ChCh, Lin MH, Yu JJ, et al. Expression of cystatin C in the female reproductive tract and its effect on human sperm capacitation. Reprod Biol Endocrinol 2018; 16: 1–10.
[19] Ghiasvand T, Goodarzi MT, Shafiee Gh, Zamani A, Karimi J, Ghorbani M, et al. Association between seminal plasma neopterin and oxidative stress in male infertility: A case-control study. Int J Reprod BioMed 2018; 16: 93– 100.
[20] Klenova EM, Morse HC, Ohlsson R, Lobanenkov VV. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Semin Cancer Biol 2020; 12: 399–414.
[21] Chan D, Cushnie DW, Neaga OR, Lawrance AK, Rozen R, Trasler JM. Strain-specific defects in testicular development and sperm epigenetic patterns in 5, 10-methylenetetrahydrofolate reductase-deficient mice. Endocrinology 2010; 151: 3363–3373.
[22] Nikzad H, Karimian M, Sareban K, Khoshsokhan M, Hosseinzadeh Colagar A. MTHFR-Ala222Val and male infertility: A study in Iranian men, an updated metaanalysis and an in silico-analysis. Reprod BioMed Online 2015; 31: 668–680.
[23] Karimian M, Hosseinzadeh Colagar A. Association of C677T transition of the human methylenetetrahydrofolate reductase (MTHFR) gene with male infertility. Reprod Fertil Dev 2016; 28: 785– 794.
[24] Filippo G, Rossella C, Laura M, Angela A, Rosita A, Aldo E, et al. Epigenetics of male fertility: Effects on assisted reproductive techniques. World J Mens Health 2019; 37: 148–156.
[25] Swayne BG, Kawata A, Behan NA, Williams A, Wade MG, Macfarlane AJ, et al. Investigating the effects of dietary folic acid on sperm count, DNA damage and mutation in Balb/c mice. Mutat Res 2012; 737: 1–7.
[26] Gupta N, Sarkar S, David A, Gangwar PK, Gupta R, Khanna G, et al. Significant impact of the MTHFR polymorphisms and haplotypes on male infertility risk. PloS One 2013; 8: e69180.
[27] Mfady DS, Sadiq MF, Khabour OF, Fararjeh AS, Abu- Awad A, Khader Y. Associations of variants in MTHFR and MTRR genes with male infertility in the Jordanian population. Gene 2014; 536: 40–44.
[28] Karimian M, Hosseinzadeh Colagar A. Human MTHFRG1793A transition may be a protective mutation against male infertility: A genetic association study and in silico analysis. Hum Fertil 2018; 21: 128–136.
[29] Aarabi M, Christensen KE, Chan D, Leclerc D, Landry M, Ly L, et al. Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation. Hum Mol Genet 2018; 27: 1123–1135.
[30] Wen-Jie H, Xi-Lan L, Jun-Tao L, Jian-Min Z. Effects of folic acid on oligozoospermia with MTHFR polymorphisms in term of seminal parameters, DNA fragmentation, and live birth rate: A double-blind, randomized, placebocontrolledtrial. Andrology 2020; 8: 110–116.
[31] Ahmadi MSZ, Bahadori M. [The study of GPx1 Pro198Leu lolymorphism in idiopathic male infertility]. Sci J Hamadan Univ Med Sci 2015; 22: 76–82. (in Persian)
[32] Yi-Le WC, Shan-Shan L, Feng-Feng G, Fang F, Zhen-Zhong Q, Xiu-Xiu D, et al. Association between methylenetetrahydrofolate reductase (MTHFR)C677T/A1298C polymorphisms and essential hypertension. Metabolism 2014; 63: 1503–1511.
[33] Kulac T, Hekim N, Kocamanoglu F, Beyaz C, Gunes S, Asci R. Methylation patterns of methylenetetrahydrofolate reductase gene promoter in infertile males. Andrologia 2021; 53: e13942–e13945.
[34] Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: A key to pregnancy outcome: A case series. J Assist Reprod Genet 2018; 35: 1431–1435.
[2] Machado Gava M, de Oliveira Chagas E, Bianco B, Christofolini DM, Pompeo ACL, Glina S, et al. Methylenetetrahydrofolate reductase polymorphisms are related to male infertility in Brazilian men. Genet Test Mol Biomarkers 2011; 15: 153–157.
[3] Gunes S, Arslan MA, Hekim GNT, Asci R. The role of epigenetics in idiopathic male infertility. J Assist Reprod Genet 2016; 33: 553–569.
[4] Singh K, Jaiswal D. One-carbon metabolism, spermatogenesis, and male infertility. Reprod Sci 2012; 20: 622–630.
[5] Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis and male infertility. Mutat Res 2011; 727: 62–71.
[6] Stuppia L, Franzago M, Ballerini P, Gatta V, Antonucci I. Epigenetics and male reproduction: The consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics 2015; 7: 120– 127.
[7] Karimian M, Hosseinzadeh Colagar A. Methionine synthase A2756G transition might be a risk factor for male infertility: Evidences from seven case-control studies. Mol Cell Endocrinol 2016; 425: 1–10.
[8] Mazloomi S, Alimohammadi Sh, Khodadadi I, Ghiasvand T, Shafiee Gh. Evaluation of methylene tetrahydrofolate reductase (MTHFR) activity and the levels of homocysteine and malondialdehyde (MDA) in the serum of women with preeclampsia. Clin Exp Hypertens 2020; 42: 590–594.
[9] Wu W, Shen O, Qin Y, Niu X, Lu C, Xia Y, et al. Idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (MTHFR). PloS One 2010; 5: e13884.
[10] Botezatu A, Socolov R, Socolov D, Iancu IV, Anton G. Methylation pattern of methylene tetrahydrofolate reductase and small nuclear ribonucleoprotein polypeptide N promoters in oligoasthenospermia: A case-control study. Reprod Biomed Online 2014; 28: 225–231.
[11] Huang L, Zhang J, Hayakawa T, Tsuge H. Assays of methylenetetrahydrofolate reductase and methionine synthase activities by monitoring 5- methyltetrahydrofolate and tetrahydrofolate using highperformance liquid chromatography with fluorescence detection. Anal Biochem 2011; 299: 253–259.
[12] Ali F, Zeb F, Almajwal A, Fatima S, Wu X. Relationship of nutrigenomics and aging: Involvement of DNA methylation. J Nutr Inter Metab 2019; 16; 100098.
[13] Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, et al. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet 2007; 16: 2542–2551.
[14] Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World health organization reference values for human semen characteristics. Hum Reprod Update 2010; 16: 231–245.
[15] Khabour OF, Al-azzam AM, Alfaouri AA, Zayed F. Association of polymorphisms in DAZL gene with male infertility. J Adv Med Med Res 2013; 3: 41–48.
[16] Zalata A, El-Baz A, Othman G, Hassan A, Mostaf T. Seminal plasma S-adenosylmethionine and Sadenosylhomocysteine associations in infertile men. Hum Androl 2011; 1: 103–107.
[17] Rosner B. Fundamentas of biostatistics. 4th ed. Belmont: Duxbury Press; 1995. 283.
[18] Kuo-Kuang Lee R, Tseng HCh, Hwu YM, Fan ChCh, Lin MH, Yu JJ, et al. Expression of cystatin C in the female reproductive tract and its effect on human sperm capacitation. Reprod Biol Endocrinol 2018; 16: 1–10.
[19] Ghiasvand T, Goodarzi MT, Shafiee Gh, Zamani A, Karimi J, Ghorbani M, et al. Association between seminal plasma neopterin and oxidative stress in male infertility: A case-control study. Int J Reprod BioMed 2018; 16: 93– 100.
[20] Klenova EM, Morse HC, Ohlsson R, Lobanenkov VV. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Semin Cancer Biol 2020; 12: 399–414.
[21] Chan D, Cushnie DW, Neaga OR, Lawrance AK, Rozen R, Trasler JM. Strain-specific defects in testicular development and sperm epigenetic patterns in 5, 10-methylenetetrahydrofolate reductase-deficient mice. Endocrinology 2010; 151: 3363–3373.
[22] Nikzad H, Karimian M, Sareban K, Khoshsokhan M, Hosseinzadeh Colagar A. MTHFR-Ala222Val and male infertility: A study in Iranian men, an updated metaanalysis and an in silico-analysis. Reprod BioMed Online 2015; 31: 668–680.
[23] Karimian M, Hosseinzadeh Colagar A. Association of C677T transition of the human methylenetetrahydrofolate reductase (MTHFR) gene with male infertility. Reprod Fertil Dev 2016; 28: 785– 794.
[24] Filippo G, Rossella C, Laura M, Angela A, Rosita A, Aldo E, et al. Epigenetics of male fertility: Effects on assisted reproductive techniques. World J Mens Health 2019; 37: 148–156.
[25] Swayne BG, Kawata A, Behan NA, Williams A, Wade MG, Macfarlane AJ, et al. Investigating the effects of dietary folic acid on sperm count, DNA damage and mutation in Balb/c mice. Mutat Res 2012; 737: 1–7.
[26] Gupta N, Sarkar S, David A, Gangwar PK, Gupta R, Khanna G, et al. Significant impact of the MTHFR polymorphisms and haplotypes on male infertility risk. PloS One 2013; 8: e69180.
[27] Mfady DS, Sadiq MF, Khabour OF, Fararjeh AS, Abu- Awad A, Khader Y. Associations of variants in MTHFR and MTRR genes with male infertility in the Jordanian population. Gene 2014; 536: 40–44.
[28] Karimian M, Hosseinzadeh Colagar A. Human MTHFRG1793A transition may be a protective mutation against male infertility: A genetic association study and in silico analysis. Hum Fertil 2018; 21: 128–136.
[29] Aarabi M, Christensen KE, Chan D, Leclerc D, Landry M, Ly L, et al. Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation. Hum Mol Genet 2018; 27: 1123–1135.
[30] Wen-Jie H, Xi-Lan L, Jun-Tao L, Jian-Min Z. Effects of folic acid on oligozoospermia with MTHFR polymorphisms in term of seminal parameters, DNA fragmentation, and live birth rate: A double-blind, randomized, placebocontrolledtrial. Andrology 2020; 8: 110–116.
[31] Ahmadi MSZ, Bahadori M. [The study of GPx1 Pro198Leu lolymorphism in idiopathic male infertility]. Sci J Hamadan Univ Med Sci 2015; 22: 76–82. (in Persian)
[32] Yi-Le WC, Shan-Shan L, Feng-Feng G, Fang F, Zhen-Zhong Q, Xiu-Xiu D, et al. Association between methylenetetrahydrofolate reductase (MTHFR)C677T/A1298C polymorphisms and essential hypertension. Metabolism 2014; 63: 1503–1511.
[33] Kulac T, Hekim N, Kocamanoglu F, Beyaz C, Gunes S, Asci R. Methylation patterns of methylenetetrahydrofolate reductase gene promoter in infertile males. Andrologia 2021; 53: e13942–e13945.
[34] Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: A key to pregnancy outcome: A case series. J Assist Reprod Genet 2018; 35: 1431–1435.