Underestimated Aspects in Male Infertility: Epigenetics is A New Approach in Men with Obesity or Diabetes: A Review

Document Type : Review Article

Authors

1 Department of Reproductive Biology, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, ACECR, Tehran, Iran

2 Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

3 Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

4 Department of Embryology, Reproduction Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, Iran

5 Department of Poultry Sciences, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran

Abstract

Infertility is a complex multifactorial problem that affects about 7% of men and 15% of couples worldwide. Many molecular mechanisms involved in male infertility. Destructive effects of infertility on the next generations are not well understood. Approximately 60-75% of male infertility cases have idiopathic causes, and there is a need for additional investigations other than routine examinations. Molecular factors that surround DNA, which are mitotically stable and independently regulate genome activity of DNA sequences, are known as epigenetics. The known epigenetic mechanisms are DNA methylation, histone modifications and non-coding RNAs. Prevalence of metabolic diseases has been increased dramatically because of changes in lifestyle and the current levels of inactivity. Metabolic disorders, such
as obesity and diabetes, are prevalent reasons for male infertility; despite the association between metabolic diseases and male infertility, few studies have been conducted on the effects of epigenetic alterations associated with these diseases and sperm abnormalities. Diabetes can affect the reproductive system and testicular function at multiple levels;
however, there are very few molecular and epigenetic studies related to sperm from males with diabetes. On the other hand, obesity has similar conditions, while male obesity is linked to notable alterations in the sperm molecular architecture affecting both function and embryo quality. Therefore, in this review article, we presented new and developed technologies to study different patterns of epigenetic changes, and explained the exact mechanisms of epigenetic changes linked to metabolic diseases and their relationship with male infertility.

Keywords

References

  1. Horsthemke B. A critical view on transgenerational epigenetic inheritance in humans. Nat Commun. 2018; 9(1): 1-4.
  2. Shnorhavorian M, Schwartz SM, Stansfeld B, Sadler-Riggleman I, Beck D, Skinner MK. Differential DNA methylation regions in adult human sperm following adolescent chemotherapy: potential for epigenetic inheritance. PLoS One. 2017; 12(2): e0170085.
  3. Holliday R. Epigenetics: a historical overview. Epigenetics. 2006; 1(2): 76-80.
  4. Noble D. Conrad Waddington and the origin of epigenetics. J Exp Biol. 2015; 218(6): 816-818.
  5. Ingerslev LR, Donkin I, Fabre O, Versteyhe S, Mechta M, Pattamaprapanont P, et al. Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots. Clin Epigenet. 2018; 10(1): 1-11.
  6. De Nigris F, Cacciatore F, Mancini FP, Vitale DF, Mansueto G, D’Armiento FP, et al. Epigenetic hallmarks of fetal early atherosclerotic lesions in humans. JAMA Cardiol. 2018; 3(12): 1184-1191.
  7. Adiga D, Eswaran S, Sriharikrishnaa S, Khan GN, Kabekkodu SP. Role of epigenetic changes in reproductive inflammation and male infertility. Chem Biol Lett. 2020; 7(2): 140-155.
  8. Jenkins TG, Turek PJ. Epigenetics and male infertility. In: Parekattil S, Esteves S, Agarwal A, editors. Male infertility. Springer, Cham; 2020; 139-146.
  9. James E, Jenkins TG. Epigenetics, infertility, and cancer: future directions. Fertil Steril. 2018; 109(1): 27-32.
  10. Rashki Ghaleno L, Alizadeh A, Drevet JR, Shahverdi A, Valojerdi MR. Oxidation of sperm dna and male infertility. Antioxidants. 2021; 10(1): 97.
  11. Ibrahim Y, Hotaling J, editors. Sperm epigenetics and its impact on male fertility, pregnancy loss, and somatic health of future offsprings. Semin Reprod Med. 2018; 36(3-04): 233-239.
  12. Schon SB, Luense LJ, Wang X, Bartolomei MS, Coutifaris C, Garcia BA, et al. Histone modification signatures in human sperm distinguish clinical abnormalities. Assist Reprod Genet. 2019; 36(2): 267-275.
  13. Sujit KM, Singh V, Trivedi S, Singh K, Gupta G, Rajender S. Increased DNA methylation in the spermatogenesis-associated (SPATA) genes correlates with infertility. Andrology. 2020; 8(3): 602-609.
  14. 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(11): e13884.
  15. Urdinguio RG, Bayón GF, Dmitrijeva M, Toraño EG, Bravo C, Fraga MF, et al. Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility. Hum Reprod. 2015; 30(5): 1014- 1028.
  16. Camprubí C, Salas-Huetos A, Aiese-Cigliano R, Godo A, Pons M-C, Castellano G, et al. Spermatozoa from infertile patients exhibit differences of DNA methylation associated with spermatogenesis- related processes: an array-based analysis. Reprod Biomed Online. 2016; 33(6): 709-719.
  17. Santi D, De Vincentis S, Magnani E, Spaggiari G. Impairment of sperm DNA methylation in male infertility: a metaanalytic study. Andrology. 2017; 5(4): 695-703.
  18. Zhang W, Li M, Sun F, Xu X, Zhang Z, Liu J, et al. Association of sperm methylation at LINE-1, four candidate genes, and nicotine/ alcohol exposure with the risk of infertility. Front Genet. 2019; 10: 1001.
  19. Ni W, Pan C, Pan Q, Fei Q, Huang X, Zhang C. Methylation levels of IGF2 and KCNQ1 in spermatozoa from infertile men are associated with sperm DNA damage. Andrologia. 2019; 51(5): e13239.
  20. Al-Qazzaz HK, Al-Awadi SJ. Epigenetic Alteration in DNA methylation pattern and gene expression level using H19 on oligospermia patients in Iraqi Men. Gene Reports. 2020; 20: 100780.
  21. Oluwayiose OA, Wu H, Saddiki H, Whitcomb BW, Balzer LB, Brandon N, et al. Sperm DNA methylation mediates the association of male age on reproductive outcomes among couples undergoing infertility treatment. Sci Rep. 2021; 11(1): 1-14.
  22. Oliva R, Ballescà JL. Altered histone retention and epigenetic modifications in the sperm of infertile men. Asian J Androl. 2012; 14(2): 239-240.
  23. Wu L, Wei Y, Li H, Li W, Gu C, Sun J, et al. The ubiquitination and acetylation of histones are associated with male reproductive disorders induced by chronic exposure to arsenite. Toxicol Appl Pharmacol. 2020; 408: 115253.
  24. Patankar A, Gajbhiye R, Surve S, Parte P. Epigenetic landscape of testis specific histone H2B variant and its influence on sperm function. Clin Epigenet. 2021; 13(1): 1-18.
  25. Su Y, Zhou LL, Zhang YQ, Ni LY. Long noncoding RNA HOTTIP is associated with male infertility and promotes testicular embryonal carcinoma cell proliferation. Mol Genet Genomic Med. 2019; 7(9): e870.
  26. Joshi M, Rajender S. Long non-coding RNAs (lncRNAs) in spermatogenesis and male infertility. Reprod Biol Endocrinol. 2020; 18(1): 1-18. 27. Marcho C, Oluwayiose OA, Pilsner JR. The preconception environment nd sperm epigenetics. Andrology. 2020; 8(4): 924-942.
  27. Tunc O, Tremellen K. Oxidative DNA damage impairs global sperm DNA methylation in infertile men. J Assist Reprod Genet. 2009; 26(9): 537-544.
  28. Skinner MK, Nilsson E, Sadler-Riggleman I, Beck D, Ben Maamar M, McCarrey JR. Transgenerational sperm DNA methylation epimutation developmental origins following ancestral vinclozolin exposure. Epigenetics. 2019; 14(7): 721-739.
  29. Ishida M, Moore GE. The role of imprinted genes in humans. Mol Aspects Med. 2013; 34(4): 826-840.
  30. Okada Y, Tateishi K, Zhang Y. Histone demethylase JHDM2A is involved in male infertility and obesity. J Androl. 2010; 31(1): 75-78.
  31. Fang L, Wuptra K, Chen D, Li H, Huang S-K, Jin C, et al. Environmental- stress-induced chromatin regulation and its heritability. J Carcinog Mutagen. 2014; 5(1): 22058.
  32. Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, et al. FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat Commun. 2012; 3(1): 1-12.
  33. Zhang Y, Shi J, Rassoulzadegan M, Tuorto F, Chen Q. Sperm RNA code programmes the metabolic health of offspring. Nat Rev Endocrinol. 2019; 15(8): 489-498.
  34. Abraham M, Dror O, Nussinov R, Wolfson HJ. Analysis and classification of RNA tertiary structures. RNA. 2008; 14(11): 2274-2289. 36. Shukla K, Chambial S, Dwivedi S, Misra S, Sharma P. Recent scenario of obesity and male fertility. Andrology. 2014; 2(6): 809-818.
  35. Palmer NO, Bakos HW, Fullston T, Lane M. Impact of obesity on male fertility, sperm function and molecular composition. Spermatogenesis. 2012; 2(4): 253-263.
  36. Yan M, Zhai Q. Sperm tsRNAs and acquired metabolic disorders. J Endocrinol. 2016; 230(3): F13-F18.
  37. Chen Q, Yan M, Cao Z, Li X, Zhang Y, Shi J, et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science. 2016; 351(6271): 397-400.
  38. Leisegang K, Sengupta P, Agarwal A, Henkel R. Obesity and male infertility: Mechanisms and management. Andrologia. 2021; 53(1): e13617.
  39. Leisegang K, Henkel R, Agarwal A. Obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system. Am J Reprod Immunol. 2019; 82(5): e13178.
  40. Hayden RP, Flannigan R, Schlegel PN. The role of lifestyle in male infertility: diet, physical activity, and body habitus. Curr Urol Rep. 2018; 19(7): 1-10.
  41. Abbasihormozi S, Babapour V. Stress hormone and oxidative stress biomarkers link obesity and diabetes with reduced fertility potential. Cell J. 2019; 21(3): 307.
  42. Ding GL, Liu Y, Liu ME, Pan JX, Guo MX, Sheng JZ, et al. The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis. Asian J Androl. 2015; 17(6): 948-953.
  43. Aeeni M, Razi M, Alizadeh A, Alizadeh A. The molecular mechanism behind insulin protective effects on testicular tissue of hyperglycemic rats. Life Sci. 2021; 277: 119394.
  44. Abbasi M, Smith AD, Swaminathan H, Sangngern P, Douglas A, Horsager A, et al. Establishing a stable, repeatable platform for measuring changes in sperm DNA methylation. Clin Epigenetics. 2018; 10(1): 1-12.
  45. Laleethambika N, Anila V, Manojkumar C, Muruganandam I, Giridharan B, Ravimanickam T, et al. Diabetes and sperm DNA damage: Efficacy of antioxidants. SN Compr Clin Med. 2019; 1(1): 49-59.
  46. Chen X, Lin Q, Wen J, Lin W, Liang J, Huang H, et al. Whole genome bisulfite sequencing of human spermatozoa reveals differentially methylated patterns from type 2 diabetic patients. J Diabetes Investig. 2020; 11(4): 856-864.
  47. Huang Q, Li J. Research progress of lncRNAs in diabetic retinopathy. Eur J Ophthalmol. 2020; 31(4): 1606-1617.
  48. Jiang GJ, Zhang T, An T, Zhao DD, Yang XY, Zhang DW, et al. Differential expression of long noncoding RNAs between sperm samples from diabetic and non-diabetic mice. PLoS One. 2016; 11(4): e0154028.
  49. Dupont C, Faure C, Sermondade N, Boubaya M, Eustache F, Clément P, et al. Obesity leads to higher risk of sperm DNA damage in infertile patients. Asian J Androl. 2013; 15(5): 622-625.
  50. Craig JR, Jenkins TG, Carrell DT, Hotaling JM. Obesity, male infertility, and the sperm epigenome. Fertil Steril. 2017; 107(4): 848-859.
  51. Soubry A, Guo L, Huang Z, Hoyo C, Romanus S, Price T, et al. Obesity- related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin Epigenet. 2016; 8(1): 1-11.
  52. Donkin I, Versteyhe S, Ingerslev LR, Qian K, Mechta M, Nordkap L, et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab. 2016; 23(2): 369-378.
  53. Potabattula R, Dittrich M, Schorsch M, Hahn T, Haaf T, El Hajj N. Male obesity effects on sperm and next-generation cord blood DNA methylation. PLoS One. 2019; 14(6): e0218615.
  54. Wang F, Chen H, Chen Y, Cheng Y, Li J, Zheng L, et al. Diet-induced obesity is associated with altered expression of sperm motility- related genes and testicular post-translational modifications in a mouse model. Theriogenology. 2020; 158: 233-238.
  55. An T, Zhang T, Teng F, Zuo JC, Pan YY, Liu YF, et al. Long noncoding RNAs could act as vectors for paternal heredity of high fat diet-induced obesity. Oncotarget. 2017; 8(29): 47876.
  56. Johnson GD, Mackie P, Jodar M, Moskovtsev S, Krawetz SA. Chromatin and extracellular vesicle associated sperm RNAs. Nucleic Acids Res. 2015; 43(14): 6847-6859.
  57. Tang Q, Pan F, Yang J, Fu Z, Lu Y, Wu X, et al. Idiopathic male infertility is strongly associated with aberrant DNA methylation of imprinted loci in sperm: a case-control study. Clin Epigenet. 2018; 10(1): 1-10.
  58. Luján S, Caroppo E, Niederberger C, Arce JC, Sadler-Riggleman I, Beck D, et al. Sperm DNA methylation epimutation biomarkers for male infertility and FSH therapeutic responsiveness. Sci Rep. 2019; 9(1): 1-12.
  59. Mousavi MS, Shahverdi A, Drevet J, Akbarinejad V, Esmaeili V, Sayahpour FA, et al. Peroxisome proliferator-activated receptors (PPARs) levels in spermatozoa of normozoospermic and asthenozoospermic men. Syst Biol Reprod Med. 2019; 65(6): 409-419.
  60. Rahimizadeh P, Topraggaleh TR, Nasr-Esfahani MH, Ziarati N, Mirshahvaladi S, Esmaeili V, et al. The alteration of PLCζ protein expression in unexplained infertile and asthenoteratozoospermic patients: A potential effect on sperm fertilization ability. Mol Reprod Dev. 2020; 87(1): 115-123.
  61. Heidary Z, Saliminejad K, Zaki-Dizaji M, Khorram Khorshid HR. Genetic aspects of idiopathic asthenozoospermia as a cause of male infertility. Hum Fertil. 2020; 23(2): 83-92.
  62. Zhang S, Xu L, Yu M, Zhang J. Hypomethylation of the DAZ3 promoter in idiopathic asthenospermia: a screening tool for liquid biopsy. Sci Rep. 2020; 10(1): 1-7.
  63. Hekim N, Gunes S, Asci R, Henkel R, Abur U. Semiquantitative promoter methylation of MLH1 and MSH2 genes and their impact on sperm DNA fragmentation and chromatin condensation in infertile men. Andrologia. 2020: e13827.
  64. Saki J, Sabaghan M, Arjmand R, Teimoori A, Rashno M, Saki G, et al. Curcumin as an indirect methylation inhibitor modulates the effects of Toxoplasma gondii on genes involved in male fertility. EXCLI J. 2020; 19: 1196 -1207.
  65. Saleh AAEW, Amin EM, Elfallah AA, Hamed AM. Insulin resistance and idiopathic infertility: a potential possible link. Andrologia. 2020; 52(11): e13773.

Files

Cited by

Share

How to cite

Statistics