Journal of Infertility and Reproductive Biology
ISSN: 2310-7588
The latest research in infertility and reproductive medicine from across the world
Ethnic Differences in Genetic and Epigenetic Factors Related to Male Infertility: A Narrative Review
Published date: Mar 20 2025
Journal Title: Journal of Infertility and Reproductive Biology
Issue title: Journal of Infertility and Reproductive Biology: Volume 13, Issue 1
Pages: 37 - 54
Authors:
Abstract:
Male infertility causes problems in 7% of worldwide men which creates major difficulties for reproductive health and family planning. A combination of genetic factors and epigenetic factors with environmental elements and lifestyle choices creates causes of this condition. The treatment options available through assisted reproductive technologies (ART) give hope to couples yet we still know only a few aspects of genetic and epigenetic influences related to male infertility. Studies regarding ethnic differences have demonstrated that infertility incidence rates together with biological causes show substantial variation between different cultural groups. The differences become visible through both genetic mutation frequencies along with alterations in epigenetic controls of reproductive functions. Male infertility suffers from genetic elements that comprise Y-chromosome microdeletions and gene mutations in addition to single nucleotide polymorphisms (SNPs). Fewer studies have been conducted on different ethnic groups because their occurrence rates between populations show significant differences. The development of sperm cells depends critically on epigenetic processes which include DNA methylation and histone modification mechanisms. The modifications affect spermatogenesis and result from genetic factors along with environmental conditions that include diet and lifestyle habits and toxic exposures where these variances differ among ethnic groups. The understanding of genetic and epigenetic variations across ethnic populations creates essential effects on diagnosing and treating male infertility. The use of ethnic-specific profiles for diagnostic and treatment selection enhances both accuracy rates and treatment success outcomes. The analysis of ethnic differences makes the possibility of developing targeted reproductive healthcare initiatives along with methods to decrease reproductive health inequality. The article investigates the ways that genetic along epigenetic variations between ethnic populations affect male infertility rates. This review brings together existing knowledge while demonstrating unmet needs to underline the need for ethnic perspectives in studies involving infertility. The research advances methods for developing better specific diagnoses and treatment options for male infertility worldwide.
Keywords: male infertility, genetic factors, epigenetics, ethnic differences, Y chromosome microdeletions, Spermatogenesis, infertility treatmen
References:
[1] Marzouni ET, Ilkhani H, Harchegani AB, Shafaghatian H, Layali I, Shahriary A, et al. Epigenetic modifications, a new approach to male infertility etiology: a review. Int J Fertil Steril. 2022;16(1):1.
[2] Gunes S, Esteves SC. Role of genetics and epigenetics in male infertility. Andrologia. 2021;53(1):e13586.
[3] Bukulmez O. Genetic aspects of male infertility. In: Male Infertility: Contemporary Clinical Approaches, Andrology, ART and Antioxidants. Springer; 2012:171-189. doi:10.1007/978-1-4614-3335-4_18.
[4] Mohan S, Deshpande S, Balasinor NH. Male Infertility: An Epigenetic Perspective. In: Male Infertility: Understanding, Causes and Treatment. 2017:271-294.
[5] Rotondo JC, Lanzillotti C, Mazziotta C, Tognon M, Martini F, et al. Epigenetics of male infertility: the role of DNA methylation. Front Cell Dev Biol. 2021;9:689624.
[6] Punjani N, Nayan M, Jarvi K, Lo K, Lau S, Grober ED, et al. The effect of ethnicity on semen analysis and hormones in the infertile patient. Can Urol Assoc J. 2019;14(2):31.
[7] Dehghanbanadaki H, Kim B, Fendereski K, Ramsay J, Horns J, Jimbo M, et al. Racial/ethnic differences in semen parameters and male reproductive hormones in the United States: A systematic review and meta-analysis. J Sex Med. 2024;21(Suppl 1):qdae001.88.
[8] Nemati H, Sadeghi M, Nazeri M, Mohammadi M, et al. Evaluation of the association between polymorphisms of PRM1 and PRM2 and the risk of male infertility: a systematic review, meta-analysis, and meta-regression. Sci Rep. 2020;10(1):17228.
[9] Oud MS, Volozonoka L, Smits RM, Vissers LE, Ramos L, Veltman JA, et al. A systematic review and standardized clinical validity assessment of male infertility genes. Hum Reprod. 2019;34(5):932-941.
[10] Burni S, Nadeem F, Ahmed F, Ghaffar R, Ali T, et al. Exploring the relationship between ethnicity, age, pH, and sperm concentration in male infertility. J Community Med Public Health Rep. 2024;5(05).
[11] Shi M, Ma S, Huang L, Huang C, Wang J, Qin X, et al. Clinical analysis of Y chromosome microdeletions and chromosomal aberrations in 1596 male infertility patients of the Zhuang ethnic group in Guangxi. Reprod Sci. 2024;31(10):3074-3085.
[12] Punjani N, Nayan M, Jarvi K, Lo K, Lau S, Grober ED, et al. The effect of ethnicity on semen analysis and hormones in the infertile patient. Can Urol Assoc J. 2019;14(2):31.
[13] Sudhakar DV, Shah R, Gajbhiye RK. Genetics of male infertility–present and future: a narrative review. J Hum Reprod Sci. 2021;14(3):217-227.
[14] Gumus E, Kati B, Pelit ES, Ordek E, Ciftci H, et al. A different look at genetic factors in individuals with non-obstructive azoospermia or oligospermia in our research study: to whom, which threshold, when, in what way? Rev Int Androl. 2021;19(1):41-48.
[15] Krausz C, Giachini C. Genetic risk factors in male infertility. Arch Androl. 2007;53(3):125-133.
[16] Birowo P, Deswanto I, Atmoko W, Rasyid N, et al. Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: a systematic review. F1000Res. 2021;10:1244.
[17] Kumari A, Yadav SK, Misro MM, Ahmad J, Ali S, et al. Copy number variation and microdeletions of the Y chromosome linked genes and loci across different categories of Indian infertile males. Sci Rep. 2015;5:17780.
[18] Ferlin A, Arredi B, Speltra E, Cazzadore C, Selice R, Garolla A, et al. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab. 2007;92(3):762-770.
[19] Al-Achkar W, Wafa A, Moassass F. Cytogenetic abnormalities and Y-chromosome microdeletions in infertile Syrian males. Biomed Rep. 2013;1(2):275-279.
[20] Dutta S, Paladhi P, Pal S, Bose G, Ghosh P, Chattopadhyay R, et al. Prevalence of Y chromosome microdeletion in azoospermia factor subregions among infertile men from West Bengal, India. Mol Genet Genomic Med. 2021;9(10):e1769.
[21] Bansal SK, Jaiswal D, Gupta N, Singh K, Dada R, Sankhwar SN, et al. Gr/gr deletions on Y-chromosome correlate with male infertility: an original study, meta-analyses and trial sequential analyses. Sci Rep. 2016;6:19798.
[22] Alechine E, Schempp W, Corach D. Characterization of the AZF region of the Y chromosome in Native American haplogroup Q. J Art Hum Soci Sci. 2016; 3(4): 1-58.
[23] Vogt PH. AZF deletions and Y chromosomal haplogroups: history and update based on sequence. Hum Reprod Update. 2005;11(4):319–336.
[24] Skowronek MF, Velazquez T, Mut P, Figueiro G, Sans M, Bertoni B, et al. Associations between male infertility and ancestry in South Americans: a case-control study. BMC Med Genet. 2017;18:1–10.
[25] Javed N, Irfan M, Arshad A, Bibi A, Nik Hussain N, Ismail S, et al. Association of ESRα T397C (rs2234693) with male infertility: a meta-analysis. J Sex Med. 2023;20(Suppl 1):qdad060.83.
[26] Gunes S, Esteves SC. Role of genetics and epigenetics in male infertility. Andrologia. 2021;53(1):e13586.
[27] Dada R, Kumar M, Jesudasan R, Fernández JL, Gosálvez J, Agarwal A, et al. Epigenetics and its role in male infertility. J Assist Reprod Genet. 2012;29:213–223.
[28] Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis and male infertility. Mutat Res Rev Mutat Res. 2011;727(3):62–71.
[29] Stuppia L, Franzago M, Ballerini P, Gatta V, Antonucci I, et al. Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics. 2015;7:1–15.
[30] Guerrero-Bosagna C, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of male infertility. Curr Opin Genet Dev. 2014;26:79–88.
[31] Montjean D, Rolland AD, Ravel C. Epigenetics of male infertility. In: Epigenetics in Human Reproduction and Development. 2017:87–111.
[32] Rotondo JC, Lanzillotti C, Mazziotta C, Tognon M, Martini F, et al. Epigenetics of male infertility: the role of DNA methylation. Front Cell Dev Biol. 2021;9:689624.
[33] Cui X, Jing X, Wu X, Yan M, Li Q, Shen Y, et al. DNA methylation in spermatogenesis and male infertility. Exp Ther Med. 2016;12(4):1973–1979.
[34] Urdinguio RG, Bayon GF, Dmitrijeva M, Torano 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.
[35] Zhang J, Li X, Wang R, Feng X, Wang S, Wang H, et al. DNA methylation patterns in patients with asthenospermia and oligoasthenospermia. BMC Genomics. 2024;25(1):602.
[36] Tang Q, Chen Y, Wu W, Ding H, Xia Y, Chen D, et al. Idiopathic male infertility and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. Sci Rep. 2017;7:11219.
[37] 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.
[38] Poplinski A, Tüttelmann F, Kanber D, Horsthemke B, Gromoll J, et al. Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1. Int J Androl. 2010;33(4):642–649.
[39] Li XP, Hao CL, Wang Q, Yi XM, Jiang ZS, et al. H19 gene methylation status is associated with male infertility. Exp Ther Med. 2016;12(1):451–456.
[40] Cannarella R, Crafa A, Barbagallo F, Lundy SD, La Vignera S, Condorelli RA, et al. H19 sperm methylation in male infertility: a systematic review and meta-analysis. Int J Mol Sci. 2023;24(8):7224.
[41] Shi Z, Yu M, Guo T, Sui Y, Tian Z, Ni X, et al. MicroRNAs in spermatogenesis dysfunction and male infertility: Clinical phenotypes, mechanisms, and potential diagnostic biomarkers. Front Endocrinol. 2024;15:1293368.
[42] Mima M, Greenwald D, Ohlander S. Environmental toxins and male fertility. Curr Urol Rep. 2018;19:1-8.
[43] Cescon M, Chianese R, Tavares RS. Environmental impact on male (in)fertility via epigenetic route. J Clin Med. 2020;9(8):2520.
[44] Osadchuk LV, Osadchuk AV. Individual lifestyle and male fertility. Hum Physiol. 2023;49(2):196-207.
[45] Saftić Martinović L, Mladenić T, Lovrić D, Ostojić S, Dević Pavlić S, et al. Decoding the Epigenetics of Infertility: Mechanisms, Environmental Influences, and Therapeutic Strategies. Epigenomes. 2024;8(3):34.
[46] Sengupta P, Dutta S, Liew FF, Dhawan V, Das B, Mottola F, et al. Environmental and genetic traffic in the journey from sperm to offspring. Biomolecules. 2023;13(12):1759.
[47] Akbarzadeh-Jahromi M, Jafari F, Parsanezhad ME, Alaee SJA. Evaluation of supplementation of cryopreservation medium with gallic acid as an antioxidant in quality of post-thaw human spermatozoa. Andrologia. 2022;54(11):e14571.
[48] Mohammadi Z, Alaee S, Namavar MR, Khodabandeh Z, Ahmadi N, Rashidipour N, et al. The antioxidant properties of resveratrol on sperm parameters, testicular tissue, antioxidant capacity, and lipid peroxidation in isoflurane-induced toxicity in mice. Hum Exp Toxicol. 2023;42:09603271231215036.
[49] Karayiannis D, Kontogianni MD, Mendorou C, Douka L, Mastrominas M, Yiannakouris N, et al. Association between adherence to the Mediterranean diet and semen quality parameters in male partners of couples attempting fertility. Hum Reprod. 2017;32(1):215-222.
[50] Pascoal GdFL, Geraldi MV, Maróstica Jr MR, Ong TP. Effect of paternal diet on spermatogenesis and offspring health: focus on epigenetics and interventions with food bioactive compounds. Nutrients. 2022;14(10):2150.
[51] Salas-Huetos A, Babio N, Carrell DT, Bulló M, Salas-Salvadó J, et al. Adherence to the Mediterranean diet is positively associated with sperm motility: A cross-sectional analysis. Sci Rep. 2019;9(1):3389.
[52] Alaee SJ. Air pollution and infertility - a letter to the editor. J Environ Treat Tech. 2018;6(4):72-73.
[53] Krzastek SC, Farhi J, Gray M, Smith RP. Impact of environmental toxin exposure on male fertility potential. Transl Androl Urol. 2020;9(6):2797.
[54] Pelzman DL, Hwang K. Genetic testing for men with infertility: techniques and indications. Transl Androl Urol. 2021;10(3):1354.
[55] Samplaski M. Ethnic differences in men undergoing reproductive urology evaluation. Transl Androl Urol. 2022; 50(7).
[56] Hotaling J, Carrell D. Clinical genetic testing for male factor infertility: current applications and future directions. Andrology. 2014;2(3):339-350.
[57] Wosnitzer MS. Genetic evaluation of male infertility. Transl Androl Urol. 2014;3(1):17.
[58] Walker Z, Rucker L, Owen J, Wiltshire A, Kendall L, Edmonds J, et al. Investigation of racial disparities in semen parameters among white, black, and Asian men. Andrology. 2021;9(4):1086-1091.
[59] Oz O. Evaluation of Y chromosome microdeletions and chromosomal anomalies in infertile men. Horm Mol Biol Clin Investig. 2021;42(3):279-283.
[60] Kurzawski M, Wajda A, Malinowski D, Kazienko A, Kurzawa R, Drozdzik M, et al. Association study of folate-related enzymes (MTHFR, MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population. Genet Mol Biol. 2015;38(1):42-47.
[61] Gong M, Dong W, He T, Shi Z, Huang G, Ren R, et al. MTHFR 677C>T polymorphism increases the male infertility risk: a meta-analysis involving 26 studies. PLoS One. 2015;10(3):e0121147.
[62] More A, Gajbe U, Olatunji O, Singh B, Singh BR. MTHFR Gene-Polymorphism and Infertile men in Indian Population: a systematic literature review. Cureus. 2022;14(7).e27075.
[63] Chen M, Lin C, Liu C. Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric. 2015;18(2):260-269.
[64] Vitullo AD, Roldan ER, González CR. Environmental factors affecting the germline epigenome. Front Endocrinol. 2023;14:1126967.
[65] Shamsi M, Kumar K, Dada R. Genetic and epigenetic factors: Role in male infertility. Indian J Urol. 2011;27(1):110-120.
[66] Sengupta P, Banerjee R. Environmental toxins: Alarming impacts of pesticides on male fertility. Hum Exp Toxicol. 2014;33(10):1017-1039.
[67] Wdowiak N, Wójtowicz K, Wdowiak-Filip A, Pucek W, Wróbel A, Wróbel J, et al. Environmental factors as the main hormonal disruptors of male fertility. J Clin Med. 2024;13(7):1986.
[68] Bretveld R, Brouwers M, Ebisch I, Roeleveld N. Influence of pesticides on male fertility. Scand J Work Environ Health. 2007;33(1):13-28.
[69] Joffe M. Infertility and environmental pollutants. Br Med Bull. 2003;68:47-70.
[70] Gabrielsen J, Tanrikut C. Chronic exposures and male fertility: the impacts of environment, diet, and drug use on spermatogenesis. Andrology. 2016;4(4):648-661.
[71] Precone V, Cannarella R, Paolacci S, Busetto GM, Beccari T, Stuppia L, et al. Male infertility diagnosis: improvement of genetic analysis performance by the introduction of pre-diagnostic genes in a nextgeneration sequencing custom-made panel. Front Endocrinol. 2021;12:605237.
[72] Krzastek SC, Smith RP, Kovac JR. Future diagnostics in male infertility: Genomics, epigenetics, metabolomics and proteomics. Transl Androl Urol. 2020;9(Suppl 2):S195-S205.
[73] Feinberg EC, Larsen FW, Catherino WH, Zhang J, Armstrong AY. Comparison of assisted reproductive technology utilization and outcomes between Caucasian and African American patients in an equalaccess- to-care setting. Fertil Steril. 2006;85(4):888-894.
[74] Tesarik J. Lifestyle and Environmental Factors Affecting Male Fertility, Individual Predisposition, Prevention, and Intervention. Int J Mol Sci. 2025;26(6):2797.
[75] Montano L, Ceretti E, Donato F, Bergamo P, Zani C, Viola GCV, et al. Effects of a lifestyle change intervention on semen quality in healthy young men living in highly polluted areas in Italy: the FASt randomized controlled trial. Eur Urol Focus. 2022;8(1):351-359.
[76] Muhdi S, Lindo M, Firdaus MT. Male Infertility: Where is the Research Heading? A Bibliometric Perspective. Int J Med Health. 2025;4(1):24-35.
[77] Podgrajsek R, Hodzic A, Stimpfel M, Kunej T, Peterlin B. Insight into the complexity of male infertility: a multi-omics review. Syst Biol Reprod Med. 2024;70(1):73-90.
[78] Gül M, Russo GI, Kandil H, Boitrelle F, Saleh R, Chung E, et al. Male Infertility: New Developments, Current Challenges, and Future Directions. World J Mens Health. 2024;42(3):502-517.
[79] Wagner AO, Turk A, Kunej T. Towards a multi-omics of male infertility. World J Mens Health. 2023;41(2):272-288.
[80] Schilit SL. Recent advances and future opportunities to diagnose male infertility. Curr Sex Health Rep. 2019;11:331-341.