Unraveling the Impact of Sperm DNA Fragmentation on Reproductive Outcomes

Abstract

In recent years, there has been a growing interest in identifying subcellular causes of male infertility, and sperm DNA fragmentation (SDF) research has been at the forefront of this focus. DNA damage can occur during spermatogenesis due to faulty chromatin compaction or excessive abortive apoptosis. It can also happen as sperm transit through the genital tract, often induced by oxidative stress. There are several methods for SDF testing, with the sperm chromatin structure assay, terminal deoxynucleotidyl transferase d-UTI nick end labeling (TUNEL) assay, comet assay, and sperm chromatin dispersion test being the most commonly used. Numerous studies strongly support the negative impact of SDF on male fertility potential. DNA damage has been linked to various morphological and functional sperm abnormalities, ultimately affecting natural conception and assisted reproductive technology outcomes. This evidence-based review aims to explore how SDF influences male reproduction and provide insights into available therapeutic options to minimize its detrimental impact.

Keywords

sperm DNA fragmentation - male infertility - assisted reproduction - natural conception - recurrent pregnancy loss

Publication History

Article published online:
13 December 2023

• References

• 1 World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. 6th ed.. 2021
• 2 EAU Guidelines. Sexual and Reproductive Health. Edn. Presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6
• 3 Esteves SC, Humaidan P. Towards infertility care on equal terms: a prime time for male infertility. Reprod Biomed Online 2023; 47 (01) 11-14
• 4 Esteves SC, Zini A, Coward RM. et al. Sperm DNA fragmentation testing: Summary evidence and clinical practice recommendations. Andrologia 2021; 53 (02) e13874
• 5 Majzoub A, Agarwal A, Esteves SC. Understanding sperm DNA fragmentation. Transl Androl Urol 2017; 6 (Suppl. 04) S535-S538
• 6 Leduc F, Nkoma GB, Boissonneault G. Spermiogenesis and DNA repair: a possible etiology of human infertility and genetic disorders. Syst Biol Reprod Med 2008; 54 (01) 3-10
• 7 Sakkas D, Mariethoz E, St John JC. Abnormal sperm parameters in humans are indicative of an abortive apoptotic mechanism linked to the Fas-mediated pathway. Exp Cell Res 1999; 251 (02) 350-355
• 8 Shukla KK, Mahdi AA, Rajender S. Apoptosis, spermatogenesis and male infertility. Front Biosci (Elite Ed) 2012; 4 (02) 746-754
• 9 Sakkas D, Seli E, Manicardi GC, Nijs M, Ombelet W, Bizzaro D. The presence of abnormal spermatozoa in the ejaculate: did apoptosis fail?. Hum Fertil (Camb) 2004; 7 (02) 99-103
• 10 Simon L, Lutton D, McManus J, Lewis SE. Sperm DNA damage measured by the alkaline Comet assay as an independent predictor of male infertility and in vitro fertilization success. Fertil Steril 2011; 95 (02) 652-657
• 11 Dutta S, Majzoub A, Agarwal A. Oxidative stress and sperm function: a systematic review on evaluation and management. Arab J Urol 2019; 17 (02) 87-97
• 12 Esteves SC, Roque M, Bradley CK, Garrido N. Reproductive outcomes of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with high levels of DNA fragmentation in semen: systematic review and meta-analysis. Fertil Steril 2017; 108 (03) 456-467.e1
• 13 Bisht S, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nat Rev Urol 2017; 14 (08) 470-485
• 14 Smith TB, Dun MD, Smith ND, Curry BJ, Connaughton HS, Aitken RJ. The presence of a truncated base excision repair pathway in human spermatozoa that is mediated by OGG1. J Cell Sci 2013; 126 (Pt 6): 1488-1497
• 15 González-Marín C, Gosálvez J, Roy R. Types, causes, detection and repair of DNA fragmentation in animal and human sperm cells. Int J Mol Sci 2012; 13 (11) 14026-14052
• 16 Farkouh A, Agarwal A, Hamoda TAA. et al; Global Andrology Forum. Controversy and consensus on the management of elevated sperm DNA fragmentation in male infertility: a global survey, current guidelines, and expert recommendations. World J Mens Health 2023; 41 (04) 809-847
• 17 Agarwal A, Farkouh A, Saleh R. et al. Technical aspects and clinical limitations of sperm DNA fragmentation testing in male infertility: a global survey, current guidelines, and expert recommendations. World J Mens Health 2023;
• 18 Alvarez C, Castilla JA, Martínez L, Ramírez JP, Vergara F, Gaforio JJ. Biological variation of seminal parameters in healthy subjects. Hum Reprod 2003; 18 (10) 2082-2088
• 19 Riddell D, Pacey A, Whittington K. Lack of compliance by UK andrology laboratories with World Health Organization recommendations for sperm morphology assessment. Hum Reprod 2005; 20 (12) 3441-3445
• 20 Guzick DS, Overstreet JW, Factor-Litvak P. et al; National Cooperative Reproductive Medicine Network. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001; 345 (19) 1388-1393
• 21 Boeri L, Belladelli F, Capogrosso P. et al. Normal sperm parameters per se do not reliably account for fertility: a case-control study in the real-life setting. Andrologia 2021; 53 (01) e13861
• 22 Agarwal A, Cho CL, Majzoub A, Esteves SC. The Society for Translational Medicine: clinical practice guidelines for sperm DNA fragmentation testing in male infertility. Transl Androl Urol 2017; 6 (Suppl. 04) S720-S733
• 23 Bender Atik R, Christiansen OB, Elson J. et al; ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018 (02) hoy004
• 24 Colpi GM, Francavilla S, Haidl G. et al. European Academy of Andrology guideline management of oligo-astheno-teratozoospermia. Andrology 2018; 6 (04) 513-524
• 25 Tharakan T, Bettocchi C, Carvalho J. et al; EAU Working Panel on Male Sexual Reproductive Health. European Association of Urology Guidelines Panel on Male Sexual and Reproductive Health: a clinical consultation guide on the indications for performing sperm DNA fragmentation testing in men with infertility and testicular sperm extraction in nonazoospermic men. Eur Urol Focus 2022; 8 (01) 339-350
• 26 Henkel R, Hoogendijk CF, Bouic PJ, Kruger TF. TUNEL assay and SCSA determine different aspects of sperm DNA damage. Andrologia 2010; 42 (05) 305-313
• 27 Javed A, Talkad MS, Ramaiah MK. Evaluation of sperm DNA fragmentation using multiple methods: a comparison of their predictive power for male infertility. Clin Exp Reprod Med 2019; 46 (01) 14-21
• 28 Panner Selvam MK, Agarwal A. A systematic review on sperm DNA fragmentation in male factor infertility: laboratory assessment. Arab J Urol 2018; 16 (01) 65-76
• 29 Evenson DP, Larson KL, Jost LK. Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. J Androl 2002; 23 (01) 25-43
• 30 Evenson DP. Sperm chromatin structure assay (SCSA®). Methods Mol Biol 2013; 927: 147-164
• 31 Zini A, Kamal K, Phang D, Willis J, Jarvi K. Biologic variability of sperm DNA denaturation in infertile men. Urology 2001; 58 (02) 258-261
• 32 Sharma R, Ahmad G, Esteves SC, Agarwal A. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay using bench top flow cytometer for evaluation of sperm DNA fragmentation in fertility laboratories: protocol, reference values, and quality control. J Assist Reprod Genet 2016; 33 (02) 291-300
• 33 Cissen M, Wely MV, Scholten I. et al. Measuring sperm DNA fragmentation and clinical outcomes of medically assisted reproduction: a systematic review and meta-analysis. PLoS One 2016; 11 (11) e0165125
• 34 Simon L, Carrell DT. Sperm DNA damage measured by comet assay. Methods Mol Biol 2013; 927: 137-146
• 35 Simon L, Emery B, Carrell DT. Sperm DNA fragmentation: consequences for reproduction. Adv Exp Med Biol 2019; 1166: 87-105
• 36 Fernández JL, Muriel L, Goyanes V. et al. Simple determination of human sperm DNA fragmentation with an improved sperm chromatin dispersion test. Fertil Steril 2005; 84 (04) 833-842
• 37 Ribas-Maynou J, García-Peiró A, Fernández-Encinas A. et al. Comprehensive analysis of sperm DNA fragmentation by five different assays: TUNEL assay, SCSA, SCD test and alkaline and neutral Comet assay. Andrology 2013; 1 (05) 715-722
• 38 Santi D, Spaggiari G, Simoni M. Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management - meta-analyses. Reprod Biomed Online 2018; 37 (03) 315-326
• 39 Oleszczuk K, Augustinsson L, Bayat N, Giwercman A, Bungum M. Prevalence of high DNA fragmentation index in male partners of unexplained infertile couples. Andrology 2013; 1 (03) 357-360
• 40 Aktan G, Doğru-Abbasoğlu S, Küçükgergin C, Kadıoğlu A, Ozdemirler-Erata G, Koçak-Toker N. Mystery of idiopathic male infertility: Is oxidative stress an actual risk?. Fertil Steril 2013; 99 (05) 1211-1215
• 41 Homa ST, Vassiliou AM, Stone J. et al. A comparison between two assays for measuring seminal oxidative stress and their relationship with sperm DNA fragmentation and semen parameters. Genes (Basel) 2019; 10 (03) 236
• 42 Buck Louis GM, Sundaram R, Schisterman EF. et al. Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study. Fertil Steril 2014; 101 (02) 453-462
• 43 Zini A, Jamal W, Cowan L, Al-Hathal N. Is sperm DNA damage associated with IVF embryo quality? A systematic review. J Assist Reprod Genet 2011; 28 (05) 391-397
• 44 Spanò M, Bonde JP, Hjøllund HI, Kolstad HA, Cordelli E, Leter G. The Danish First Pregnancy Planner Study Team. Sperm chromatin damage impairs human fertility. Fertil Steril 2000; 73 (01) 43-50
• 45 Bungum M, Humaidan P, Axmon A. et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod 2007; 22 (01) 174-179
• 46 Duran EH, Morshedi M, Taylor S, Oehninger S. Sperm DNA quality predicts intrauterine insemination outcome: a prospective cohort study. Hum Reprod 2002; 17 (12) 3122-3128
• 47 Muriel L, Meseguer M, Fernández JL. et al. Value of the sperm chromatin dispersion test in predicting pregnancy outcome in intrauterine insemination: a blind prospective study. Hum Reprod 2006; 21 (03) 738-744
• 48 Siddhartha N, Reddy NS, Pandurangi M, Muthusamy T, Vembu R, Kasinathan K. The effect of sperm DNA fragmentation index on the outcome of intrauterine insemination and intracytoplasmic sperm injection. J Hum Reprod Sci 2019; 12 (03) 189-198
• 49 Skowronek F, Casanova G, Alciaturi J. et al. DNA sperm damage correlates with nuclear ultrastructural sperm defects in teratozoospermic men. Andrologia 2012; 44 (01) 59-65
• 50 Antoniassi MP, Intasqui P, Camargo M. et al. Analysis of the functional aspects and seminal plasma proteomic profile of sperm from smokers. BJU Int 2016; 118 (05) 814-822
• 51 Intasqui P, Camargo M, Del Giudice PT. et al. Sperm nuclear DNA fragmentation rate is associated with differential protein expression and enriched functions in human seminal plasma. BJU Int 2013; 112 (06) 835-843
• 52 Agarwal A, Panner Selvam MK, Baskaran S, Cho CL. Sperm DNA damage and its impact on male reproductive health: a critical review for clinicians, reproductive professionals and researchers. Expert Rev Mol Diagn 2019; 19 (06) 443-457
• 53 Esteves SC. Clinical relevance of routine semen analysis and controversies surrounding the 2010 World Health Organization criteria for semen examination. Int Braz J Urol 2014; 40 (04) 443-453
• 54 Chua SC, Yovich SJ, Hinchliffe PM, Yovich JL. How well do semen analysis parameters correlate with sperm DNA fragmentation? A retrospective study from 2567 semen samples analyzed by the Halosperm Test. J Pers Med 2023; 13 (03) 518
• 55 Evgeni E, Lymberopoulos G, Touloupidis S, Asimakopoulos B. Sperm nuclear DNA fragmentation and its association with semen quality in Greek men. Andrologia 2015; 47 (10) 1166-1174
• 56 Omran HM, Bakhiet M, Dashti MG. DNA integrity is a critical molecular indicator for the assessment of male infertility. Mol Med Rep 2013; 7 (05) 1631-1635
• 57 Sivanarayana T, Ravi Krishna C, Jaya Prakash G. et al. Sperm DNA fragmentation assay by sperm chromatin dispersion (SCD): correlation between DNA fragmentation and outcome of intracytoplasmic sperm injection. Reprod Med Biol 2013; 13 (02) 87-94
• 58 Le MT, Nguyen TAT, Nguyen HTT. et al. Does sperm DNA fragmentation correlate with semen parameters?. Reprod Med Biol 2019; 18 (04) 390-396
• 59 Cassuto NG, Hazout A, Hammoud I. et al. Correlation between DNA defect and sperm-head morphology. Reprod Biomed Online 2012; 24 (02) 211-218
• 60 Khalili MA, Aghaie-Maybodi F, Anvari M, Talebi AR. Sperm nuclear DNA in ejaculates of fertile and infertile men: correlation with semen parameters. Urol J 2006; 3 (03) 154-159
• 61 Karydis S, Asimakopoulos B, Papadopoulos N, Vakalopoulos I, Al-Hasani S, Nikolettos N. ICSI outcome is not associated with the incidence of spermatozoa with abnormal chromatin condensation. In Vivo 2005; 19 (05) 921-925
• 62 Busnelli A, Garolla A, Di Credico E. et al. Sperm DNA fragmentation and idiopathic recurrent pregnancy loss: results from a multicenter case-control study. Andrology 2023; 11 (08) 1673-1681
• 63 McQueen DB, Zhang J, Robins JC. Sperm DNA fragmentation and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril 2019; 112 (01) 54-60.e3
• 64 Zidi-Jrah I, Hajlaoui A, Mougou-Zerelli S. et al. Relationship between sperm aneuploidy, sperm DNA integrity, chromatin packaging, traditional semen parameters, and recurrent pregnancy loss. Fertil Steril 2016; 105 (01) 58-64
• 65 Carlini T, Paoli D, Pelloni M. et al. Sperm DNA fragmentation in Italian couples with recurrent pregnancy loss. Reprod Biomed Online 2017; 34 (01) 58-65
• 66 Dai Y, Liu J, Yuan E, Li Y, Shi Y, Zhang L. Relationship among traditional semen parameters, sperm DNA fragmentation, and unexplained recurrent miscarriage: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2022; 12: 802632
• 67 Venkatesh S, Thilagavathi J, Kumar K, Deka D, Talwar P, Dada R. Cytogenetic, Y chromosome microdeletion, sperm chromatin and oxidative stress analysis in male partners of couples experiencing recurrent spontaneous abortions. Arch Gynecol Obstet 2011; 284 (06) 1577-1584
• 68 Malić Vončina S, Stenqvist A, Bungum M, Schyman T, Giwercman A. Sperm DNA fragmentation index and cumulative live birth rate in a cohort of 2,713 couples undergoing assisted reproduction treatment. Fertil Steril 2021; 116 (06) 1483-1490
• 69 Simon L, Emery BR, Carrell DT. Review: Diagnosis and impact of sperm DNA alterations in assisted reproduction. Best Pract Res Clin Obstet Gynaecol 2017; 44: 38-56
• 70 Lourenço ML, Moura GA, Rocha YM, Rodrigues JPV, Monteiro PB. Impact of sperm DNA fragmentation on the clinical outcome of assisted reproduction techniques: a systematic review of the last five years. JBRA Assist Reprod 2023; 27 (02) 282-291
• 71 Wang Q, Gu X, Chen Y. et al. The effect of sperm DNA fragmentation on in vitro fertilization outcomes of unexplained infertility. Clinics (São Paulo) 2023; 78: 100261
• 72 Zhao J, Zhang Q, Wang Y, Li Y. Whether sperm deoxyribonucleic acid fragmentation has an effect on pregnancy and miscarriage after in vitro fertilization/intracytoplasmic sperm injection: a systematic review and meta-analysis. Fertil Steril 2014; 102 (04) 998-1005.e8
• 73 Deng C, Li T, Xie Y. et al. Sperm DNA fragmentation index influences assisted reproductive technology outcome: a systematic review and meta-analysis combined with a retrospective cohort study. Andrologia 2019; 51 (06) e13263
• 74 Casanovas A, Ribas-Maynou J, Lara-Cerrillo S. et al. Double-stranded sperm DNA damage is a cause of delay in embryo development and can impair implantation rates. Fertil Steril 2019; 111 (04) 699-707.e1
• 75 Borges Jr E, Zanetti BF, Setti AS, Braga DPAF, Provenza RR, Iaconelli Jr A. Sperm DNA fragmentation is correlated with poor embryo development, lower implantation rate, and higher miscarriage rate in reproductive cycles of non-male factor infertility. Fertil Steril 2019; 112 (03) 483-490
• 76 Coughlan C, Clarke H, Cutting R. et al. Sperm DNA fragmentation, recurrent implantation failure and recurrent miscarriage. Asian J Androl 2015; 17 (04) 681-685
• 77 Best JC, Kohn T, Patel P. et al. Elevated sperm DNA fragmentation does not predict recurrent implantation failure. Andrologia 2021; 53 (07) e14094
• 78 Evenson D, Wixon R. Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online 2006; 12 (04) 466-472
• 79 Li Z, Wang L, Cai J, Huang H. Correlation of sperm DNA damage with IVF and ICSI outcomes: a systematic review and meta-analysis. J Assist Reprod Genet 2006; 23 (9-10): 367-376
• 80 Osman A, Alsomait H, Seshadri S, El-Toukhy T, Khalaf Y. The effect of sperm DNA fragmentation on live birth rate after IVF or ICSI: a systematic review and meta-analysis. Reprod Biomed Online 2015; 30 (02) 120-127
• 81 Simon L, Zini A, Dyachenko A, Ciampi A, Carrell DT. A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome. Asian J Androl 2017; 19 (01) 80-90
• 82 Robinson L, Gallos ID, Conner SJ. et al. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Hum Reprod 2012; 27 (10) 2908-2917
• 83 Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization?. Fertil Steril 2008; 89 (04) 823-831
• 84 Zini A, Boman JM, Belzile E, Ciampi A. Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Hum Reprod 2008; 23 (12) 2663-2668
• 85 Lewis S. The place of sperm DNA fragmentation testing in current day fertility management. Middle East Fertil Soc J 2013; 18: 78-82
• 86 Acuna-Hidalgo R, Veltman JA, Hoischen A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol 2016; 17 (01) 241
• 87 Ahmadi A, Ng SC. Fertilizing ability of DNA-damaged spermatozoa. J Exp Zool 1999; 284 (06) 696-704
• 88 Genescà A, Caballín MR, Miró R, Benet J, Germà JR, Egozcue J. Repair of human sperm chromosome aberrations in the hamster egg. Hum Genet 1992; 89 (02) 181-186
• 89 McNally A, Harrity C, Marron K, Does DNA. Fragmentation level significantly impact clinical outcomes in patients undertaking assisted reproduction with using donor oocytes?. Hum Reprod 2023; 38: dead093.472
• 90 García-Díaz M, Domínguez O, López-Fernández LA. et al. DNA polymerase lambda (Pol lambda), a novel eukaryotic DNA polymerase with a potential role in meiosis. J Mol Biol 2000; 301 (04) 851-867
• 91 Aitken RJ. Reactive oxygen species as mediators of sperm capacitation and pathological damage. Mol Reprod Dev 2017; 84 (10) 1039-1052
• 92 Bošković A, Rando OJ. Transgenerational epigenetic inheritance. Annu Rev Genet 2018; 52: 21-41
• 93 Bhadsavle SS, Golding MC. Paternal epigenetic influences on placental health and their impacts on offspring development and disease. Front Genet 2022; 13: 1068408
• 94 Navarro-Costa P, Nogueira P, Carvalho M. et al. Incorrect DNA methylation of the DAZL promoter CpG island associates with defective human sperm. Hum Reprod 2010; 25 (10) 2647-2654
• 95 Hammoud SS, Purwar J, Pflueger C, Cairns BR, Carrell DT. Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil Steril 2010; 94 (05) 1728-1733
• 96 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
• 97 Xavier MJ, Roman SD, Aitken RJ, Nixon B. Transgenerational inheritance: how impacts to the epigenetic and genetic information of parents affect offspring health. Hum Reprod Update 2019; 25 (05) 518-540
• 98 Adiga SK, Upadhya D, Kalthur G, Bola Sadashiva SR, Kumar P. Transgenerational changes in somatic and germ line genetic integrity of first-generation offspring derived from the DNA damaged sperm. Fertil Steril 2010; 93 (08) 2486-2490
• 99 Bungum M, Bungum L, Lynch KF, Wedlund L, Humaidan P, Giwercman A. Spermatozoa DNA damage measured by sperm chromatin structure assay (SCSA) and birth characteristics in children conceived by IVF and ICSI. Int J Androl 2012; 35 (04) 485-490
• 100 Schmid TE, Eskenazi B, Baumgartner A. et al. The effects of male age on sperm DNA damage in healthy non-smokers. Hum Reprod 2007; 22 (01) 180-187
• 101 Gourinat A, Mazeaud C, Hubert J, Eschwege P, Koscinski I. Impact of paternal age on assisted reproductive technology outcomes and offspring health: a systematic review. Andrology 2023; 11 (06) 973-986
• 102 Szabó A, Váncsa S, Hegyi P. et al. Lifestyle-, environmental-, and additional health factors associated with an increased sperm DNA fragmentation: a systematic review and meta-analysis. Reprod Biol Endocrinol 2023; 21 (01) 5
• 103 Lee KM, Ward MH, Han S. et al. Paternal smoking, genetic polymorphisms in CYP1A1 and childhood leukemia risk. Leuk Res 2009; 33 (02) 250-258
• 104 Rumbold AR, Sevoyan A, Oswald TK, Fernandez RC, Davies MJ, Moore VM. Impact of male factor infertility on offspring health and development. Fertil Steril 2019; 111 (06) 1047-1053
• 105 Esteves SC, Roque M, Bedoschi G, Haahr T, Humaidan P. Intracytoplasmic sperm injection for male infertility and consequences for offspring. Nat Rev Urol 2018; 15 (09) 535-562
• 106 Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM. et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev 2016; 96 (01) 55-97
• 107 Durairajanayagam D. Lifestyle causes of male infertility. Arab J Urol 2018; 16 (01) 10-20
• 108 Sørensen F, Melsen LM, Fedder J, Soltanizadeh S. The influence of male ejaculatory abstinence time on pregnancy rate, live birth rate and DNA fragmentation: a systematic review. J Clin Med 2023; 12 (06) 2219
• 109 Barbagallo F, Cannarella R, Crafa A. et al. The impact of a very short abstinence period on conventional sperm parameters and sperm DNA fragmentation: a systematic review and meta-Analysis. J Clin Med 2022; 11 (24) 7303
• 110 Ferramosca A, Zara V. Diet and male fertility: the impact of nutrients and antioxidants on sperm energetic metabolism. Int J Mol Sci 2022; 23 (05) 2542
• 111 Salas-Huetos A, Bulló M, Salas-Salvadó J. Dietary patterns, foods and nutrients in male fertility parameters and fecundability: a systematic review of observational studies. Hum Reprod Update 2017; 23 (04) 371-389
• 112 Cutillas-Tolín A, Mínguez-Alarcón L, Mendiola J. et al. Mediterranean and western dietary patterns are related to markers of testicular function among healthy men. Hum Reprod 2015; 30 (12) 2945-2955
• 113 Cao LL, Chang JJ, Wang SJ. et al. The effect of healthy dietary patterns on male semen quality: a systematic review and meta-analysis. Asian J Androl 2022; 24 (05) 549-557
• 114 Tomada I, Tomada N. Mediterranean diet and male fertility. Endocrines 2023; 4: 394-406
• 115 Dai JB, Wang ZX, Qiao ZD. The hazardous effects of tobacco smoking on male fertility. Asian J Androl 2015; 17 (06) 954-960
• 116 Saleh RA, Agarwal A, Sharma RK, Nelson DR, Thomas Jr AJ. Effect of cigarette smoking on levels of seminal oxidative stress in infertile men: a prospective study. Fertil Steril 2002; 78 (03) 491-499
• 117 Fraga CG, Motchnik PA, Wyrobek AJ, Rempel DM, Ames BN. Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutat Res 1996; 351 (02) 199-203
• 118 Sepaniak S, Forges T, Gerard H, Foliguet B, Bene MC, Monnier-Barbarino P. The influence of cigarette smoking on human sperm quality and DNA fragmentation. Toxicology 2006; 223 (1-2): 54-60
• 119 Cui X, Jing X, Wu X, Wang Z, Li Q. Potential effect of smoking on semen quality through DNA damage and the downregulation of Chk1 in sperm. Mol Med Rep 2016; 14 (01) 753-761
• 120 Sharma R, Harlev A, Agarwal A, Esteves SC. Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen. Eur Urol 2016; 70 (04) 635-645
• 121 Li Y, Lin H, Li Y, Cao J. Association between socio-psycho-behavioral factors and male semen quality: systematic review and meta-analyses. Fertil Steril 2011; 95 (01) 116-123
• 122 Vine MF, Margolin BH, Morrison HI, Hulka BS. Cigarette smoking and sperm density: a meta-analysis. Fertil Steril 1994; 61 (01) 35-43
• 123 Tang Q, Pan F, Wu X. et al. Semen quality and cigarette smoking in a cohort of healthy fertile men. Environ Epidemiol 2019; 3 (04) e055
• 124 Prentki Santos E, López-Costa S, Chenlo P. et al. Impact of spontaneous smoking cessation on sperm quality: case report. Andrologia 2011; 43 (06) 431-435
• 125 Kulaksiz D, Toprak T, Tokat E. et al. Sperm concentration and semen volume increase after smoking cessation in infertile men. Int J Impot Res 2022; 34 (06) 614-619
• 126 Wu W, Chen Y, Cheng Y. et al. Association between ambient particulate matter exposure and semen quality in fertile men. Environ Health 2022; 21 (01) 16
• 127 Zhang J, Liu J, Ren L. et al. PM_2.5 induces male reproductive toxicity via mitochondrial dysfunction, DNA damage and RIPK1 mediated apoptotic signaling pathway. Sci Total Environ 2018; 634: 1435-1444
• 128 Calogero AE, La Vignera S, Condorelli RA. et al. Environmental car exhaust pollution damages human sperm chromatin and DNA. J Endocrinol Invest 2011; 34 (06) e139-e143
• 129 Zhang J, Cai Z, Ma C, Xiong J, Li H. Impacts of outdoor air pollution on human semen quality: a meta-analysis and systematic review. BioMed Res Int 2020; 2020: 7528901
• 130 Pilsner JR, Parker M, Sergeyev O, Suvorov A. Spermatogenesis disruption by dioxins: epigenetic reprograming and windows of susceptibility. Reprod Toxicol 2017; 69: 221-229
• 131 Gaspari L, Chang SS, Santella RM, Garte S, Pedotti P, Taioli E. Polycyclic aromatic hydrocarbon-DNA adducts in human sperm as a marker of DNA damage and infertility. Mutat Res 2003; 535 (02) 155-160
• 132 Akemann C, Meyer DN, Gurdziel K, Baker TR. Developmental dioxin exposure alters the methylome of adult male zebrafish gonads. Front Genet 2019; 9: 719
• 133 Castellini C, Totaro M, Parisi A. et al. Bisphenol A and male fertility: myths and realities. Front Endocrinol (Lausanne) 2020; 11: 353
• 134 Bretveld R, Brouwers M, Ebisch I, Roeleveld N. Influence of pesticides on male fertility. Scand J Work Environ Health 2007; 33 (01) 13-28
• 135 Jamalan M, Ghaffari MA, Hoseinzadeh P, Hashemitabar M, Zeinali M. Human sperm quality and metal toxicants: protective effects of some flavonoids on male reproductive function. Int J Fertil Steril 2016; 10 (02) 215-223
• 136 Liu K, Li Y, Zhang G. et al. Association between mobile phone use and semen quality: a systemic review and meta-analysis. Andrology 2014; 2 (04) 491-501
• 137 Sciorio R, Tramontano L, Esteves SC. Effects of mobile phone radiofrequency radiation on sperm quality. Zygote 2022; 30 (02) 159-168
• 138 Pandey N, Giri S, Das S, Upadhaya P. Radiofrequency radiation (900 MHz)-induced DNA damage and cell cycle arrest in testicular germ cells in Swiss albino mice. Toxicol Ind Health 2017; 33 (04) 373-384
• 139 De Iuliis GN, Newey RJ, King BV, Aitken RJ. Mobile phone radiation induces reactive oxygen species production and DNA damage in human spermatozoa in vitro. PLoS One 2009; 4 (07) e6446
• 140 Zalata A, El-Samanoudy AZ, Shaalan D, El-Baiomy Y, Mostafa T. In vitro effect of cell phone radiation on motility, DNA fragmentation and clusterin gene expression in human sperm. Int J Fertil Steril 2015; 9 (01) 129-136
• 141 Gorpinchenko I, Nikitin O, Banyra O, Shulyak A. The influence of direct mobile phone radiation on sperm quality. Cent European J Urol 2014; 67 (01) 65-71
• 142 Muthusami KR, Chinnaswamy P. Effect of chronic alcoholism on male fertility hormones and semen quality. Fertil Steril 2005; 84 (04) 919-924
• 143 Nguyen-Thanh T, Hoang-Thi AP, Anh Thu DT. Investigating the association between alcohol intake and male reproductive function: a current meta-analysis. Heliyon 2023; 9 (05) e15723
• 144 Murphy SK, Itchon-Ramos N, Visco Z. et al. Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics 2018; 13 (12) 1208-1221
• 145 Rosati L, Chianese T, Mileo A, De Falco M, Capaldo A. Cocaine effects on reproductive behavior and fertility: an overview. Vet Sci 2023; 10 (08) 484
• 146 Lewis SE, Paro R, Borriello L. et al. Long-term use of HU210 adversely affects spermatogenesis in rats by modulating the endocannabinoid system. Int J Androl 2012; 35 (05) 731-740
• 147 Schifano N, Chiappini S, Mosca A. et al. Recreational drug misuse and its potential contribution to male fertility levels' decline: a narrative review. Brain Sci 2022; 12 (11) 1582
• 148 Safarinejad MR, Asgari SA, Farshi A. et al. The effects of opiate consumption on serum reproductive hormone levels, sperm parameters, seminal plasma antioxidant capacity and sperm DNA integrity. Reprod Toxicol 2013; 36: 18-23
• 149 Kaewman P, Nudmamud-Thanoi S, Thanoi S. GABAergic alterations in the rat testis after methamphetamine exposure. Int J Med Sci 2018; 15 (12) 1349-1354
• 150 Yamamoto Y, Yamamoto K, Hayase T, Abiru H, Shiota K, Mori C. Methamphetamine induces apoptosis in seminiferous tubules in male mice testis. Toxicol Appl Pharmacol 2002; 178 (03) 155-160
• 151 Yamamoto Y, Yamamoto K, Hayase T. Effect of methamphetamine on male mice fertility. J Obstet Gynaecol Res 1999; 25 (05) 353-358
• 152 Khodamoradi K, Kuchakulla M, Narasimman M. et al. Laboratory and clinical management of leukocytospermia and hematospermia: a review. Ther Adv Reprod Health 2020; 14: 2633494120922511
• 153 Alvarez JG, Sharma RK, Ollero M. et al. Increased DNA damage in sperm from leukocytospermic semen samples as determined by the sperm chromatin structure assay. Fertil Steril 2002; 78 (02) 319-329
• 154 Erenpreiss J, Hlevicka S, Zalkalns J, Erenpreisa J. Effect of leukocytospermia on sperm DNA integrity: a negative effect in abnormal semen samples. J Androl 2002; 23 (05) 717-723
• 155 Fariello RM, Del Giudice PT, Spaine DM, Fraietta R, Bertolla RP, Cedenho AP. Effect of leukocytospermia and processing by discontinuous density gradient on sperm nuclear DNA fragmentation and mitochondrial activity. J Assist Reprod Genet 2009; 26 (2-3): 151-157
• 156 Eini F, Kutenaei MA, Zareei F, Dastjerdi ZS, Shirzeyli MH, Salehi E. Effect of bacterial infection on sperm quality and DNA fragmentation in subfertile men with Leukocytospermia. BMC Mol Cell Biol 2021; 22 (01) 42
• 157 Domes T, Lo KC, Grober ED, Mullen JB, Mazzulli T, Jarvi K. The incidence and effect of bacteriospermia and elevated seminal leukocytes on semen parameters. Fertil Steril 2012; 97 (05) 1050-1055
• 158 Rivero MJ, Kulkarni N, Thirumavalavan N, Ramasamy R. Evaluation and management of male genital tract infections in the setting of male infertility: an updated review. Curr Opin Urol 2023; 33 (03) 180-186
• 159 Skau PA, Folstad I. Do bacterial infections cause reduced ejaculate quality? A meta-analysis of antibiotic treatment of male infertility. Behav Ecol 2003; 14: 40-47
• 160 Majzoub A, Agarwal A. Systematic review of antioxidant types and doses in male infertility: benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. Arab J Urol 2018; 16 (01) 113-124
• 161 Dimitriadis F, Borgmann H, Struck JP, Salem J, Kuru TH. Antioxidant supplementation on male fertility - a systematic review. Antioxidants 2023; 12 (04) 836
• 162 Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev 2019; 3 (03) CD007411
• 163 Majzoub A, Agarwal A, Esteves SC. Antioxidants for elevated sperm DNA fragmentation: a mini review. Transl Androl Urol 2017; 6 (Suppl. 04) S649-S653
• 164 Nguyen ND, Le MT, Tran NQT, Nguyen QHV, Cao TN. Micronutrient supplements as antioxidants in improving sperm quality and reducing DNA fragmentation. Basic Clin Androl 2023; 33 (01) 23
• 165 Steiner AZ, Hansen KR, Barnhart KT. et al; Reproductive Medicine Network. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil Steril 2020; 113 (03) 552-560.e3
• 166 Schisterman EF, Sjaarda LA, Clemons T. et al. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: a randomized clinical trial. JAMA 2020; 323 (01) 35-48
• 167 Zhang Y, Zhang W, Wu X. et al. Effect of varicocele on sperm DNA damage: a systematic review and meta-analysis. Andrologia 2022; 54 (01) e14275
• 168 Agarwal A, Sharma R, Harlev A, Esteves SC. Effect of varicocele on semen characteristics according to the new 2010 World Health Organization criteria: a systematic review and meta-analysis. Asian J Androl 2016; 18 (02) 163-170
• 169 Lewis SEM, Esteves SC. What does a varicocele do to a man's fertility? There is much more than meets the eye. Int Braz J Urol 2021; 47 (02) 284-286
• 170 Mahdi M, Khalafalla K, Al Saeedi A. et al. Varicocele induced testicular hyperthermia: infrared digital thermographic assessment exploring the effect of surgical varicocele correction on postoperative testicular temperature and reproductive outcome. J Urol 2023; 209: e607
• 171 Zini A, Dohle G. Are varicoceles associated with increased deoxyribonucleic acid fragmentation?. Fertil Steril 2011; 96 (06) 1283-1287
• 172 Lira Neto FT, Roque M, Esteves SC. Effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation rates in infertile men with clinical varicocele: a systematic review and meta-analysis. Fertil Steril 2021; 116 (03) 696-712
• 173 Soetandar A, Noegroho BS, Siregar S, Adriansjah R, Mustafa A. Microsurgical varicocelectomy effects on sperm DNA fragmentation and sperm parameters in infertile male patients: a systematic review and meta-analysis of more recent evidence. Arch Ital Urol Androl 2022; 94 (03) 360-365
• 174 Schlegel PN, Sigman M, Collura B. et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. Fertil Steril 2021; 115 (01) 54-61
• 175 Zini A, Sigman M. Are tests of sperm DNA damage clinically useful? Pros and cons. J Androl 2009; 30 (03) 219-229
• 176 Simon L, Brunborg G, Stevenson M, Lutton D, McManus J, Lewis SE. Clinical significance of sperm DNA damage in assisted reproduction outcome. Hum Reprod 2010; 25 (07) 1594-1608
• 177 Muratori M, Tamburrino L, Marchiani S. et al. Investigation on the origin of sperm DNA fragmentation: role of apoptosis, immaturity and oxidative stress. Mol Med 2015; 21 (01) 109-122
• 178 Steele EK, McClure N, Maxwell RJ, Lewis SE. A comparison of DNA damage in testicular and proximal epididymal spermatozoa in obstructive azoospermia. Mol Hum Reprod 1999; 5 (09) 831-835
• 179 Moskovtsev SI, Jarvi K, Mullen JB, Cadesky KI, Hannam T, Lo KC. Testicular spermatozoa have statistically significantly lower DNA damage compared with ejaculated spermatozoa in patients with unsuccessful oral antioxidant treatment. Fertil Steril 2010; 93 (04) 1142-1146
• 180 Suganuma R, Yanagimachi R, Meistrich ML. Decline in fertility of mouse sperm with abnormal chromatin during epididymal passage as revealed by ICSI. Hum Reprod 2005; 20 (11) 3101-3108
• 181 Esteves SC, Roque M, Garrido N. Use of testicular sperm for intracytoplasmic sperm injection in men with high sperm DNA fragmentation: a SWOT analysis. Asian J Androl 2018; 20 (01) 1-8
• 182 Esteves SC, Sánchez-Martín F, Sánchez-Martín P, Schneider DT, Gosálvez J. Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm. Fertil Steril 2015; 104 (06) 1398-1405
• 183 Esteves SC, Agarwal A, Majzoub A. Comparison of strategies to reduce sperm DNA fragmentation in couples undergoing ICSI. Transl Androl Urol 2017; 6 (Suppl. 04) S570-S573
• 184 Bradley CK, McArthur SJ, Gee AJ, Weiss KA, Schmidt U, Toogood L. Intervention improves assisted conception intracytoplasmic sperm injection outcomes for patients with high levels of sperm DNA fragmentation: a retrospective analysis. Andrology 2016; 4 (05) 903-910
• 185 Hozyen M, Hasanen E, Elqusi K. et al. Reproductive outcomes of different sperm selection techniques for ICSI patients with abnormal sperm DNA fragmentation: a randomized controlled trial. Reprod Sci 2022; 29 (01) 220-228
• 186 Nosrati R, Graham PJ, Zhang B. et al. Microfluidics for sperm analysis and selection. Nat Rev Urol 2017; 14 (12) 707-730
• 187 Parrella A, Keating D, Cheung S. et al. A treatment approach for couples with disrupted sperm DNA integrity and recurrent ART failure. J Assist Reprod Genet 2019; 36 (10) 2057-2066
• 188 Lara-Cerrillo S, Urda Muñoz C, de la Casa Heras M. et al. Microfluidic sperm sorting improves ICSI outcomes in patients with increased values of double-strand breaks in sperm DNA. Rev Int Androl 2023; 21 (01) 100338