Genetics and epigenetics of varicocele pathophysiology: an overview

Journal of Assisted Reproduction and Genetics

Volumn 34, Issue 7, 2017, Pages 839-847

  Santana, Viviane Paiva ^a   Miranda Furtado, Cristiana Libardi ^a,b   de Oliveira Gennaro, Flavia Gaona ^a   dos Reis, Rosana Maria ^a  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b INSTITUTO OSWALDO CRUZ   (Brazil)

Author keywords

Epigenetics; Genetics; Genome; Male infertility; Varicocele

Indexed keywords

MITOCHONDRIAL DNA;

CHROMOSOME DAMAGE; CLINICAL FEATURE; DNA FRAGMENTATION; DNA POLYMORPHISM; EPIGENETICS; GENE EXPRESSION; GENE MUTATION; GENETICS; HUMAN; MALE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SOMATIC CELL; SPERM; VARICOCELE; CHEMISTRY; COMPLICATION; GENETIC EPIGENESIS; MALE INFERTILITY; OXIDATIVE STRESS; PATHOLOGY; SEMEN ANALYSIS;

DNA FRAGMENTATION; DNA, MITOCHONDRIAL; EPIGENESIS, GENETIC; HUMANS; INFERTILITY, MALE; MALE; OXIDATIVE STRESS; SEMEN ANALYSIS; VARICOCELE;

EID: 85019868389     PISSN: 10580468     EISSN: 15737330     Source Type: Journal    
DOI: 10.1007/s10815-017-0931-5     Document Type: Review

References (128)

1. Noske HD, Weidner W. Varicocele—a historical perspective. World J Urol. 1999;17(3):151–7.
2. Weidner W, Pilatz A, Altinkilic B. Andrology: varicocele: an update. Urologe A. 2010;49(Suppl 1):163–5.
3. Inci K, Gunay LM. The role of varicocele treatment in the management of non-obstructive azoospermia. Clinics (Sao Paulo). 2013;68(Suppl 1):89–98.
4. Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril. 1993;59(3):613–6.
5. Choi WS, Kim SW. Current issues in varicocele management: a review. World J Mens Health. 2013;31(1):12–20.
6. MacLeod J. Seminal cytology in the presence of varicocele. Fertil Steril. 1965;16(6):735–57.
7. Xue J. Abnormalities of the testes and semen parameters in clinical varicocele. J South Med Univ. 2012;32(4):439–42.
8. Kadioglu TC, Aliyev E, Celtik M. Microscopic varicocelectomy significantly decreases the sperm DNA fragmentation index in patients with infertility. Biomed Res Int. 2014;2014:695713.
9. Zini A, et al. Effect of microsurgical varicocelectomy on human sperm chromatin and DNA integrity: a prospective trial. Int J Androl. 2011;34(1):14–9.
10. Tavalaee M, et al. Semen parameters and chromatin packaging in microsurgical varicocelectomy patients. Int J Fertil Steril. 2012;6(3):165–74.
11. Santana VP, Furtado CLM, Molina CAF, Nobre YTDA, Ferriani RA, dos Reis RM. A randomized clinical trial study of the effects of varicocelectomy on sperm clinical analysis and DNA fragmentation: a preliminary data. Gynecol Obstet Res Open J. 2015;2(1):29–34.
12. Agarwal A, et al. Role of oxidative stress in pathogenesis of varicocele and infertility. Urology. 2009;73(3):461–9.
13. Fretz PC, Sandlow JI. Varicocele: current concepts in pathophysiology, diagnosis, and treatment. Urol Clin North Am. 2002;29:921–37.
14. Benoff S, Marmar JL, Hurley IR. Molecular and other predictors for infertility in patients with varicoceles. Front Biosci (Landmark Ed). 2009;14:3641–72.
15. Marmar JL. The emergence of specialized procedures for the acquisition, processing, and cryopreservation of epididymal and testicular sperm in connection with intracytoplasmic sperm injection. J Androl. 1998;19(5):517–26.
16. Benoff S, Gilbert BR. Varicocele and male infertility: part I. Preface. Hum Reprod Update. 2001;7(1):47–54.
17. Raman JD, Walmsley K, Goldstein M. Inheritance of varicoceles. Urology. 2005;65(6):1186–9.
18. Beigi FM, Mehrabi S, Javaherforooshzadeh A. Varicocele in brothers of patients with varicocele. Urol J (Tehran). 2007;4:33–5.
19. Benoff S, et al. Deletions in L-type calcium channel alpha1 subunit testicular transcripts correlate with testicular cadmium and apoptosis in infertile men with varicoceles. Fertil Steril. 2005;83(3):622–34.
20. Dada R, Gupta NP, Kucheria K. Cytogenetic and molecular analysis of male infertility. Biochemistry and Biophysics. 2006;44:171–7.
21. Rao L, et al. Chromosomal abnormalities and y chromosome microdeletions in infertile men with varicocele and idiopathic infertility of south Indian origin. J Androl. 2004;25(1):147–53.
22. Song NH, et al. Screening for Y chromosome microdeletions in idiopathic and nonidiopathic infertile men with varicocele and cryptorchidism. Chin Med J. 2005;118(17):1462–7.
23. Stahl BC, et al. Supernumerary minute ring chromosome 14 in a man with primary infertility and left varicocele. Fertil Steril. 2007;87(5):1213 e1–3.
24. Lee J, et al. Detailed analysis of isodicentric Y in a case with azoospermia and 45,x/46,x,idic(Y) mosaicism. Ann Clin Lab Sci. 2015;45(2):206–8.
25. Baccetti BM, et al. Studies on varicocele III: ultrastructural sperm evaluation and 18, X and Y aneuploidies. J Androl. 2006;27(1):94–101.
26. Tang K, et al. Genetic polymorphisms of glutathione S-transferase M1, T1, and P1, and the assessment of oxidative damage in infertile men with varicoceles from northwestern China. J Androl. 2012;33(2):257–63.
27. Acar H, et al. Glutathione S-transferase M1 and T1 polymorphisms in Turkish patients with varicocele. Andrologia. 2011;44(1):34–7.
28. Gentile V, et al. ACP1 genetic polymorphism and spermatic parameters in men with varicocele. Andrologia. 2014;46(2):147–50.
29. Ucar VB, et al. Is methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism related with varicocele risk? Andrologia. 2014;47(1):42–6.
30. Heidari MM, et al. Mutation analysis of TNP1 gene in infertile men with varicocele. Iran J Reprod Med. 2014;12(4):257–62.
31. Kahraman CY, et al. The relationship between endothelial nitric oxide synthase Gene (NOS3) polymorphisms, NOS3 expression, and varicocele. Genet Test Mol Biomarkers. 2016;20(4):191–6.
32. Gashti NG, et al. 4977-bp mitochondrial DNA deletion in infertile patients with varicocele. Andrologia. 2014;46(3):258–62.
33. Heidari MM, Khatami M, and Talebi AR. The POLG Gene Polymorphism in Iranian Varicocele-Associated Infertility Patients. Iran J Basic Med Sci. 2012;15(2):739–44.
34. Lima SB, et al. Expression of the HSPA2 gene in ejaculated spermatozoa from adolescents with and without varicocele. Fertil Steril. 2006;86(6):1659–63.
35. Tu LH, et al. Potential role of prokineticin 2 in experimental varicocele-induced rat testes. Urology. 2012;80(4):952 e15–9.
36. Mostafa T, et al. Seminal BAX and BCL2 gene and protein expressions in infertile men with varicocele. Urology. 2014;84(3):590–5.
37. Zalata AA, et al. Androgen receptor expression relationship with semen variables in infertile men with varicocele. J Urol. 2013;189(6):2243–7.
38. Soares TS, et al. Experimental varicocoele in rats affects mechanisms that control expression and function of the androgen receptor. Andrology. 2013;1(5):670–81.
39. Oliveira A, et al. Comparative study of gene expression in patients with varicocele by microarray technology. Andrologia. 2012;44(Suppl 1):260–5.
40. Amer MK, et al. Ropporin gene expression in infertile asthenozoospermic men with varicocele before and after repair. Urology. 2015;85(4):805–8.
41. Bahreinian M, et al. DNA hypomethylation predisposes sperm to DNA damage in individuals with varicocele. Syst Biol Reprod Med. 2015;61(4):179–86.
42. Tavalaee M, et al. Effect of varicocelectomy on sperm functional characteristics and DNA methylation. Andrologia. 2014;47(8):904–9.
43. Ji Z, et al. Expressions of miR-15a and its target gene HSPA1B in the spermatozoa of patients with varicocele. Reproduction. 2014;147(5):693–701.
44. Aitken RJ, De Iuliis GN, McLachlan RI. Biological and clinical significance of DNA damage in the male germ line. Int J Androl. 2009;32(1):46–56.
45. Rubes J, et al. Episodic air pollution is associated with increased DNA fragmentation in human sperm without other changes in semen quality. Hum Reprod. 2005;20:2776–83.
46. Sharma R, et al. Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol. 2013;11:66.
47. Sharma R, et al. 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(4):635–45.
48. Gosalvez J, et al. Unpacking the mysteries of sperm DNA fragmentation: ten frequently asked questions. J Reprod Biotechnol Fertil. 2015;4:1–16.
49. Shiraishi K, Matsuyama H, Takihara H. Pathophysiology of varicocele in male infertility in the era of assisted reproductive technology. Int J Urol. 2012;19(6):538–50.
50. Baumber J, et al. The effect of reactive oxygen species on equine sperm motility, viability, acrosomal integrity, mitochondrial membrane potential, and membrane lipid peroxidation. J Androl. 2000;21(6):895–902.
51. Aitken RJ, De Iuliis GN. On the possible origins of DNA damage in human spermatozoa. Mol Hum Reprod. 2010;16(1):3–13.
52. Cho CL, Esteves SC, Agarwal A. Novel insights into the pathophysiology of varicocele and its association with reactive oxygen species and sperm DNA fragmentation. Asian J Androl. 2016;18(2):186–93.
53. Naughton CK, Nangia AK, Agarwal A. Pathophysiology of varicoceles in male infertility. Hum Reprod Update. 2001;7(5):473–81.
54. Saleh RA, Agarwal A. Oxidative stress and male infertility: from research bench to clinical practice. J Androl. 2002;23(6):737–52.
55. Tremellen K. Oxidative stress and male infertility—a clinical perspective. Hum Reprod Update. 2008;14(3):243–58.
56. 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.
57. Hamada A, Esteves SC, Agarwal A. Insight into oxidative stress in varicocele-associated male infertility: part 2. Nat Rev Urol. 2013;10(1):26–37.
58. Mitropoulos D, et al. Nitric oxide synthase and xanthine oxidase activities in the spermatic vein of patients with varicocele: a potential role for nitric oxide and peroxynitrite in sperm dysfunction. J Urol. 1996;156(6):1952–8.
59. Allamaneni SS, et al. Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size. Fertil Steril. 2004;82(6):1684–6.
60. Sheehan MM, Ramasamy R, Lamb DJ. Molecular mechanisms involved in varicocele-associated infertility. J Assist Reprod Genet. 2014;31(5):521–6.
61. Saleh RA, et al. Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil Steril. 2003;80(6):1431–6.
62. Blumer CG, et al. Sperm nuclear DNA fragmentation and mitochondrial activity in men with varicocele. Fertil Steril. 2008;90(5):1716–22.
63. Zini A and Dohle G. Are varicoceles associated with increased deoxyribonucleic acid fragmentation? Fertil Steril. 2011;96(6):1283–7.
64. Smith R, et al. Increased sperm DNA damage in patients with varicocele: relationship with seminal oxidative stress. Hum Reprod. 2006;21(4):986–93.
65. Wright C, Milne S, and Leeson H. Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility. Reprod Biomed Online. 2014;28(6):684–703.
66. Gonzalez-Marin C, Gosalvez J, Roy R. Types, causes, detection and repair of DNA fragmentation in animal and human sperm cells. Int J Mol Sci. 2012;13(11):14026–52.
67. Wang YJ, et al. Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-analysis. Reprod BioMed Online. 2012;25(3):307–14.
68. Enciso M, et al. Infertile men with varicocele show a high relative proportion of sperm cells with intense nuclear damage level, evidenced by the sperm chromatin dispersion test. J Androl. 2006;27(1):106–11.
69. Baker K, et al. Pregnancy after varicocelectomy: impact of postoperative motility and DFI. Urology. 2013;81(4):760–6.
70. Smit M, et al. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. J Urol. 2013;189(1 Suppl):S146–50.
71. Li F, et al. Significant improvement of sperm DNA quality after microsurgical repair of varicocele. Syst Biol Reprod Med. 2012;58(5):274–7.
72. Telli O, et al. Does varicocelectomy affect DNA fragmentation in infertile patients? Indian J Urol. 2015;31(2):116–9.
73. Hurtado de Catalfo GE, et al. Oxidative stress biomarkers and hormonal profile in human patients undergoing varicocelectomy. Int J Androl. 2007;30(6):519–30.
74. Sakamoto Y, et al. The assessment of oxidative stress in infertile patients with varicocele. BJU Int. 2008;101(12):1547–52.
75. Dada R, et al. Attenuation of oxidative stress & DNA damage in varicocelectomy: implications in infertility management. Indian J Med Res. 2010;132:728–30.
76. Sago H. Prenatal diagnosis of chromosomal abnormalities through amniocentesis. J Mamm Ova Res. 2004;21.
77. Martinez MC, et al. Screening for AZF deletion in a large series of severely impaired spermatogenesis patients. J Androl. 2000;21(5):651–5.
78. Egozcue J, et al. Genetic analysis of sperm and implications of severe male infertility—a review. Placenta. 2003;24(Suppl B):S62–5.
79. Sarrate Z, et al. FISH studies of chromosome abnormalities in germ cells and its relevance in reproductive counseling. Asian J Androl. 2005;7(3):227–36.
80. Holmes JM, Martin RH. Aneuploidy detection in human sperm nuclei using fluorescence in situ hybridization. Hum Genet. 1993;91(1):20–4.
81. Acar H, et al. Comparison of semen profile and frequency of chromosome aneuploidies in sperm nuclei of patients with varicocele before and after varicocelectomy. Andrologia. 2009;41(3):157–62.
82. Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Am J Pharmacogenomics. 2001;1(3):189–201.
83. Smith G, et al. Metabolic polymorphisms and cancer susceptibility. Cancer Surv. 1995;25:27–65.
84. Ichioka K, et al. Genetic polymorphisms in glutathione S-transferase T1 affect the surgical outcome of varicocelectomies in infertile patients. Asian J Androl. 2009;11(3):333–41.
85. Stefani M, et al. Dephosphorylation of tyrosine phosphorylated synthetic peptides by rat liver phosphotyrosine protein phosphatase isoenzymes. FEBS Lett. 1993;326(1–3):131–4.
86. Cool J, DeFalco TJ, Capel B. Vascular-mesenchymal cross-talk through Vegf and Pdgf drives organ patterning. Proc Natl Acad Sci U S A. 2011;108(1):167–72.
87. Fodinger M, Horl WH, Sunder-Plassmann G. Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol. 2000;13(1):20–33.
88. La Salle S, et al. Loss of spermatogonia and wide-spread DNA methylation defects in newborn male mice deficient in DNMT3L. BMC Dev Biol. 2007;7:104.
89. Singh K, et al. Mutation C677T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population. Int J Androl. 2005;28(2):115–9.
90. Lee HC, et al. Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Hum Reprod. 2006;21(12):3162–70.
91. Mylonis I, et al. Temporal association of protamine 1 with the inner nuclear membrane protein lamin B receptor during spermiogenesis. J Biol Chem. 2004;279(12):11626–31.
92. Garcia-Peiro A, et al. Protamine 1 to protamine 2 ratio correlates with dynamic aspects of DNA fragmentation in human sperm. Fertil Steril. 2011;95(1):105–9.
93. Miyagawa Y, et al. Single-nucleotide polymorphisms and mutation analyses of the TNP1 and TNP2 genes of fertile and infertile human male populations. J Androl. 2005;26(6):779–86.
94. Siasi E, et al. Association study of six SNPs in PRM1, PRM2 and TNP2 genes in Iranian infertile men with idiopathic azoospermia. Iran J Reprod Med. 2012;10(4):329–36.
95. Malinsk T. The vital role of nitric oxide. Oakland J. 2000;1:47–56.
96. Kanner J, Harel S, Granit R. Nitric oxide as an antioxidant. Arch Biochem Biophys. 1991;289:130–6.
97. Spiropoulos J, Turnbull DM, Chinnery PF. Can mitochondrial DNA mutations cause sperm dysfunction? Mol Hum Reprod. 2002;8(8):719–21.
98. Kao SH, Chao HT, Wei YH. Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod. 1998;4(7):657–66.
99. St John JC, Sakkas D, Barratt CL. A role for mitochondrial DNA and sperm survival. J Androl. 2000;21(2):189–99.
100. Bertazzoni U, Scovassi AI, Brun GM. Chick-embryo DNA polymerase gamma. Identity of gamma-polymerases purified from nuclei and mitochondria. Eur J Biochem. 1977;81(2):237–48.
101. Rovio AT, et al. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet. 2001;29:261–2.
102. Zhao Y, et al. Characterization and quantification of mRNA transcripts in ejaculated spermatozoa of fertile men by serial analysis of gene expression. Hum Reprod. 2006;21(6):1583–90.
103. Wykes SM, Miller D, Krawetz SA. Mammalian spermatozoal mRNAs: tools for the functional analysis of male gametes. J Submicrosc Cytol Pathol. 2000;32(1):77–81.
104. Miller D. Analysis and significance of messenger RNA in human ejaculated spermatozoa. Mol Reprod Dev. 2000;56(2 Suppl):259–64.
105. Ni K, et al. Sperm protamine mRNA ratio and DNA fragmentation index represent reliable clinical biomarkers for men with varicocele after microsurgical varicocele ligation. J Urol. 2014;192(1):170–6.
106. Del Giudice PT, et al. Expression of the Fas-ligand gene in ejaculated sperm from adolescents with and without varicocele. J Assist Reprod Genet. 2010;27(2–3):103–9.
107. Santoro MG. Heat shock factors and the control of the stress response. Biochem Pharmacol. 2000;59(1):55–63.
108. Georgopoulos C, Welch WJ. Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol. 1993;9:601–34.
109. Afiyani AA, et al. Evaluation of heat-shock protein A2 (HSPA2) in male rats before and after varicocele induction. Mol Reprod Dev. 2014;81(8):766–76.
110. LeCouter J, et al. The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: localization of Bv8 receptors to endothelial cells. Proc Natl Acad Sci U S A. 2003;100(5):2685–90.
111. Wechselberger C, et al. The mammalian homologues of frog Bv8 are mainly expressed in spermatocytes. FEBS Lett. 1999;462(1–2):177–81.
112. Almeida C, et al. Caspase signalling pathways in human spermatogenesis. J Assist Reprod Genet. 2013;30(4):487–95.
113. Chen H, et al. New insights into germ cell migration and survival/apoptosis in spermatogenesis: lessons from CD147. Spermatogenesis. 2012;2:264–72.
114. Luo DY, et al. Effects of varicocele on testosterone, apoptosis and expression of StAR mRNA in rat Leydig cells. Asian J Androl. 2011;13(2):287–91.
115. Fujita A, et al. Ropporin, a sperm-specific binding protein of rhophilin that is localized in the fibrous sheath of sperm flagella. J Cell Sci. 2000;113:103–12.
116. Inbar-Feigenberg M, et al. Basic concepts of epigenetics. Fertil Steril. 2013;99(3):607–15.
117. Feinberg AP, Cui H, Ohlsson R. DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms. Semin Cancer Biol. 2002;12(5):389–98.
118. Payer B, Lee JT. X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet. 2008;42:733–72.
119. Rice JC, Allis CD. Histone methylation versus histone acetylation: new insights into epigenetic regulation. Curr Opin Cell Biol. 2001;13(3):263–73.
120. Hammoud SS, et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature. 2009a;460(7254):473–8.
121. Hammoud S, Liu L, Carrell DT. Protamine ratio and the level of histone retention in sperm selected from a density gradient preparation. Andrologia. 2009b;41(2):88–94.
122. Hammoud SS, et al. Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil Steril. 2010;94(5):1728–33.
123. Landgraf P, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 2007;129(7):1401–14.
124. Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol. 2010;11(4):252–63.
125. Romero Y, et al. Dicer1 depletion in male germ cells leads to infertility due to cumulative meiotic and spermiogenic defects. PLoS One. 2011;6(10):e25241.
126. Li G, et al. Alterations in microRNA expression in stress-induced cellular senescence. Mech Dev. 2009;130:731–41.
127. Wilmink GJ, et al. Identification of microRNAs associated with hyperthermia-induced cellular stress response. Cell Stress Chaperones. 2010;15(6):1027–38.
128. Guo SJ, Sun ZJ, Li W. New insights about the early diagnosis of fertility impairment in varicoceles: the DNA repair gene example. Med Hypotheses. 2012;78(4):536–8.