Serbest seminal nükleik asitlerin erkek infertilitesi ile ilişkisi

İnfertilite dünya genelinde üreme çağındaki çiftlerin yaklaşık olarak %8–12’sini etkileyen ve son yıllarda artış eğilimi gösteren önemli bir problemdir. Erkek faktörün infertilite sorununa katkısı ~ %50’dir. Erkek infertilitesinden konjenital anomaliler, endokrin disfonksiyonu, inflamatuvar hastalıklar, ereksiyon ya da ejekulasyon problemleri, genital sistem obstrüksiyonu, gametogenez fonksiyon bozuklukları ve genetik faktörlerin de dâhil olduğu bir çok etken sorumludur. Erkek infertilitesinin genetik özellikleri testisin histolojik fenotiplerinin ve semenin oldukça heterojen olması ve spermatogenez sürecinde çok sayıda genin görev almasından dolayı oldukça karmaşıktır. Serbest (cell free, cf) nükleik asitler semenin de aralarında bulunduğu birçok vücut sıvısında bulunmaktadır. Son yıllarda, semende bol miktarda bulunan serbest nükleik asitlerin erkek infertilitesinin tanı ve prognozunda kullanılabileceği bildirilmektedir. Serbest seminal nükleik asitler (cfs-DNA ve cfs-RNA) bilateral testisler ve epididimis gibi farklı üreme organlarının genetik ve epigenetik bilgisini içermekte ve invaziv olmayan yöntemlerle elde edilebilmektedir. Bu derlemede, serbest seminal nükleik asitlerin semen parametreleri ve erkek infertilitesi ile ilişkisini araştıran çalışmalar özetlenmekte ve bunların erkek infertilitesi alanında yapılan çalışmalar için önemi tartışılmaktadır.

Cell-free nucleic acids and male infertility relationship

Infertility is an important problem affecting 8% -12% of couples of reproductive age all around the world and tends to increase in recent decades. The contribution of male factor to this problem is nearly 50%. Male infertility results from numerous factors including congenital abnormalities, endocrine dysfunction, inflammatory diseases, erection or ejaculation problems, genital system obstruction, gametogenesis dysfunctions and genetic factors. The genetic characteristic of male infertility is very complicated due to the heterogeneous histological phenotype of testis and semen heterogeneity, and many genes involved in the spermatogenesis process. Cell-free (cf) nucleic acids are present in several body fluids including semen. In recent years, cell-free nucleic acids which are found abundantly in semen have been suggested to be used in the diagnosis and prognosis of male infertility. Cell-free seminal nucleic acids (cfs-DNA and cfs-RNA) contain genetic and epigenetic information of different reproductive organs such as bilateral testis and epididymis, and can be obtained by using non-invasive methods. In this review, studies investigating the association of cell-free seminal nucleic acids with semen parameters and male infertility are summarized, and their importance for studies in the field of male infertility is discussed.

PDF

___

1. Boissiere A, Gala A, Ferrieres-Hoa A, Mullet T, Baillet S, Petiton A, et al. Cell-free and intracellular nucleic acids: new non-invasive biomarkers to explore male infertility. Basic Clin Androl 2017;27:7. [CrossRef ]
2. Leon S, Shapiro B, Sklaroff D, Yaros M. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 1977;37:646– 50. https://cancerres.aacrjournals.org/content/37/3/646.long
3. Su Y-H, Wang M, Brenner DE, Ng A, Melkonyan H, Umansky S, et al. Human urine contains small, 150 to 250 nucleotide-sized, soluble DNA derived from the circulation and may be useful in the detection of colorectal cancer. J Mol Diagn 2004;6:101–7. [CrossRef ]
4. Chou JS, Jacobson JD, Patton WC, King A, Chan PJ. Modified isocratic capillary electrophoresis detection of cell-free DNA in semen. J Assist Reprod Genet 2004;21:397–400. [CrossRef ]
5. Li H-G, Huang S-Y, Zhou H, Liao A-H, Xiong C-L. Quick recovery and characterization of cell-free DNA in seminal plasma of n ormozoospermia and azoospermia: implications for noninvasive genetic utilities. Asian J Androl 2009;11:703–9. [CrossRef ]
6. Gahan PB, Swaminathan R. Circulating nucleic acids in plasma and serum: recent developments. Ann N Y Acad Sci 2008;1137:1– 6. [CrossRef ]
7. Hazout A, Montjean D, Cassuto N, Belloc S, Dalleac A, Tesarik J, et al. Free circulating nucleic acids and infertility. J Gynecol Women Health 2018;11:1–11. [CrossRef ]
8. Ponti G, Maccaferri M, Mandrioli M, Manfredini M, Micali S, Cotugno M, et al. Seminal Cell-Free DNA Assessment as a Novel Prostate Cancer Biomarker. Pathol Oncol Res 2018;24:941–5. [CrossRef ]
9. Ponti G, Maccaferri M, Manfredini M, Micali S, Torricelli F, Milandri R, et al. Quick assessment of cell-free DNA in seminal fluid and fragment size for early non-invasive prostate cancer diagnosis. Clin Chim Acta 2019;497:76–80. [CrossRef ]
10. Swarup V, Rajeswari MR. Circulating (cell-free) nucleic acids--a promising, non-invasive tool for early detection of several human diseases. FEBS Lett 2007;581:795–9. [CrossRef ]
11. Lee TJ, Rolnik DL, Menezes MA, McLennan AC, da Silva Costa F. Cell-free fetal DNA testing in singleton IVF conceptions. Hum Reprod 2018;33:572–8. [CrossRef ]
12. Shamonki MI, Jin H, Haimowitz Z, Liu L. Proof of concept: preimplantation genetic screening without embryo biopsy through analysis of cell-free DNA in spent embryo culture media. Fertil Steril 2016;106:1312–8. [CrossRef ]
13. Gunes S, Metin Mahmutoglu A. Transcriptomics and Oxidative Stress in Male Infertility. In: Henkel R, Samanta L, Agarwal A, editors. Oxidants, Antioxidants and Impact of the Oxidative Status in Male Reproduction. US: Elsevier; 2019. p.249–60. [CrossRef ]
14. Gunes S, Metin Mahmutoglu AM, Arslan MA, Henkel R. Smoking‐induced genetic and epigenetic alterations in infertile men. Andrologia 2018;50:e13124. [CrossRef ]
15. Cheung S, Parrella A, Rosenwaks Z, Palermo GD. Genetic and epigenetic profiling of the infertile male. PLoS One 2019;14:e0214275. [CrossRef ]
16. 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;40:433–53. [CrossRef ]
17. Wu C, Ding X, Li H, Zhu C, Xiong C. Genome-wide promoter methylation profile of human testis and epididymis: identified from cell-free seminal DNA. BMC Genom 2013;14:288. [CrossRef ]
18. Yu Q, Gu X, Shang X, Li H, Xiong C. Discrimination and characterization of Sertoli cell-only syndrome in non-obstructive azoospermia using cell-free seminal DDX4. Reprod Biomed Online 2016;33:189–96. [CrossRef ]
19. Wu C, Ding X, Tan H, Li H, Xiong C. Alterations of testis-specific promoter methylation in cell-free seminal deoxyribonucleic acid of idiopathic nonobstructive azoospermic men with different testicular phenotypes. Fertil Steril 2016;106:1331–7. [CrossRef ]
20. Draškovič T. Isolation of Cell-Free DNA from Seminal Fluid. J Pharm Pharmacol 2017;5:554–60. [CrossRef ]
21. Costa F, Barbisan F, Assmann CE, Araujo NKF, de Oliveira AR, Signori JP, et al. Seminal cell-free DNA levels measured by PicoGreen fluorochrome are associated with sperm fertility criteria. Zygote 2017;25:111–9. [CrossRef ]
22. Bounartzi T, Dafopoulos K, Anifandis G, Messini CI, Koutsonikou C, Kouris S, et al. Pregnancy prediction by free sperm DNA and sperm DNA fragmentation in semen specimens of IVF/ICSI-ET patients. Hum Fertil (Camb) 2016;19:56–62. [CrossRef ]
23. Chen Y, Liao T, Zhu L, Lin X, Wu R, Jin L. Seminal plasma cellfree mitochondrial DNA copy number is associated with human semen quality. Eur J Obstet Gynecol Reprod Biol 2018;231:164– 8. [CrossRef ]
24. Krausz C, Riera-Escamilla A. Genetics of male infertility. Nat Rev Urol 2018;15:369–84. [CrossRef ]
25. Gunes S, Agarwal A, Henkel R, Metin Mahmutoglu A, Sharma R, Esteves S, et al. Association between promoter methylation of MLH 1 and MSH 2 and reactive oxygen species in oligozoospermic men—A pilot study. Andrologia 2018;50:e12903. [CrossRef ]
26. Gunes SO, Metin Mahmutoglu A, Agarwal A. Genetic and epigenetic effects in sex determination. Birth Defects Research Part C. Embryo Today Rev 2016;108:321–36. [CrossRef ]
27. Bieniek JM, Drabovich AP, Lo KC. Seminal biomarkers for the evaluation of male infertility. Asian J Androl 2016;18:426–33. [CrossRef ]
28. Huang S, Li H, Ding X, Xiong C. Presence and characterization of cell-free seminal RNA in healthy individuals: implications for noninvasive disease diagnosis and gene expression studies of the male reproductive system. Clin Chem 2009;55:1967–76. [CrossRef ]
29. Li H, Huang S, Guo C, Guan H, Xiong C. Cell-free seminal mRNA and microRNA exist in different forms. PloS one 2012;7:e34566. [CrossRef ]
30. Li H, Wu C, Gu X, Xiong C. A novel application of cell-free seminal mRNA. non-invasive identification of the presence of germ cells or complete obstruction in men with azoospermia. Hum Reprod 2012;27:991–7. [CrossRef ]
31. Dong TT, Yu Q, Qing XR, Ma XL, Dong WW, Shi J, Li HG. Potential confounding factors in measurement of specific cellfree seminal mRNAs and microRNAs derived from human reproductive organs. Andrology 2016;4:1010–9. [CrossRef ]
32. Shilpa M, Selvaraju S, GirishKumar V, Parthipan S, Binsila KB, Arangasamy A, Ravindra JP. Novel insights into the role of cell-free seminal mRNAs on semen quality and cryotolerance of spermatozoa in bulls (Bos taurus). Reprod Fertil Dev 2017;29:2446–56. [CrossRef ]
33. Abdallah W, Hashad D, Abdelmaksoud R, Hashad MM. Does detection of DDX4 mRNA in cell-free seminal plasma represents a reliable noninvasive germ cell marker in patients with nonobstructive azoospermia? Andrologia 2017;49. [CrossRef ]