Normospermic Patients Infected With Ureaplasma parvum: Role of Dysregulated miR-122-5p, miR-34c-5, and miR-141-3p
Article Sidebar
Main Article Content
Abstract
Background: Ureaplasma parvum (UP) is a causative agent of non-gonococcal urethritis, involved in the pathogenesis of prostatitis and epididymitis, and it could impair human fertility. Although UP infection is a frequent cause of male infertility the study evidence assessing their prevalence and the association in patients with infertility is still scarce. The molecular processes leading to defects in spermatozoa quality are not completely investigated. MicroRNAs (miRNAs) have been extensively reported as gene regulatory molecules on post-transcriptional levels involved in various biological processes such as gametogenesis, embryogenesis, and the quality of sperm, oocyte, and embryos.
Methods: Therefore, the study design was to demonstrate that miRNAs in body fluids like sperm could be utilized as non-invasive diagnostic biomarkers for pathological and physiological conditions such as infertility. A post-hoc bioinformatics analysis was carried out to predict the pathways modulated by the miRNAs dysregulated in the differently motile spermatozoa.
Results: Here it is shown that normospermic patients infected by UP had spermatozoa with increased quantity of superoxide anions, reduced expression of miR-122-5p, miR-34c-5, and increased miR-141-3p compared with non-infected normospermic patients. This corresponded to a reduction of sperm motility in normospermic infected patients compared with normospermic non-infected ones. A target gene prediction presumed that an essential role of these miRNAs resided in the regulation of lipid kinase activity, accounting for the changes in the constitution of spermatozoa membrane lipids caused by UP.
Conclusions: Altogether, the data underline the influence of UP on epigenetic mechanisms regulating spermatozoa motility.
Downloads
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Pathogens and Immunity abides by Creative Commons BY 4.0:
http://creativecommons.org/licenses/by/4.0/
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
References
1. Schuppe HC, Pilatz A, Hossain H, Diemer T, Wagenlehner F, Weidner W. Urogenital Infection as a Risk Factor for Male Infertility. Dtsch Arztebl Int. 2017;114(19):339-46. doi: 10.3238/arztebl.2017.0339. PubMed PMID: 28597829; PMCID: PMC5470348.
2. Solomon M, Henkel R. Semen culture and the assessment of genitourinary tract infections. Indian J Urol. 2017;33(3):188-93. doi: 10.4103/iju.IJU_407_16. PubMed PMID: 28717267; PMCID: PMC5508428.
3. Zhou Y, Ma H, Shi X, Liu Y. Ureaplasma spp. in male infertility and its relationship with semen quality and seminal plasma components. Journal of Microbiology, Immunology and Infection. 2017;51. doi: 10.1016/j.jmii.2016.09.004.
4. Eley A, Pacey AA, Galdiero M, Galdiero M, Galdiero F. Can Chlamydia trachomatis directly damage your sperm? Lancet Infect Dis. 2005;5(1):53-7. doi: 10.1016/S1473-3099(04)01254-X. PubMed PMID: 15620561.
5. Moridi K, Hemmaty M, Azimian A, Fallah MH, Khaneghahi Abyaneh H, Ghazvini K. Epidemiology of genital infections caused by Mycoplasma hominis, M. genitalium and Ureaplasma urealyticum in Iran; a systematic review and meta-analysis study (2000–2019). BMC Public Health. 2020;20(1):1020. doi: 10.1186/s12889-020-08962-5.
6. Sameni F, Zadehmodarres S, Dabiri H, Khaledi M, Nezamzadeh F. Evaluation of Ureaplasma urealyticum, Chlamydia trachomatis, Mycoplasma genitalium and Neisseria gonorrhoeae in infertile women compared to pregnant women. J Obstet Gynaecol. 2022;42(6):2151-5. doi: 10.1080/01443615.2022.2035328. PubMed PMID: 35579283.
7. Friberg J, Gnarpe H. Mycoplasmas in semen from fertile and infertile men. Andrologia. 1974;6(1):45-52. doi: 10.1111/j.1439-0272.1974.tb01590.x. PubMed PMID: 4414753.
8. Knox CL, Allan JA, Allan JM, Edirisinghe WR, Stenzel D, Lawrence FA, Purdie DM, Timms P. Ureaplasma parvum and Ureaplasma urealyticum are detected in semen after washing before assisted reproductive technology procedures. Fertil Steril. 2003;80(4):921-9. doi: 10.1016/s0015-0282(03)01125-7. PubMed PMID: 14556813.
9. Ito K, Akai K, Nishiumi F, Nakura Y, Ning Wu H, Kurata T, Onodera A, Kawai Y, Kajiyama S, Yanagihara I. Ability of Ureaplasma parvum to invade mouse sperm, fertilize eggs through infected sperm, and impair mouse sperm function and embryo development. F S Sci. 2021;2(1):13-23. doi: 10.1016/j.xfss.2020.12.003. PubMed PMID: 35559760.
10. Yang T, Pan L, Wu N, Wang L, Liu Z, Kong Y, Ruan Z, Xie X, Zhang J. Antimicrobial Resistance in Clinical Ureaplasma spp. and Mycoplasma hominis and Structural Mechanisms Underlying Quinolone Resistance. Antimicrob Agents Chemother. 2020;64(6). doi: 10.1128/AAC.02560-19. PubMed PMID: 32229497; PMCID: PMC7269463.
11. Ny Z, Bt K-A, Js L, C D, L K, Yg L. Ureaplasma Urealyticum or Mycoplasma Hominis Infections and Semen Quality of Infertile Men in Abidjan. Journal of Reproduction and Contraception. 2008;19(2):65-72. doi: 10.1016/s1001-7844(08)60008-5.
12. Xianchun F, Jun F, Zhijun D, Mingyun H. Effects of Ureaplasma urealyticum infection on semen quality and sperm morphology. Front Endocrinol (Lausanne). 2023;14:1113130. doi: 10.3389/fendo.2023.1113130. PubMed PMID: 36950686; PMCID: PMC10025488.
13. Song T, Liu Z, Zhang Y, Han Y, Huang J. Detection of Ureaplasma spp. serovars in genital tract of infertile males. J Clin Lab Anal. 2019;33(5):e22865. doi: 10.1002/jcla.22865. PubMed PMID: 30803037; PMCID: PMC6595327.
14. Ruan Z, Yang T, Shi X, Kong Y, Xie X, Zhang J. Clonality and distribution of clinical Ureaplasma isolates recovered from male patients and infertile couples in China. PLoS One. 2017;12(8):e0183947. doi: 10.1371/journal.pone.0183947. PubMed PMID: 28859153; PMCID: PMC5578651.
15. Mousavi A, Farhadifar F, Mirnejad R, Ramazanzadeh R. Detection of genital mycoplasmal infections among infertile females by multiplex PCR. Iran J Microbiol. 2014;6(6):398-403. PubMed PMID: 25926957; PMCID: PMC4411425.
16. Wu C, Blondin P, Vigneault C, Labrecque R, Sirard M-A. Sperm miRNAs— potential mediators of bull age and early embryo development. BMC Genomics. 2020;21(1):798. doi: 10.1186/s12864-020-07206-5.
17. Dell’Annunziata F, Ilisso CP, Dell’Aversana C, Greco G, Coppola A, Martora F, Dal Piaz F, Donadio G, Falanga A, Galdiero M, Altucci L, Galdiero M, Porcelli M, Folliero V, Franci G. Outer Membrane Vesicles Derived from Klebsiella pneumoniae Influence the miRNA Expression Profile in Human Bronchial Epithelial BEAS-2B Cells. Microorganisms. 2020;8(12). doi: 10.3390/microorganisms8121985. PubMed PMID: 33322147; PMCID: PMC7764071.
18. Loh HY, Norman BP, Lai KS, Rahman N, Alitheen NBM, Osman MA. The Regulatory Role of MicroRNAs in Breast Cancer. Int J Mol Sci. 2019;20(19). doi: 10.3390/ijms20194940. PubMed PMID: 31590453; PMCID: PMC6801796.
19. Mostafa T, Rashed LA, Nabil NI, Osman I, Mostafa R, Farag M. Seminal miRNA Relationship with Apoptotic Markers and Oxidative Stress in Infertile Men with Varicocele. Biomed Res Int. 2016;2016:4302754. doi: 10.1155/2016/4302754. PubMed PMID: 28105423; PMCID: PMC5220416.
20. Khatun A, Rahman MS, Pang M-G. Clinical assessment of the male fertility. Obstet Gynecol Sci. 2018;61(2):179-91. doi: 10.5468/ogs.2018.61.2.179.
21. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16(3):231-45. doi: 10.1093/humupd/dmp048. PubMed PMID: 19934213.
22. Riesco MF, Valcarce DG, Martínez-Vázquez JM, Robles V. Effect of low sperm quality on progeny: a study on zebrafish as model species. Scientific Reports. 2019;9(1):11192. doi: 10.1038/s41598-019-47702-7.
23. Guo W, Xie B, Xiong S, Liang X, Gui J-F, Mei J. miR-34a Regulates Sperm Motility in Zebrafish. International journal of molecular sciences. 2017;18(12):2676. doi: 10.3390/ijms18122676. PubMed PMID: 29232857.
24. López P, Castro A, Flórez M, Miranda K, Aranda P, Sánchez-González C, Llopis J, Arredondo M. miR-155 and miR-122 Expression of Spermatozoa in Obese Subjects. Frontiers in genetics. 2018;9:175-. doi: 10.3389/fgene.2018.00175. PubMed PMID: 29896216.
25. Abu-Halima M, Hammadeh M, Schmitt J, Leidinger P, Keller A, Meese E, Backes C. Altered microRNA expression profiles of human spermatozoa in patients with different spermatogenic impairments. Fertil Steril. 2013;99(5):1249-55.e16. doi: 10.1016/j.fertnstert.2012.11.054. PubMed PMID: 23312218.
26. Xiong S, Ma W, Jing J, Zhang J, Dan C, Gui JF, Mei J. An miR-200 Cluster on Chromosome 23 Regulates Sperm Motility in Zebrafish. Endocrinology. 2018;159(5):1982-91. doi: 10.1210/en.2018-00015. PubMed PMID: 29579206.
27. Goodrich R, Johnson G, Krawetz SA. The Preparation of Human Spermatozoal RNA for Clinical Analysis. Archives of Andrology. 2007;53(3):161-7. doi: 10.1080/01485010701216526.
28. Robinet S, Parisot F. Performance assessment of the Allplex™ STI Essential real-time PCR assay for the diagnosis of Neisseria gonorrhoeae and Chlamydia trachomatis infections in genital and extra-genital sites. Journal of Laboratory Medicine. 2019;43(4):191-200. doi: 10.1515/labmed-2019-0030.
29. Ostermeier GC, Dix DJ, Miller D, Khatri P, Krawetz SA. Spermatozoal RNA profiles of normal fertile men. Lancet. 2002;360(9335):772-7. doi: 10.1016/S0140-6736(02)09899-9. PubMed PMID: 12241836.
30. Corral-Vazquez C, Blanco J, Salas-Huetos A, Vidal F, Anton E. Normalization matters: tracking the best strategy for sperm miRNA quantification. Molecular Human Reproduction. 2017;23(1):45-53. doi: 10.1093/molehr/gaw072.
31. Trotta MC, Gesualdo C, Platania CBM, De Robertis D, Giordano M, Simonelli F, D’Amico M, Drago F, Bucolo C, Rossi S. Circulating miRNAs in diabetic retinopathy patients: Prognostic markers or pharmacological targets? Biochemical Pharmacology. 2021;186:114473. doi: 10.1016/j.bcp.2021.114473.
32. Folliero V, Dell’Annunziata F, Roscetto E, Amato A, Gasparro R, Zannella C, Casolaro V, De Filippis A, Catania MR, Franci G, Galdiero M. Rhein: A novel antibacterial compound against Streptococcus mutans infection. Microbiol Res. 2022;261:127062. doi: 10.1016/j.micres.2022.127062. PubMed PMID: 35597077.
33. Folliero V, Franci G, Dell’Annunziata F, Giugliano R, Foglia F, Sperlongano R, De Filippis A, Finamore E, Galdiero M. Evaluation of Antibiotic Resistance and Biofilm Production among Clinical Strain Isolated from Medical Devices. Int J Microbiol. 2021;2021:9033278. doi: 10.1155/2021/9033278. PubMed PMID: 34426740; PMCID: PMC8380152.
34. Sabbatino F, Conti V, Franci G, Sellitto C, Manzo V, Pagliano P, De Bellis E, Masullo A, Salzano FA, Caputo A, Peluso I, Zeppa P, Scognamiglio G, Greco G, Zannella C, Ciccarelli M, Cicala C, Vecchione C, Filippelli A, Pepe S. PD-L1 Dysregulation in COVID-19 Patients. Front Immunol. 2021;12:695242. doi: 10.3389/fimmu.2021.695242. PubMed PMID: 34163490; PMCID: PMC8215357.
35. Beeton ML, Payne MS, Jones L. The Role of Ureaplasma spp. in the Development of Nongonococcal Urethritis and Infertility among Men. Clin Microbiol Rev. 2019;32(4). doi: 10.1128/CMR.00137-18. PubMed PMID: 31270127; PMCID: PMC6750135.
36. Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A, Bentwich I, Einav U, Gilad S, Hurban P, Karov Y, Lobenhofer EK, Sharon E, Shiboleth YM, Shtutman M, Bentwich Z, Einat P. MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res. 2004;14(12):2486-94. doi: 10.1101/gr.2845604. PubMed PMID: 15574827.
37. Liang Y, Ridzon D, Wong L, Chen C. Characterization of microRNA expression profiles in normal human tissues. BMC Genomics. 2007;8:166. doi: 10.1186/1471-2164-8-166. PubMed PMID: 17565689; PMCID: PMC1904203.
38. Salas-Huetos A, James ER, Aston KI, Carrell DT, Jenkins TG, Yeste M. The role of miRNAs in male human reproduction: a systematic review. Andrology. 2020;8(1):7-26. doi: 10.1111/andr.12714. PubMed PMID: 31578810.
39. Kotaja N. MicroRNAs and spermatogenesis. Fertility and Sterility. 2014;101(6):1552-62. doi: 10.1016/j.fertnstert.2014.04.025.
40. Wagner AO, Turk A, Kunej T. Towards a Multi-Omics of Male Infertility. World J Mens Health. 2023;41(2):272-88. doi: 10.5534/wjmh.220186. PubMed PMID: 36649926; PMCID: PMC10042660.
41. Huerta M, Thonnisen J, Koditz B, Herden J, Denil J, Paffenholz P, Heidenreich A, Brandenstein MV. EBV induced loss of sperm quality. Turk J Urol. 2021;47(4):287-92. doi: 10.5152/tud.2021.21553. PubMed PMID: 35118954; PMCID: PMC9612759.
42. Heidary Z, Zaki-Dizaji M, Saliminejad K, Khorram Khorshid HR. MicroRNA profiling in spermatozoa of men with unexplained asthenozoospermia. Andrologia. 2019;51(6):e13284. doi: 10.1111/and.13284. PubMed PMID: 31012127.
43. Batteiger TA, Spencer N, Washam CL, Byrum S, Eledge M, Batteiger BE, Rank RG, Yeruva L. Endocervical miRNA Expression Profiles in Women Positive for Chlamydia trachomatis with Clinical Signs and/or Symptoms Are Distinct from Those in Women Positive for Chlamydia trachomatis without Signs and Symptoms. Infect Immun. 2020;88(10). doi: 10.1128/IAI.00057-20. PubMed PMID: 32690634; PMCID: PMC7504953.
44. Gupta R, Arkatkar T, Yu J-J, Wali S, Haskins WE, Chambers JP, Murthy AK, Bakar SA, Guentzel MN, Arulanandam BP. Chlamydia muridarum infection associated host MicroRNAs in the murine genital tract and contribution to generation of host immune response. Am J Reprod Immunol. 2015;73(2):126-40. doi: 10.1111/aji.12281. PubMed PMID: 24976530.
45. Yeruva L, Pouncey DL, Eledge MR, Bhattacharya S, Luo C, Weatherford EW, Ojcius DM, Rank RG. MicroRNAs Modulate Pathogenesis Resulting from Chlamydial Infection in Mice. Infection and Immunity. 2017;85(1):e00768-16. doi: 10.1128/IAI.00768-16.
46. Arkatkar T, Gupta R, Li W, Yu J-J, Wali S, Neal Guentzel M, Chambers JP, Christenson LK, Arulanandam BP. Murine MicroRNA-214 regulates intracellular adhesion molecule (ICAM1) gene expression in genital Chlamydia muridarum infection. Immunology. 2015;145(4):534-42. doi: 10.1111/imm.12470.
47. Benyeogor I, Simoneaux T, Wu Y, Lundy S, George Z, Ryans K, McKeithen D, Pais R, Ellerson D, Lorenz WW, Omosun T, Thompson W, Eko FO, Black CM, Blas-Machado U, Igietseme JU, He Q, Omosun Y. A unique insight into the MiRNA profile during genital chlamydial infection. BMC genomics. 2019;20(1):143-. doi: 10.1186/s12864-019-5495-6. PubMed PMID: 30777008.
48. Lu C, Zhou D, Wang Q, Liu W, Yu F, Wu F, Chen C. Crosstalk of MicroRNAs and Oxidative Stress in the Pathogenesis of Cancer. Oxid Med Cell Longev. 2020;2020:2415324. doi: 10.1155/2020/2415324. PubMed PMID: 32411322; PMCID: PMC7204110.
49. Ayaz L, Dinç E. Evaluation of microRNA responses in ARPE-19 cells against the oxidative stress. Cutaneous and Ocular Toxicology. 2018;37(2):121-6. doi: 10.1080/15569527.2017.1355314.
50. Wang J, Smith SB. A Novel Mechanism of Sigma 1 Receptor Neuroprotection: Modulation of miR-214-3p. Adv Exp Med Biol. 2019;1185:463-7. doi: 10.1007/978-3-030-27378-1_76. PubMed PMID: 31884655.
51. Martora F, Della Pepa ME, Grimaldi E, Franci G, Folliero V, Petrillo A, Schettino MT, De Franciscis P, Galdiero M, Galdiero M. Seven years prevalence and distribution of high and low risk HPV genotypes in women living in the metropolitan area of Naples. Cancer Epidemiology. 2019;63:101625. doi: 10.1016/j.canep.2019.101625.
52. Capra E, Turri F, Lazzari B, Cremonesi P, Gliozzi TM, Fojadelli I, Stella A, Pizzi F. Small RNA sequencing of cryopreserved semen from single bull revealed altered miRNAs and piRNAs expression between High- and Low-motile sperm populations. BMC Genomics. 2017;18(1):14. doi: 10.1186/s12864-016-3394-7. PubMed PMID: 28052756; PMCID: PMC5209821.
53. Dickson DA, Paulus JK, Mensah V, Lem J, Saavedra-Rodriguez L, Gentry A, Pagidas K, Feig LA. Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress. Translational Psychiatry. 2018;8(1):101. doi: 10.1038/s41398-018-0146-2.
54. Kiani M, Salehi M, Mogheiseh A. MicroRNA expression in infertile men: its alterations and effects. Zygote. 2019;27(5):263-71. doi: 10.1017/S0967199419000340. PubMed PMID: 31412971.
55. Matsuzaki J, Ochiya T. Extracellular microRNAs and oxidative stress in liver injury: a systematic mini review. J Clin Biochem Nutr. 2018;63(1):6-11. doi: 10.3164/jcbn.17-123. PubMed PMID: 30087537; PMCID: PMC6064810.
56. Muñoz X, Mata A, Bassas L, Larriba S. Altered miRNA Signature of Developing Germ-cells in Infertile Patients Relates to the Severity of Spermatogenic Failure and Persists in Spermatozoa. Scientific Reports. 2015;5(1):17991. doi: 10.1038/srep17991.
57. Bouhallier F, Allioli N, Lavial F, Chalmel F, Perrard MH, Durand P, Samarut J, Pain B, Rouault JP. Role of miR-34c microRNA in the late steps of spermatogenesis. RNA. 2010;16(4):720-31. doi: 10.1261/rna.1963810. PubMed PMID: 20150330; PMCID: PMC2844620.
58. Lian J, Zhang X, Tian H, Liang N, Wang Y, Liang C, Li X, Sun F. Altered microRNA expression in patients with non-obstructive azoospermia. Reproductive Biology and Endocrinology. 2009;7(1):13. doi: 10.1186/1477-7827-7-13.
59. Shan S, Xu F, Hirschfeld M, Brenig B. Sperm Lipid Markers of Male Fertility in Mammals. International Journal of Molecular Sciences. 2021;22(16):8767. PubMed PMID: doi: 10.3390/ijms22168767.
60. Alves MBR, de Arruda RP, De Bem THC, Florez-Rodriguez SA, Sá Filho MFd, Belleannée C, Meirelles FV, da Silveira JC, Perecin F, Celeghini ECC. Sperm-borne miR-216b modulates cell proliferation during early embryo development via K-RAS. Scientific Reports. 2019;9(1):10358. doi: 10.1038/s41598-019-46775-8.
61. Yuan S, Schuster A, Tang C, Yu T, Ortogero N, Bao J, Zheng H, Yan W. Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development. Development. 2016;143(4):635-47. doi: 10.1242/dev.131755. PubMed PMID: 26718009; PMCID: PMC4760322.
62. Luconi M, Marra F, Gandini L, Filimberti E, Lenzi A, Forti G, Baldi E. Phosphatidylinositol 3-kinase inhibition enhances human sperm motility. Human Reproduction. 2001;16(9):1931-7. doi: 10.1093/humrep/16.9.1931.
63. Nunez-Calonge R, Caballero P, Redondo C, Baquero F, Martinez-Ferrer M, Meseguer MA. Ureaplasma urealyticum reduces motility and induces membrane alterations in human spermatozoa. Hum Reprod. 1998;13(1O):2756-61. doi: 10.1093/humrep/13.10.2756. PubMed PMID: 9804226.
64. Wu W, Qin Y, Li Z, Dong J, Dai J, Lu C, Guo X, Zhao Y, Zhu Y, Zhang W, Hang B, Sha J, Shen H, Xia Y, Hu Z, Wang X. Genome-wide microRNA expression profiling in idiopathic non-obstructive azoospermia: significant up-regulation of miR-141, miR-429 and miR-7-1-3p. Hum Reprod. 2013;28(7):1827-36. doi: 10.1093/humrep/det099. PubMed PMID: 23559187.
65. Cao X, Cui Y, Zhang X, Lou J, Zhou J, Bei H, Wei R. Proteomic profile of human spermatozoa in healthy and asthenozoospermic individuals. Reproductive Biology and Endocrinology. 2018;16(1):16. doi: 10.1186/s12958-018-0334-1.