Semin Reprod Med 2023; 41(06): 213-225
DOI: 10.1055/s-0044-1779726
Review Article

Small Non-Coding RNAs in Male Reproduction

Opeyemi Olotu
1   Integrative Physiology and Pharmacology Unit, Institute of Biomedicine, University of Turku, Turku, Finland
,
Ammar Ahmedani
1   Integrative Physiology and Pharmacology Unit, Institute of Biomedicine, University of Turku, Turku, Finland
,
1   Integrative Physiology and Pharmacology Unit, Institute of Biomedicine, University of Turku, Turku, Finland
› Author Affiliations
Funding A.A. and O.O. were funded by the Turku Doctoral Programme of Molecular Medicine and the Jane and Atos Erkko Foundation.

Abstract

Male reproductive functions are strictly regulated in order to maintain sperm production and fertility. All processes are controlled by precise regulation of gene expression, which creates specific gene expression programs for different developmental stages and cell types, and forms the functional basis for the reproductive system. Small non-coding RNAs (sncRNAs) are involved in gene regulation by targeting mRNAs for translational repression and degradation through complementary base pairing to recognize their targets. This review article summarizes the current knowledge on the function of different classes of sncRNAs, in particular microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), during male germ cell differentiation, with the focus on sncRNAs expressed in the germline. Although transcriptionally inactive, mature spermatozoa contain a complex population of sncRNAs, and we also discuss the recently identified role of sperm sncRNAs in the intergenerational transmission of epigenetic information on father's environmental and lifestyle exposures to offspring. Finally, we summarize the current information on the utility of sncRNAs as potential biomarkers of infertility that may aid in the diagnosis and prediction of outcomes of medically assisted reproduction.



Publication History

Article published online:
12 February 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Almstrup K. Small RNAs in andrology: small messengers with large perspectives. Andrology 2023; 11 (04) 625-627
  • 2 Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 2015; 16 (07) 421-433
  • 3 Ozata DM, Gainetdinov I, Zoch A, O'Carroll D, Zamore PD. PIWI-interacting RNAs: small RNAs with big functions. Nat Rev Genet 2019; 20 (02) 89-108
  • 4 Yadav RP, Kotaja N. Small RNAs in spermatogenesis. Mol Cell Endocrinol 2014; 382 (01) 498-508
  • 5 Peng H, Shi J, Zhang Y. et al. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res 2012; 22 (11) 1609-1612
  • 6 Mann U, Shiff B, Patel P. Reasons for worldwide decline in male fertility. Curr Opin Urol 2020; 30 (03) 296-301
  • 7 Larriba S, Vigués F, Bassas L. Using small non-coding RNAs in extracellular vesicles of semen as biomarkers of male reproductive system health: opportunities and challenges. Int J Mol Sci 2023; 24 (06) 5447
  • 8 Sellem E, Jammes H, Schibler L. Sperm-borne sncRNAs: potential biomarkers for semen fertility?. Reprod Fertil Dev 2021; 34 (02) 160-173
  • 9 Kretschmer M, Gapp K. Deciphering the RNA universe in sperm in its role as a vertical information carrier. Environ Epigenet 2022; 8 (01) dvac011
  • 10 Roelen BAJ, Chuva de Sousa Lopes SM. Stay on the road: from germ cell specification to gonadal colonization in mammals. Philos Trans R Soc Lond B Biol Sci 2022; 377 (1865): 20210259
  • 11 Mäkelä JA, Hobbs RM. Molecular regulation of spermatogonial stem cell renewal and differentiation. Reproduction 2019; 158 (05) R169-R187
  • 12 Houda A, Nyaz S, Sobhy BM. et al. Seminiferous tubules and spermatogenesis. In: Wu W. ed. Rijeka: IntechOpen; 2021. Ch. 3
  • 13 Griswold MD. Spermatogenesis: the commitment to meiosis. Physiol Rev 2016; 96 (01) 1-17
  • 14 Azhar M, Altaf S, Uddin I. et al. Towards post-meiotic sperm production: genetic insight into human infertility from mouse models. Int J Biol Sci 2021; 17 (10) 2487-2503
  • 15 Gervasi MG, Visconti PE. Molecular changes and signaling events occurring in spermatozoa during epididymal maturation. Andrology 2017; 5 (02) 204-218
  • 16 Oakberg EF. Duration of spermatogenesis in the mouse and timing of stages of the cycle of the seminiferous epithelium. Am J Anat 1956; 99 (03) 507-516
  • 17 Heller CG, Clermont Y. Spermatogenesis in man: an estimate of its duration. Science 1963; 140 (3563): 184-186
  • 18 Amann RP. The cycle of the seminiferous epithelium in humans: a need to revisit?. J Androl 2008; 29 (05) 469-487
  • 19 Johnson L, Varner DD. Effect of daily spermatozoan production but not age on transit time of spermatozoa through the human epididymis. Biol Reprod 1988; 39 (04) 812-817
  • 20 Bedford JM. The status and the state of the human epididymis. Hum Reprod 1994; 9 (11) 2187-2199
  • 21 Sullivan R, Mieusset R. The human epididymis: its function in sperm maturation. Hum Reprod Update 2016; 22 (05) 574-587
  • 22 Perillo G, Shibata K, Wu P-H. piRNAs in sperm function and embryo viability. Reproduction 2023; 165 (03) R91-R102
  • 23 Song R, Hennig GW, Wu Q, Jose C, Zheng H, Yan W. Male germ cells express abundant endogenous siRNAs. Proc Natl Acad Sci U S A 2011; 108 (32) 13159-13164
  • 24 Hilz S, Modzelewski AJ, Cohen PE, Grimson A. The roles of microRNAs and siRNAs in mammalian spermatogenesis. Development 2016; 143 (17) 3061-3073
  • 25 Walker WH. Regulation of mammalian spermatogenesis by miRNAs. Semin Cell Dev Biol 2022; 121: 24-31
  • 26 Chen J, Han C. In vivo functions of miRNAs in mammalian spermatogenesis. Front Cell Dev Biol 2023; 11: 1154938
  • 27 Chen X, Li X, Guo J, Zhang P, Zeng W. The roles of microRNAs in regulation of mammalian spermatogenesis. J Anim Sci Biotechnol 2017; 8: 35
  • 28 Singh A, Rappolee DA, Ruden DM. epigenetic reprogramming in mice and humans: from fertilization to primordial germ cell development. Cells 2023; 12 (14) 1874
  • 29 Kimmins S, Kotaja N, Davidson I, Sassone-Corsi P. Testis-specific transcription mechanisms promoting male germ-cell differentiation. Reproduction 2004; 128 (01) 5-12
  • 30 Chalmel F, Rolland AD, Niederhauser-Wiederkehr C. et al. The conserved transcriptome in human and rodent male gametogenesis. Proc Natl Acad Sci U S A 2007; 104 (20) 8346-8351
  • 31 Soumillon M, Necsulea A, Weier M. et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep 2013; 3 (06) 2179-2190
  • 32 Miller D, Brinkworth M, Iles D. Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction 2010; 139 (02) 287-301
  • 33 Bartel DP. Metazoan microRNAs. Cell 2018; 173 (01) 20-51
  • 34 Kozomara A, Birgaoanu M, Griffiths-Jones S. miRBase: from microRNA sequences to function. Nucleic Acids Res 2019; 47 (D1): D155-D162
  • 35 O'Brien K, Breyne K, Ughetto S, Laurent LC, Breakefield XO. RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat Rev Mol Cell Biol 2020; 21 (10) 585-606
  • 36 Jones BT, Han J, Zhang H. et al. Target-directed microRNA degradation regulates developmental microRNA expression and embryonic growth in mammals. bioRxiv Prepr Serv Biol 2023; DOI: 10.1101/2023.06.26.546601.
  • 37 Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science 2004; 303 (5654): 95-98
  • 38 Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 2004; 10 (02) 185-191
  • 39 Ruby JG, Jan CH, Bartel DP. Intronic microRNA precursors that bypass Drosha processing. Nature 2007; 448 (7149): 83-86
  • 40 Iwakawa HO, Tomari Y. Life of RISC: formation, action, and degradation of RNA-induced silencing complex. Mol Cell 2022; 82 (01) 30-43
  • 41 Liu J, Carmell MA, Rivas FV. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 2004; 305 (5689): 1437-1441
  • 42 Kotaja N. MicroRNAs and spermatogenesis. Fertil Steril 2014; 101 (06) 1552-1562
  • 43 Papaioannou MD, Nef S. microRNAs in the testis: building up male fertility. J Androl 2010; 31 (01) 26-33
  • 44 McIver SC, Roman SD, Nixon B, McLaughlin EA. miRNA and mammalian male germ cells. Hum Reprod Update 2012; 18 (01) 44-59
  • 45 Fernández-Pérez D, Brieño-Enríquez MA, Isoler-Alcaraz J, Larriba E, Del Mazo J. MicroRNA dynamics at the onset of primordial germ and somatic cell sex differentiation during mouse embryonic gonad development. RNA 2018; 24 (03) 287-303
  • 46 Niu Z, Goodyear SM, Rao S. et al. MicroRNA-21 regulates the self-renewal of mouse spermatogonial stem cells. Proc Natl Acad Sci U S A 2011; 108 (31) 12740-12745
  • 47 Chen J, Cai T, Zheng C. et al. MicroRNA-202 maintains spermatogonial stem cells by inhibiting cell cycle regulators and RNA binding proteins. Nucleic Acids Res 2017; 45 (07) 4142-4157
  • 48 Chen J, Gao C, Luo M. et al. MicroRNA-202 safeguards meiotic progression by preventing premature SEPARASE-mediated REC8 cleavage. EMBO Rep 2022; 23 (08) e54298
  • 49 Chen J, Gao C, Lin X. et al. The microRNA miR-202 prevents precocious spermatogonial differentiation and meiotic initiation during mouse spermatogenesis. Development 2021; 148 (24) dev199799
  • 50 Huszar JM, Payne CJ. MicroRNA 146 (Mir146) modulates spermatogonial differentiation by retinoic acid in mice. Biol Reprod 2013; 88 (01) 15
  • 51 Yang Q-E, Racicot KE, Kaucher AV, Oatley MJ, Oatley JM. MicroRNAs 221 and 222 regulate the undifferentiated state in mammalian male germ cells. Development 2013; 140 (02) 280-290
  • 52 Bouhallier F, Allioli N, Lavial F. et al. Role of miR-34c microRNA in the late steps of spermatogenesis. RNA 2010; 16 (04) 720-731
  • 53 Gao H, Wen H, Cao C. et al. Overexpression of microRNA-10a in germ cells causes male infertility by targeting Rad51 in mouse and human. Front Physiol 2019; 10: 765
  • 54 Romero Y, Meikar O, Papaioannou MD. et al. Dicer1 depletion in male germ cells leads to infertility due to cumulative meiotic and spermiogenic defects. PLoS One 2011; 6 (10) e25241
  • 55 Liang X, Zhou D, Wei C. et al. MicroRNA-34c enhances murine male germ cell apoptosis through targeting ATF1. PLoS One 2012; 7 (03) e33861
  • 56 Bao J, Li D, Wang L. et al. MicroRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting E2F transcription factor-retinoblastoma protein (E2F-pRb) pathway. J Biol Chem 2012; 287 (26) 21686-21698
  • 57 Comazzetto S, Di Giacomo M, Rasmussen KD. et al. Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 loci. PLoS Genet 2014; 10 (10) e1004597
  • 58 Yuan S, Tang C, Zhang Y. et al. miR-34b/c and miR-449a/b/c are required for spermatogenesis, but not for the first cleavage division in mice. Biol Open 2015; 4 (02) 212-223
  • 59 Dai L, Tsai-Morris C-H, Sato H. et al. Testis-specific miRNA-469 up-regulated in gonadotropin-regulated testicular RNA helicase (GRTH/DDX25)-null mice silences transition protein 2 and protamine 2 messages at sites within coding region: implications of its role in germ cell development. J Biol Chem 2011; 286 (52) 44306-44318
  • 60 Anbazhagan R, Kavarthapu R, Dale R, Campbell K, Faucz FR, Dufau ML. miRNA expression profiles of mouse round spermatids in GRTH/DDX25-mediated spermiogenesis: mRNA-miRNA network analysis. Cells 2023; 12 (05) 756
  • 61 Yu Z, Raabe T, Hecht NB. MicroRNA Mirn122a reduces expression of the posttranscriptionally regulated germ cell transition protein 2 (Tnp2) messenger RNA (mRNA) by mRNA cleavage. Biol Reprod 2005; 73 (03) 427-433
  • 62 Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell 2012; 148 (06) 1172-1187
  • 63 Hata A, Lieberman J. Dysregulation of microRNA biogenesis and gene silencing in cancer. Sci Signal 2015; 8 (368) re3
  • 64 Bernstein E, Kim SY, Carmell MA. et al. Dicer is essential for mouse development. Nat Genet 2003; 35 (03) 215-217
  • 65 Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet 2007; 39 (03) 380-385
  • 66 Hayashi K, Chuva de Sousa Lopes SM, Kaneda M. et al. MicroRNA biogenesis is required for mouse primordial germ cell development and spermatogenesis. PLoS One 2008; 3 (03) e1738
  • 67 Korhonen HM, Meikar O, Yadav RP. et al. Dicer is required for haploid male germ cell differentiation in mice. PLoS One 2011; 6 (09) e24821
  • 68 Greenlee AR, Shiao M-S, Snyder E. et al. Deregulated sex chromosome gene expression with male germ cell-specific loss of Dicer1. PLoS One 2012; 7 (10) e46359
  • 69 Wu Q, Song R, Ortogero N. et al. The RNase III enzyme DROSHA is essential for microRNA production and spermatogenesis. J Biol Chem 2012; 287 (30) 25173-25190
  • 70 Korhonen HM, Yadav RP, Da Ros M. et al. DICER regulates the formation and maintenance of cell-cell junctions in the mouse seminiferous epithelium. Biol Reprod 2015; 93 (06) 139
  • 71 Chang Y-F, Lee-Chang JS, Imam JS. et al. Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation. Proc Natl Acad Sci U S A 2012; 109 (15) 5750-5755
  • 72 Zimmermann C, Romero Y, Warnefors M. et al. Germ cell-specific targeting of DICER or DGCR8 reveals a novel role for endo-siRNAs in the progression of mammalian spermatogenesis and male fertility. PLoS One 2014; 9 (09) e107023
  • 73 Yadav RP, Mäkelä J-A, Hyssälä H, Cisneros-Montalvo S, Kotaja N. DICER regulates the expression of major satellite repeat transcripts and meiotic chromosome segregation during spermatogenesis. Nucleic Acids Res 2020; 48 (13) 7135-7153
  • 74 González-González E, López-Casas PP, del Mazo J. The expression patterns of genes involved in the RNAi pathways are tissue-dependent and differ in the germ and somatic cells of mouse testis. Biochim Biophys Acta 2008; 1779 (05) 306-311
  • 75 Modzelewski AJ, Hilz S, Crate EA. et al. Dgcr8 and Dicer are essential for sex chromosome integrity during meiosis in males. J Cell Sci 2015; 128 (12) 2314-2327
  • 76 Song R, Ro S, Michaels JD, Park C, McCarrey JR, Yan W. Many X-linked microRNAs escape meiotic sex chromosome inactivation. Nat Genet 2009; 41 (04) 488-493
  • 77 Modzelewski AJ, Holmes RJ, Hilz S, Grimson A, Cohen PE. AGO4 regulates entry into meiosis and influences silencing of sex chromosomes in the male mouse germline. Dev Cell 2012; 23 (02) 251-264
  • 78 Aravin A, Gaidatzis D, Pfeffer S. et al. A novel class of small RNAs bind to MILI protein in mouse testes. Nature 2006; 442 (7099): 203-207
  • 79 Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 2006; 442 (7099): 199-202
  • 80 Grivna ST, Beyret E, Wang Z, Lin H. A novel class of small RNAs in mouse spermatogenic cells. Genes Dev 2006; 20 (13) 1709-1714
  • 81 Lau NC, Seto AG, Kim J. et al. Characterization of the piRNA complex from rat testes. Science 2006; 313 (5785): 363-367
  • 82 Parhad SS, Theurkauf WE. Rapid evolution and conserved function of the piRNA pathway. Open Biol 2019; 9 (01) 180181
  • 83 Han BW, Zamore PD. piRNAs. Curr Biol 2014; 24 (16) R730-R733
  • 84 Czech B, Hannon GJ. One loop to rule them all: the ping-pong cycle and piRNA-guided silencing. Trends Biochem Sci 2016; 41 (04) 324-337
  • 85 Li XZ, Roy CK, Dong X. et al. An ancient transcription factor initiates the burst of piRNA production during early meiosis in mouse testes. Mol Cell 2013; 50 (01) 67-81
  • 86 Aravin AAA, Sachidanandam R, Bourc'his D. et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol Cell 2008; 31 (06) 785-799
  • 87 Gainetdinov I, Colpan C, Arif A, Cecchini K, Zamore PD. A single mechanism of biogenesis, initiated and directed by PIWI proteins, explains piRNA production in most animals. Mol Cell 2018; 71 (05) 775-790.e5
  • 88 Özata DM, Yu T, Mou H. et al. Evolutionarily conserved pachytene piRNA loci are highly divergent among modern humans. Nat Ecol Evol 2020; 4 (01) 156-168
  • 89 Mann JM, Wei C, Chen C. How genetic defects in piRNA trimming contribute to male infertility. Andrology 2023; 11 (05) 911-917
  • 90 Siomi MC, Sato K, Pezic D, Aravin AA. PIWI-interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol 2011; 12 (04) 246-258
  • 91 Kuramochi-Miyagawa S, Watanabe T, Gotoh K. et al. DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev 2008; 22 (07) 908-917
  • 92 Wang X, Ramat A, Simonelig M, Liu MF. Emerging roles and functional mechanisms of PIWI-interacting RNAs. Nat Rev Mol Cell Biol 2023; 24 (02) 123-141
  • 93 Goh WSS, Falciatori I, Tam OH. et al. piRNA-directed cleavage of meiotic transcripts regulates spermatogenesis. Genes Dev 2015; 29 (10) 1032-1044
  • 94 Zhang P, Kang J-Y, Gou L-T. et al. MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Res 2015; 25 (02) 193-207
  • 95 Gou L-T, Dai P, Yang J-H. et al. Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis. Cell Res 2014; 24 (06) 680-700
  • 96 Dai P, Wang X, Gou LT. et al. A translation-activating function of MIWI/piRNA during mouse spermiogenesis. Cell 2019; 179 (07) 1566-1581.e16
  • 97 Carmell MA, Girard A, van de Kant HJG. et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev Cell 2007; 12 (04) 503-514
  • 98 Deng W, Lin H. Miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev Cell 2002; 2 (06) 819-830
  • 99 Kuramochi-Miyagawa S, Kimura T, Ijiri TW. et al. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 2004; 131 (04) 839-849
  • 100 Reuter M, Berninger P, Chuma S. et al. Miwi catalysis is required for piRNA amplification-independent LINE1 transposon silencing. Nature 2011; 480 (7376): 264-267
  • 101 Li Y, Zhang Y, Liu M. Knockout gene-based evidence for PIWI-interacting RNA pathway in mammals. Front Cell Dev Biol 2021; 9: 681188
  • 102 Choi H, Wang Z, Dean J. Sperm acrosome overgrowth and infertility in mice lacking chromosome 18 pachytene piRNA. PLoS Genet 2021; 17 (04) e1009485
  • 103 Wu PH, Fu Y, Cecchini K. et al. The evolutionarily conserved piRNA-producing locus pi6 is required for male mouse fertility. Nat Genet 2020; 52 (07) 728-739
  • 104 Nagirnaja L, Lopes AM, Charng W-L. et al. Diverse monogenic subforms of human spermatogenic failure. Nat Commun 2022; 13 (01) 7953
  • 105 Ouyang JPT, Seydoux G. Nuage condensates: accelerators or circuit breakers for sRNA silencing pathways?. RNA 2022; 28 (01) 58-66
  • 106 Lehtiniemi T, Kotaja N. Germ granule-mediated RNA regulation in male germ cells. Reproduction 2018; 155 (02) R77-R91
  • 107 Meikar O, Vagin VV, Chalmel F. et al. An atlas of chromatoid body components. RNA 2014; 20 (04) 483-495
  • 108 Olotu O, Dowling M, Homolka D. et al. Intermitochondrial cement (IMC) harbors piRNA biogenesis machinery and exonuclease domain-containing proteins EXD1 and EXD2 in mouse spermatocytes. Andrology 2023; 11 (04) 710-723
  • 109 Huang H, Gao Q, Peng X. et al. piRNA-associated germline nuage formation and spermatogenesis require MitoPLD profusogenic mitochondrial-surface lipid signaling. Dev Cell 2011; 20 (03) 376-387
  • 110 Watanabe T, Chuma S, Yamamoto Y. et al. MITOPLD is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline. Dev Cell 2011; 20 (03) 364-375
  • 111 Ma L, Buchold GM, Greenbaum MP. et al. GASZ is essential for male meiosis and suppression of retrotransposon expression in the male germline. PLoS Genet 2009; 5 (09) e1000635
  • 112 Meikar O, Kotaja N. Isolation of chromatoid bodies from mouse testis as a rich source of short RNAs. Methods Mol Biol 2014; 1173: 11-25
  • 113 Lehtiniemi T, Bourgery M, Ma L. et al. SMG6 localizes to the chromatoid body and shapes the male germ cell transcriptome to drive spermatogenesis. Nucleic Acids Res 2022; 50 (20) 11470-11491
  • 114 Xu C, Cao Y, Bao J. Building RNA-protein germ granules: insights from the multifaceted functions of DEAD-box helicase Vasa/Ddx4 in germline development. Cell Mol Life Sci 2021; 79 (01) 4
  • 115 Spichal M, Heestand B, Billmyre KK, Frenk S, Mello CC, Ahmed S. Germ granule dysfunction is a hallmark and mirror of Piwi mutant sterility. Nat Commun 2021; 12 (01) 1420
  • 116 Kierszenbaum AL, Tres LL. Structural and transcriptional features of the mouse spermatid genome. J Cell Biol 1975; 65 (02) 258-270
  • 117 Krawetz SA, Kruger A, Lalancette C. et al. A survey of small RNAs in human sperm. Hum Reprod 2011; 26 (12) 3401-3412
  • 118 Jodar M, Selvaraju S, Sendler E, Diamond MP, Krawetz SA. Reproductive Medicine Network. The presence, role and clinical use of spermatozoal RNAs. Hum Reprod Update 2013; 19 (06) 604-624
  • 119 Chen Q, Yan M, Cao Z. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 2016; 351 (6271): 397-400
  • 120 Sharma U, Conine CC, Shea JM. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 2016; 351 (6271): 391-396
  • 121 Sharma U, Sun F, Conine CC. et al. Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev Cell 2018; 46 (04) 481-494.e6
  • 122 Wang H, Wang Z, Zhou T. et al. Small RNA shuffling between murine sperm and their cytoplasmic droplets during epididymal maturation. Dev Cell 2023; 58 (09) 779-790.e4
  • 123 Shi J, Zhang Y, Tan D. et al. PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications. Nat Cell Biol 2021; 23 (04) 424-436
  • 124 Chen Q, Zhang X, Shi J, Yan M, Zhou T. Origins and evolving functionalities of tRNA-derived small RNAs. Trends Biochem Sci 2021; 46 (10) 790-804
  • 125 Anderson P, Ivanov P. tRNA fragments in human health and disease. FEBS Lett 2014; 588 (23) 4297-4304
  • 126 Jawaid A, Jehle KL, Mansuy IM. Impact of parental exposure on offspring health in humans. Trends Genet 2021; 37 (04) 373-388
  • 127 Lismer A, Kimmins S. Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development. Nat Commun 2023; 14 (01) 2142
  • 128 Rassoulzadegan M, Cuzin F. Nutrition meets heredity: a case of RNA-mediated transmission of acquired characters. Environ Epigenet 2018; 4 (02) dvy006
  • 129 Champroux A, Cocquet J, Henry-Berger J, Drevet JR, Kocer A. A decade of exploring the mammalian sperm epigenome: paternal epigenetic and transgenerational inheritance. Front Cell Dev Biol 2018; 6: 50
  • 130 Radford EJ. Exploring the extent and scope of epigenetic inheritance. Nat Rev Endocrinol 2018; 14 (06) 345-355
  • 131 Chen Q, Yan W, Duan E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat Rev Genet 2016; 17 (12) 733-743
  • 132 Donkin I, Barrès R. Sperm epigenetics and influence of environmental factors. Mol Metab 2018; 14: 1-11
  • 133 Nilsson EE, Sadler-Riggleman I, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenet 2018; 4 (02) dvy016
  • 134 Donkin I, Versteyhe S, Ingerslev LR. et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab 2016; 23 (02) 369-378
  • 135 Ingerslev LR, Donkin I, Fabre O. et al. Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots. Clin Epigenetics 2018; 10 (01) 12
  • 136 Nätt D, Kugelberg U, Casas E. et al. Human sperm displays rapid responses to diet. PLoS Biol 2019; 17 (12) e3000559
  • 137 Gapp K, Jawaid A, Sarkies P. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014; 17 (05) 667-669
  • 138 Rodgers AB, Morgan CP, Bronson SL, Revello S, Bale TL. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 2013; 33 (21) 9003-9012
  • 139 Rodgers AB, Morgan CP, Leu NA, Bale TL. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci U S A 2015; 112 (44) 13699-13704
  • 140 Skvortsova K, Iovino N, Bogdanović O. Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Mol Cell Biol 2018; 19 (12) 774-790
  • 141 Kimmins S, Anderson RA, Barratt CLR. et al. Frequency, morbidity and equity - the case for increased research on male fertility. Nat Rev Urol 2023; (October) DOI: 10.1038/S41585-023-00820-4.
  • 142 Campbell MJ, Lotti F, Baldi E. et al. Distribution of semen examination results 2020 - A follow up of data collated for the WHO semen analysis manual 2010. Andrology 2021; 9 (03) 817-822
  • 143 Keihani S, Verrilli LE, Zhang C. et al. Semen parameter thresholds and time-to-conception in subfertile couples: how high is high enough?. Hum Reprod 2021; 36 (08) 2121-2133
  • 144 DeVilbiss EA, Sjaarda LA, Peterson CM. et al. Longitudinal semen parameter assessments and live birth: variability and implications for treatment strategies. Fertil Steril 2022; 118 (05) 852-863
  • 145 Bartolacci A, Pagliardini L, Makieva S, Salonia A, Papaleo E, Viganò P. Abnormal sperm concentration and motility as well as advanced paternal age compromise early embryonic development but not pregnancy outcomes: a retrospective study of 1266 ICSI cycles. J Assist Reprod Genet 2018; 35 (10) 1897-1903
  • 146 Zhang J, Campion S, Catlin N. et al. Circulating microRNAs as promising testicular translatable safety biomarkers: current state and future perspectives. Arch Toxicol 2023; 97 (04) 947-961
  • 147 Nik Mohamed Kamal NNSB, Shahidan WNS. Non-exosomal and exosomal circulatory microRNAs: Which are more valid as biomarkers?. Front Pharmacol 2020; 10: 1500
  • 148 Wu J, Bao J, Kim M. et al. Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proc Natl Acad Sci U S A 2014; 111 (28) E2851-E2857
  • 149 Chan SY, Wan CWT, Law TYS, Chan DYL, Fok EKL. The sperm small RNA transcriptome: implications beyond reproductive disorder. Int J Mol Sci 2022; 23 (24) 15716
  • 150 Salas-Huetos A, Blanco J, Vidal F. et al. Spermatozoa from normozoospermic fertile and infertile individuals convey a distinct miRNA cargo. Andrology 2016; 4 (06) 1028-1036
  • 151 Xu H, Wang X, Wang Z. et al. MicroRNA expression profile analysis in sperm reveals hsa-mir-191 as an auspicious omen of in vitro fertilization. BMC Genomics 2020; 21 (01) 165
  • 152 Hua M, Liu W, Chen Y. et al. Identification of small non-coding RNAs as sperm quality biomarkers for in vitro fertilization. Cell Discov 2019; 5 (01) 20
  • 153 Cui L, Fang L, Shi B, Qiu S, Ye Y. Spermatozoa expression of piR-31704, piR-39888, and piR-40349 and their correlation to sperm concentration and fertilization rate after ICSI. Reprod Sci 2018; 25 (05) 733-739
  • 154 Samanta L, Parida R, Dias TR, Agarwal A. The enigmatic seminal plasma: a proteomics insight from ejaculation to fertilization. Reprod Biol Endocrinol 2018; 16 (01) 41
  • 155 Vojtech L, Woo S, Hughes S. et al. Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic Acids Res 2014; 42 (11) 7290-7304
  • 156 Chen H, Xie Y, Li Y. et al. Outcome prediction of microdissection testicular sperm extraction based on extracellular vesicles piRNAs. J Assist Reprod Genet 2021; 38 (06) 1429-1439
  • 157 Han X, Hao L, Shi Z. et al. Seminal plasma extracellular vesicles tRF-Val-AAC-010 can serve as a predictive factor of successful microdissection testicular sperm extraction in patients with non-obstructive azoospermia. Reprod Biol Endocrinol 2022; 20 (01) 106
  • 158 Barceló M, Mata A, Bassas L, Larriba S. Exosomal microRNAs in seminal plasma are markers of the origin of azoospermia and can predict the presence of sperm in testicular tissue. Hum Reprod 2018; 33 (06) 1087-1098
  • 159 Larriba S, Sánchez-Herrero JF, Pluvinet R, López-Rodrigo O, Bassas L, Sumoy L. Seminal extracellular vesicle sncRNA sequencing reveals altered miRNA/isomiR profiles as sperm retrieval biomarkers for azoospermia. Andrology 2023; DOI: 10.1111/ANDR.13461.