Abstract
Liquid biopsy has the advantage of diagnosing diseases in a non-invasive manner. Seminal
plasma contains secretions from the bilateral testes, epididymides, seminal vesicles,
bulbourethral glands, and the prostate. These organs are relatively small and contain
delicate tubes that are prone to damage by invasive diagnosis. Cell-free seminal nucleic
acids test is a newly emerged item in liquid biopsy. Here, we present a comprehensive
overview of all known cell-free DNA and cell-free RNAs (mRNA, miRNA, lncRNA, circRNA,
piRNA, YRNA, tsRNA, etc.) and discuss their roles as biomarker candidates in liquid
biopsy. With great advantages, including high stability, sensitivity, representability,
and non-invasiveness, cell-free DNA/RNAs may be developed as promising biomarkers
for the screening, diagnosis, prognosis, and follow-up of diseases in semen-secreting
organs. Moreover, RNAs in semen may participate in important processes, including
sperm maturation, early embryo development, and transgenerational disease inheritance,
which may be developed as potential treatment targets for future clinical use.
Key words
Abbreviation:
cf-NA (cell-free DNAs/RNAs), cfs-NA (cell-free seminal DNAs/RNAs), NOA (non-obstructive azoospermia), SCOS (sertoli-cell syndrome), MA (maturation arrest), HO (hypospermatogenesis), SMV (seminal microvesicles), SE (seminal exosome), MF (microfilter), UF (ultrafilter)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
Maddirevula S, Awartani K, Coskun S, et al. A genomics approach to females with infertility and recurrent pregnancy loss. 2020;139:605-13.
- Genetics of male infertility.Nature reviews Urology. 2018; 15: 369-384
- Genetics of human male infertility.Singapore medical journal. 2009; 50: 336-347
- Liquid Biopsy: General Concepts.Acta cytologica. 2019; 63: 449-455
- Identification and characterization of human testis derived circular RNAs and their existence in seminal plasma.Cancers. 2016; 6: 39080
- Liquid biopsy with cell free DNA: new horizons for prostate cancer.Critical reviews in clinical laboratory sciences. 2021; 58: 60-76
Ruiz-Plazas X, Altuna-Coy A, Alves-Santiago M, et al. Liquid Biopsy-Based Exo-oncomiRNAs Can Predict Prostate Cancer Aggressiveness. 2021;13.
- Quick recovery and characterization of cell-free DNA in seminal plasma of normozoospermia and azoospermia: implications for non-invasive genetic utilities.Asian journal of andrology. 2009; 11: 703-709
- Quantification by magnetic resonance spectroscopy of metabolites in seminal plasma able to differentiate different forms of azoospermia.Human reproduction (Oxford, England). 1998; 13: 132-135
- Advancement in biochemical assays in andrology.Asian journal of andrology. 1999; 1: 45-51
- Spermatogenesis in humans and its affecting factors.Seminars in cell & developmental biology. 2016; 59: 10-26
- About the possible origin and mechanism of circulating DNA apoptosis and active DNA release.Clinica chimica acta; international journal of clinical chemistry. 2001; 313: 139-142
- Potential confounding factors in measurement of specific cell-free seminal mRNAs and microRNAs derived from human reproductive organs.Andrology. 2016; 4: 1010-1019
- A novel application of cell-free seminal mRNA: non-invasive identification of the presence of germ cells or complete obstruction in men with azoospermia.Human reproduction (Oxford, England). 2012; 27: 991-997
- The contribution of epididymosomes to the sperm small RNA profile.Reproduction (Cambridge, England). 2019; 157: R209-Rr23
- Extracellular microRNAs from the epididymis as potential mediators of cell-to-cell communication.Asian journal of andrology. 2015; 17: 730-736
- Characterisation of mouse epididymosomes reveals a complex profile of microRNAs and a potential mechanism for modification of the sperm epigenome.Scientific reports. 2016; 6: 31794
- Mechanisms of tethering and cargo transfer during epididymosome-sperm interactions.BMC biology. 2019; 17: 35
- Modified isocratic capillary electrophoresis detection of cell-free DNA in semen.Journal of assisted reproduction and genetics. 2004; 21: 397-400
- Prostasomes are heterogeneous regarding size and appearance but affiliated to one DNA-containing exosome family.The Prostate. 2012; 72: 1736-1745
- DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells.Cancer research. 2001; 61: 1659-1665
- Detecting testis- and epididymis-specific methylated promoters in human cell-free seminal DNA by MeDIP-qPCR.Zhonghua nan ke xue. 2013; 19: 977-983
- Single exposure to heat induces stage-specific germ cell apoptosis in rats: role of intratesticular testosterone on stage specificity.Endocrinology. 1999; 140: 1709-1717
- Abdominal temperature induces region-specific p53-independent apoptosis in the cauda epididymidis of the mouse.Biology of reproduction. 2002; 67: 1189-1196
- Is the role of circulating DNA as a biomarker of cancer being prematurely overrated?.Clinical biochemistry. 2010; 43: 26-36
- Method for extraction of high-quantity and -quality cell-free DNA from amniotic fluid.Methods in molecular biology (Clifton, NJ). 2008; 444: 303-309
- Isolation and comparative study of cell-free nucleic acids from human urine.Annals of the New York Academy of Sciences. 2006; 1075: 334-340
- Detection of cell-free DNA in bronchial lavage fluid supernatants of patients with lung cancer.Annals of the New York Academy of Sciences. 2004; 1022: 202-210
- 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.Clinical chemistry. 2009; 55: 1967-1976
- Identification of pregnancy-associated microRNAs in maternal plasma.Clinical chemistry. 2010; 56: 1767-1771
- Spermatogenesis, DNA damage and DNA repair mechanisms in male infertility.Reproductive biomedicine online. 2015; 31: 309-319
- Apoptosis during spermatogenesis and in ejaculated spermatozoa: importance for fertilization.Annales de biologie clinique. 2001; 59: 531-545
- The microRNA spectrum in 12 body fluids.Clinical chemistry. 2010; 56: 1733-1741
- u68-EDTA is a better anticoagulant than heparin or citrate for delayed blood processing for plasma DNA analysis.Clinical chemistry. 2004; 50: 256-257
- A new blood collection device minimizes cellular DNA release during sample storage and shipping when compared to a standard device.Journal of clinical laboratory analysis. 2013; 27: 305-311
- Cell-free DNA (cfDNA): Clinical Significance and Utility in Cancer Shaped By Emerging Technologies.Molecular cancer research: MCR. 2016; 14: 898-908
- Deoxyribonuclease activity in semen.Journal of reproduction and fertility. 1968; 17: 35-39
- Purification and properties of bull seminal plasma Ca2+,Mg2+-dependent endonuclease.The Journal of biological chemistry. 1982; 257: 13114-13119
- Altered profile of seminal plasma microRNAs in the molecular diagnosis of male infertility.Clinical chemistry. 2011; 57: 1722-1731
Zhao K, Chen Y, Yang R, et al. miR-424/322 is downregulated in the semen of patients with severe DNA damage and may regulate sperm DNA damage. Reproduction, fertility, and development. 2015.
- Identification and characterization of human testis derived circular RNAs and their existence in seminal plasma.Scientific reports. 2016; 6: 39080
- Cell-free seminal mRNA and microRNA exist in different forms.PloS one. 2012; 7: e34566
- Prostasomes–their effects on human male reproduction and fertility.Human reproduction update. 2006; 12: 283-292
- The role of apocrine released proteins in the post-testicular regulation of human sperm function.Advances in experimental medicine and biology. 1997; 424: 193-219
- New insights into epididymal biology and function.Human reproduction update. 2009; 15: 213-227
- The content of DNA and RNA in microparticles released by Jurkat and HL-60 cells undergoing in vitro apoptosis.Experimental cell research. 2009; 315: 760-768
- Cell-free fetal DNA in maternal blood: kinetics, source and structure.Human reproduction update. 2005; 11: 59-67
- Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions.Nucleic acids research. 2014; 42: 7290-7304
Szilágyi M, Pös O. Circulating Cell-Free Nucleic Acids: Main Characteristics and Clinical Application. 2020;21.
- A panel of extracellular vesicle long noncoding RNAs in seminal plasma for predicting testicular spermatozoa in nonobstructive azoospermia patients.Human reproduction (Oxford, England). 2020; 35: 2413-2427
- Seminal plasma microRNAs: potential biomarkers for spermatogenesis status.Molecular human reproduction. 2012; 18: 489-497
- Consensus miRNA expression profiles derived from interplatform normalization of microarray data.RNA (New York, NY). 2010; 16: 16-25
- Evolution of an X-linked primate-specific micro RNA cluster.Molecular biology and evolution. 2010; 27: 671-683
- Recovery of cell-free mRNA and microRNA from human semen based on their physical nature.Biotechnology and applied biochemistry. 2014; 61: 342-348
Wu C. Developing noninvasive epigenetic biomarkers for human testis/epididymis from cell-free seminal nucleic acids Huazhong Universtity of Science and Technology; 2013.
- Current status of sperm functional genomics and its diagnostic potential of fertility in bovine (Bos taurus).Syst Biol Reprod Med. 2018; 64: 484-501
- Human sperm tsRNA as potential biomarker and therapy target for male fertility.Reproduction (Cambridge, England). 2021; 161: 111-122
- Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder.Science (New York, NY). 2016; 351: 397-400
- Cell-free RNA as a Fetal Timekeeper.Clin Chem. 2018; 64: 1800-1801
- Multi-stage screening cell-free seminal mRNAs to diagnose completion of meiosis and predict testicular sperm retrieval in men with non-obstructive azoospermia.Andrology. 2022; 10: 749-757
- ESX1 mRNA expression in seminal fluid is an indicator of residual spermatogenesis in non-obstructive azoospermic men.Human reproduction (Oxford, England). 2014; 29: 2620-2627
- The expression, function, and utilization of Protamine1: a literature review.Translational cancer research. 2021; 10: 4947-4957
- Genome-wide microRNA expression profiling in idiopathic non-obstructive azoospermia: significant up-regulation of miR-141, miR-429 and miR-7-1-3p.Human reproduction (Oxford, England). 2013; 28: 1827-1836
- The sperm chromatin structure assay as a diagnostic tool in the human fertility clinic.Human reproduction (Oxford, England). 2006; 21: 1576-1582
- Microarray analysis of microRNA expression patterns in the semen of infertile men with semen abnormalities.Molecular medicine reports. 2012; 6: 535-542
- Altered micro-ribonucleic acid expression profiles of extracellular microvesicles in the seminal plasma of patients with oligoasthenozoospermia.Fertility and sterility. 2016; 106 (e3): 1061-1069
- Altered non-coding RNA profiles of seminal plasma extracellular vesicles of men with poor semen quality undergoing In Vitro fertilization treatment.Andrology. 2022;
- Identification of microRNAs predominately derived from testis and epididymis in human seminal plasma.Clinical biochemistry. 2014; 47: 967-972
- Many X-linked microRNAs escape meiotic sex chromosome inactivation.Nature genetics. 2009; 41: 488-493
- Dysregulation of an X-linked primate-specific epididymal microRNA cluster in unexplained asthenozoospermia.Oncotarget. 2017; 8: 56839-56849
Plata-Peña L, López-Rodrigo O, Bassas L, Larriba S. Experimental validation of seminal miR-31-5p as biomarker for azoospermia and evaluation of the effect of preanalytical variables. 2022.
- microRNA signature is altered in both human epididymis and seminal microvesicles following vasectomy.Human reproduction (Oxford, England). 2013; 28: 1455-1467
- A mammalian microRNA expression atlas based on small RNA library sequencing.Cell. 2007; 129: 1401-1414
Ozata DM, Gainetdinov I. PIWI-interacting RNAs: small RNAs with big functions. 2019;20:89-108.
- Deep sequencing analysis of small non-coding RNAs reveals the diversity of microRNAs and piRNAs in the human epididymis.Gene. 2012; 497: 330-335
- Testicular piRNA profile comparison between successful and unsuccessful micro-TESE retrieval in NOA patients.Journal of assisted reproduction and genetics. 2018; 35: 801-808
- Systematic characterization of seminal plasma piRNAs as molecular biomarkers for male infertility.Scientific reports. 2016; 6: 24229
Li HM, Tan X, Zhang S, Yao J. Transfer- or 'transmission'-RNA fragments? The roles of tsRNAs in the reproductive system. 2021;27.
- Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals.Science (New York, NY). 2016; 351: 391-396
- Identification of small non-coding RNAs as sperm quality biomarkers for in vitro fertilization.Cell discovery. 2019; 5: 20
- Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress.Proceedings of the National Academy of Sciences of the United States of America. 2015; 112: 13699-13704
Zhang Y, Zhang X. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. 2018;20:535-40.
- 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.Reproductive biology and endocrinology: RB&E. 2022; 20: 106
- Heterogeneity of RNA protein antigens reactive with sera of patients with systemic lupus erythematosus. Description of a cytoplasmic nonribosomal antigen.Arthritis and rheumatism. 1974; 17: 421-429
- Rapid nucleolytic degradation of the small cytoplasmic Y RNAs during apoptosis.The Journal of biological chemistry. 1999; 274: 24799-24807
- An RNA degradation machine sculpted by Ro autoantigen and noncoding RNA.Cell. 2013; 153: 166-177
- Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins.Arthritis and rheumatism. 2005; 52: 1517-1521
- Low molecular weight serum cell-free DNA concentration is associated with clinicopathologic indices of poor prognosis in women with uterine cancer.Journal of translational medicine. 2020; 18: 323
- Cell-free nucleic acids as biomarkers in cancer patients.Nature reviews Cancer. 2011; 11: 426-437
- DNA methylation patterns and epigenetic memory.Genes & development. 2002; 16: 6-21
- Liquid biopsies: DNA methylation analyses in circulating cell-free DNA.Journal of genetics and genomics. 2018; 45: 185-192
- New gene family defined by MORC, a nuclear protein required for mouse spermatogenesis.Human molecular genetics. 1999; 8: 1201-1207
- ELF5 inhibits the proliferation and invasion of breast cancer cells by regulating CD24.Mol Biol Rep. 2021; 48: 5023-5032
- Acrosome markers of human sperm.Anat Sci Int. 2016; 91: 128-142
- Alterations of testis-specific promoter methylation in cell-free seminal deoxyribonucleic acid of idiopathic nonobstructive azoospermic men with different testicular phenotypes.Fertility and sterility. 2016; 106: 1331-1337
- Spermatozoal RNAs: what about their functions?.Microscopy research and technique. 2009; 72: 536-551
- Mighty Piwis defend the germline against genome intruders.Cell. 2007; 129: 37-44
- A small-RNA perspective on gametogenesis, fertilization, and early zygotic development.Science (New York, NY). 2010; 330: 617-622
- Sperm-borne microRNA-34c is required for the first cleavage division in mouse.Proceedings of the National Academy of Sciences of the United States of America. 2012; 109: 490-494
- Reproductive biology: delivering spermatozoan RNA to the oocyte.Nature. 2004; 429: 154
- Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation.The Journal of neuroscience: the official journal of the Society for Neuroscience. 2013; 33: 9003-9012
- Role of miRNA in the Transmission of Metabolic Diseases Associated With Paternal Diet-Induced Obesity.Frontiers in genetics. 2019; 10: 337
- Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring.Translational psychiatry. 2016; 6: e837
Wang Y, Chen ZP. Sperm microRNAs confer depression susceptibility to offspring. 2021;7.
- Proteomic changes in mammalian spermatozoa during epididymal maturation.Asian journal of andrology. 2007; 9: 554-564
- Expression Patterns of Circular RNAs in High Quality and Poor Quality Human Spermatozoa.Frontiers in endocrinology. 2019; 10: 435
- Clinical values and advances in round spermatid injection (ROSI).Reproductive biology. 2021; 21100530
- In Vitro fertilization and adverse obstetric and perinatal outcomes.Seminars in perinatology. 2017; 41: 345-353
Luo J, Tan X, Li H, Ding X. sncRNAs in Epididymosomes: The Contribution to Embryonic Development and Offspring Health. 2022;23.
Chen M, Heilbronn LK. The health outcomes of human offspring conceived by assisted reproductive technologies (ART). 2017;8:388-402.
Rodriguez-Martinez H, Martinez EA. Seminal Plasma: Relevant for Fertility? 2021;22.
- Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma.Proceedings of the National Academy of Sciences of the United States of America. 2011; 108: 5003-5008
- Sperm motility inhibitor from human seminal plasma: presence of a precursor molecule in seminal vesicle fluid and its molecular processing after ejaculation.International journal of andrology. 1994; 17: 232-240
- Genome-wide promoter methylation profile of human testis and epididymis: identified from cell-free seminal DNA.BMC genomics. 2013; 14: 288
- Cell-free and intracellular nucleic acids: new non-invasive biomarkers to explore male infertility.Basic and clinical andrology. 2017; 27: 7
- Panel of five microRNAs as potential biomarkers for the diagnosis and assessment of male infertility.Fertility and sterility. 2014; 102 (e1): 989-997
- Altered microRNA expression profiles of human spermatozoa in patients with different spermatogenic impairments.Fertility and sterility. 2013; 99 (e16): 1249-1255
- The epigenome of testicular germ cell tumors.APMIS: acta pathologica, microbiologica, et immunologica Scandinavica. 2007; 115: 1147-1160
- MicroRNA markers for forensic body fluid identification obtained from microarray screening and quantitative RT-PCR confirmation.International journal of legal medicine. 2010; 124: 217-226
- The exploratory study of the characterization and potential function of cell-free mRNA present in semen and epididymal fluid.Huazhong University of Science and Technology, 2010
- Screening cell-free seminal mRNAs for non-invasive diagnosis of meiosis arrest in non-obstructive azoospermia patients.Huazhong University of Science and Technology, 2020
- Role of microRNAs in controlling gene expression in different segments of the human epididymis.PloS one. 2012; 7: e34996
- Epigenetics, spermatogenesis and male infertility.Mutation research. 2011; 727: 62-71
- Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety.Translational psychiatry. 2017; 7: e1114
- Forensic miRNA: potential biomarker for body fluids?.Forensic science international Genetics. 2015; 14: 1-10
Article info
Publication history
Published online: December 28, 2022
Accepted:
December 21,
2022
Received in revised form:
December 10,
2022
Received:
October 18,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Funding: This work was supported by National Natural Fund Youth Project (82001621), National Key Research and Development Program of China (2022YFC2702700), Guangxi Science and Technology Base and Talents Special Project (2021AC19397), and Scientific Research Project of Wuhan Municipal Health Commission (WX21B05).
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
