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Manfrevola F, Mosca N, Mele VG, Chioccarelli T, Migliaccio A, Mattia M, Pezzullo M, Cobellis G, Potenza N, Chianese R. Epididymal-Born circRNA Cargo and Its Implications in Male Fertility. Int J Mol Sci 2025; 26:2614. [PMID: 40141256 PMCID: PMC11942175 DOI: 10.3390/ijms26062614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
The epididymis represents a pivotal organ for sperm maturation and male fertility maintenance. During the epididymal journey, sperm cells undergo morphological and molecular changes that need to acquire the morpho-functional skills necessary for successful oocyte fertilization. Not last, a great enrichment of the spermatozoa RNA payload occurs via an epithelium-derived epididymosome transfer. Currently, circular RNAs (circRNAs), a class of non-coding RNAs (ncRNAs), are acquiring a prominent role in the setting of sperm quality parameters. In this regard, they are considered potential targets in several male infertility conditions. Despite their consolidated role, few notions are known regarding the alleged epididymal backsplicing activity. In the current review, we discuss the main aspects of spermatozoa maturation along the epididymis and the circRNA role in the field of male reproduction. We also report the most recent findings on the circRNA biogenesis that occurs in the epididymal duct, providing new fascinating evidence on epididymal-derived circRNAs. Finally, we show preliminary compelling data on epididymal backsplicing by exploiting the experimental mouse model of aging. Collectively, these data evidence a remarkable role of the epididymis in remodeling the circRNA payload and in shaping its profile in maturating spermatozoa.
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Affiliation(s)
- Francesco Manfrevola
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (T.C.); (A.M.); (M.M.); (G.C.)
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Science and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (N.P.)
| | - Vincenza Grazia Mele
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (T.C.); (A.M.); (M.M.); (G.C.)
| | - Teresa Chioccarelli
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (T.C.); (A.M.); (M.M.); (G.C.)
| | - Antonella Migliaccio
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (T.C.); (A.M.); (M.M.); (G.C.)
| | - Monica Mattia
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (T.C.); (A.M.); (M.M.); (G.C.)
| | - Mariaceleste Pezzullo
- Department of Environmental, Biological and Pharmaceutical Science and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (N.P.)
| | - Gilda Cobellis
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (T.C.); (A.M.); (M.M.); (G.C.)
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Science and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (N.P.)
| | - Rosanna Chianese
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (T.C.); (A.M.); (M.M.); (G.C.)
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Mehta P, Singh R. The composition of human sperm sncRNAome: a cross-country small RNA profiling. Reprod Biol Endocrinol 2025; 23:36. [PMID: 40050854 PMCID: PMC11883963 DOI: 10.1186/s12958-025-01358-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 02/07/2025] [Indexed: 03/10/2025] Open
Abstract
BACKGROUND Over the last decade, numerous studies have implicated sperm-borne small non-coding RNAs (sncRNAs) in fertility and transgenerational inheritance. Spermatozoa contain a variety of small RNAs; however, inter-individual and inter-population variations in the human sperm sncRNA content (sncRNAome) have not yet been ascertained. METHODS We performed sncRNA sequencing in 54 normozoospermic proven fertile Indian donors. We also obtained a second semen sample from 13 donors and a third semen sample from eight donors and repeated sncRNA sequencing. To better understand sperm sncRNAome similarities and variations, sncRNA sequencing data for eligible Chinese (n = 87), US (n = 14), and Spanish (n = 2) normozoospermic (fertile or presumptive fertile) samples were downloaded and analyzed in a uniform manner. sncRNA data were compared within and across populations to identify similarities and differences. RESULTS In Indian samples, rsRNAs (13.71-78.76%), YsRNAs (0.64-76.53%) and tsRNAs (5.63-35.16%) constituted the major fraction and miRNAs, piRNAs, mt-tsRNAs, and other sncRNAs constituted the minor fraction. Across three other populations, rsRNAs (11-80%) and tsRNAs (10-60%) constituted the major fraction, and YsRNAs (0.62-4.28%), miRNAs (0.41-7.37%), piRNAs (1.37-4.36%), mt-tsRNAs (0.14-4.33%), and other sncRNAs constituted the minor fraction. Only 47 miRNAs were consistent across the Indian samples, and only 17 miRNAs were consistent across the four populations. Interestingly, all piRNAs detected in Indian samples were derived from the chromosome 15 piRNA cluster, which were also predominantly present in other populations. tRNA-Gly-GCC contributed approximately 50% of the tsRNA pool across all populations. The mt-tsRNAs also originated majorly from one mt-tRNA that differed across populations. Among the rsRNAs, the maximum number of reads belonged to 28S, followed by 18S, 5S, 5.8S, and 45S in decreasing order. Y4sRNAs were the most abundant YsRNAs, while the second most common contributor differed across populations. CONCLUSIONS The human sperm sncRNAome has a 'core component' that shows small variations and a 'peripheral component' that shows significant variations across individuals and populations. The availability of the normal human sperm sncRNAome would help delineate biologically meaningful variations from sample-to-sample natural/random variations.
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Affiliation(s)
- Poonam Mehta
- CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rajender Singh
- CSIR-Central Drug Research Institute, Lucknow, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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González B, González CR. Sperm-borne mRNAs: potential roles in zygote genome activation and epigenetic inheritance. Open Biol 2025; 15:240321. [PMID: 40132645 PMCID: PMC11936680 DOI: 10.1098/rsob.240321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/18/2024] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
It is well accepted that sperm carry an RNA cargo with functions in early embryo development. However, most research has focused on the role of small RNAs, such as microRNAs, transfer RNAs and long non-coding RNAs, while protein-coding messenger RNAs (mRNAs) received less attention, even though they represent a substantial amount of the sperm RNA pool. Here, we curated mouse transcriptomic data from mature sperm and selected the most abundant mRNAs (above the 0.7 quantile). The obtained gene list was further filtered using two criteria: (i) mRNAs that are statistically higher in the one-cell embryo compared to the MII oocyte transcriptome, indicative of paternal mRNA contribution after fertilization; and (ii) mRNAs that are found bound to ribosomes in the one-cell embryo, indicative of positive translation in the zygote translatome. Our analysis identified 94 genes that form networks functionally involved in epigenetic chromatin organization, gene expression, RNA processing and translation during zygote genome activation. These findings underscore the significant role of sperm-borne mRNAs in early embryonic development and epigenetic inheritance, highlighting the need for further research to fully understand their functions.
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Affiliation(s)
- Betina González
- Instituto de Investigaciones Farmacológicas, Buenos Aires, Argentina
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Li W, Yu Z, Xu S, Li Z, Xia W. Extracellular Vesicles in the Aging Male Reproductive System: Progresses and Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1469:375-394. [PMID: 40301265 DOI: 10.1007/978-3-031-82990-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/01/2025]
Abstract
Extracellular vesicles (EVs) serve as crucial mediators of intercellular communication in spermatogenesis, steroidogenesis, and age-related pathophysiological processes within the male reproductive system. These EVs exhibit promising prospects for disease diagnosis and therapeutic administration. This review explores the impact of advanced paternal age on male fertility and testosterone decline, shedding light on the underlying mechanisms. It highlights the decline in semen quality, DNA damage, and alterations in sperm miRNA profiles associated with aging. The interplay between oxidative stress and antioxidants crucially regulates male reproductive aging. Currently, most studies focus on Sertoli cell-derived EVs, while understanding of Leydig cell-derived vesicles remains limited. Multi-omics integration will enhance the understanding of male reproductive aging and guide personalized interventions, revealing potential biomarkers and targets in the future.
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Affiliation(s)
- Wenbo Li
- School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Depart. of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Lab of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Depart. of ART, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziwen Yu
- School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Shuai Xu
- Depart. of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Lab of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Depart. of ART, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng Li
- Depart. of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Key Lab of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Depart. of ART, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Bengbu Hospital of Shanghai General Hospital (The Second Affiliated Hospital of Bengbu Medical University), Bengbu, Anhui, China.
| | - Weiliang Xia
- School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
- State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Al-Kass Z, Eriksson S, Peippo J, Ntallaris T, Morrell JM. Comparison of two methods of extracting bull epididymal spermatozoa. Vet Anim Sci 2024; 26:100407. [PMID: 39582943 PMCID: PMC11585817 DOI: 10.1016/j.vas.2024.100407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024] Open
Abstract
Extraction of epididymal spermatozoa may be necessary to avoid losing valuable genetic material, for example, from individuals of rare breeds or endangered species, but the resulting sperm samples may be of poor quality. Two methods of extracting bull epididymal spermatozoa from slaughterhouse material were compared. The bulls were 16-23 months of age. Spermatozoa were extracted by making an incision one cm in length in the tail of the epididymis to allow the spermatozoa to flow out (method A), or by flushing the tail of epididymis (method B). The two methods were used for each bull, alternating between right and left epididymis, i.e. if method A was used for the left epididymis in Bull 1, it was used for the right epididymis in bull 2, etc. Sperm concentration in the extracted samples was adjusted to 69 × 106/mL in Andromed; the sperm sample was packed in 0.25 mL straws. After cooling for two h at 5 °C, the straws were placed 4 cm above liquid nitrogen for 20 min before transferring them to liquid nitrogen. Sperm motility, viability, reactive oxygen species, membrane integrity and DNA fragmentation were analysed in the fresh samples and again after thawing. The results for all parameters in fresh semen were not different between methods. Although sperm quality was lower in thawed samples than in fresh samples, there was no difference in sperm quality between the two extraction methods in the thawed samples. In conclusion, both methods are useful for the extraction of bull epididymal spermatozoa.
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Affiliation(s)
- Ziyad Al-Kass
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Box 7054, SE-75007 Uppsala, Sweden
- Department of Surgery and Theriogenology, College of Veterinary Medicine, university of Mosul, Mosul, Iraq
| | - Sanna Eriksson
- Department of Surgery and Theriogenology, College of Veterinary Medicine, university of Mosul, Mosul, Iraq
| | - Jaana Peippo
- Nordic Genetic Resource Center (NordGen), c/o NMBU – Biovit Box 5003, 1432 Ås, Norway
| | - Theodoros Ntallaris
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Box 7054, SE-75007 Uppsala, Sweden
| | - Jane M. Morrell
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Box 7054, SE-75007 Uppsala, Sweden
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Xu Z, Zhang K, Yang Y, Chang H, Wen F, Li X. The role of reproductive tract extracellular vesicles on boar sperm function. Theriogenology 2024; 230:278-284. [PMID: 39357166 DOI: 10.1016/j.theriogenology.2024.09.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 10/04/2024]
Abstract
Extracellular vesicles (EVs) are abundant in reproductive tract fluids and serve as important mediators of paracrine communication, influencing the function of gametes. Sperm undergo development in the male reproductive tract and exert their function within the female reproductive tract, engaging in interactions with various types of EVs present throughout the reproductive system. Previous studies have demonstrated that both male and female reproductive tract EVs can impact sperm function by transferring regulatory cargoes to them. Nevertheless, inconsistencies of previous research regarding the effects of EVs on sperm function, coupled with a lack of investigation into the influence of female reproductive tract EVs on sperm fertilization, have left the true role and underlying mechanisms of reproductive tract EVs on sperm function largely unexplored. Given that pigs represent significant economic livestock and serve as an ideal biomedical model for human diseases, this review aims to provide a comprehensive summary of the current knowledge regarding reproductive tract EVs and their influence on boar sperm function, while highlighting their potential roles. We anticipate that this review will facilitate future research on reproductive tract EVs and their impact on sperm function, contributing to improved animal reproductive efficiency and advancements in the treatment of male infertility.
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Affiliation(s)
- Zhiqian Xu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, Henan, China
| | - Ke Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, Henan, China
| | - Youbing Yang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, Henan, China
| | - Huixian Chang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, Henan, China
| | - Fengyun Wen
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, Henan, China.
| | - Xiaoxia Li
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, Henan, China.
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Zhao Z, Yang T, Li F. Sperm RNA code in spermatogenesis and male infertility. Reprod Biomed Online 2024; 49:104375. [PMID: 39481211 DOI: 10.1016/j.rbmo.2024.104375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/22/2024] [Accepted: 07/05/2024] [Indexed: 11/02/2024]
Abstract
Spermatozoa are traditionally thought to be transcriptionally inert, but recent studies have revealed the presence of sperm RNA, some of which is derived from the residues of spermatocyte transcription and some from epididymosomes. Paternal sperm RNA can be affected by external factors and further modified at the post-transcriptional level, for example N6-methyladenosine (m6A), thus shaping spermatogenesis and reproductive outcome. This review briefly introduces the origin of sperm RNA and, on this basis, summarizes the current knowledge on RNA modifications and their functional role in spermatogenesis and male infertility. The bottlenecks and knowledge gaps in the current research on RNA modification in male reproduction have also been indicated. Further investigations are needed to elucidate the functional consequences of these modifications, providing new therapeutic and preventive strategies for reproductive health and genetic inheritance.
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Affiliation(s)
- Zhongyi Zhao
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Tingting Yang
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
| | - Fuping Li
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
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Trigg N, Schjenken JE, Martin JH, Skerrett-Byrne DA, Smyth SP, Bernstein IR, Anderson AL, Stanger SJ, Simpson ENA, Tomar A, Teperino R, Conine CC, De Iuliis GN, Roman SD, Bromfield EG, Dun MD, Eamens AL, Nixon B. Subchronic elevation in ambient temperature drives alterations to the sperm epigenome and accelerates early embryonic development in mice. Proc Natl Acad Sci U S A 2024; 121:e2409790121. [PMID: 39527742 PMCID: PMC11588121 DOI: 10.1073/pnas.2409790121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
Forecasted increases in the prevalence and severity of extreme weather events accompanying changes in climatic behavior pose potential risk to the reproductive capacity of humans and animals of ecological and agricultural significance. While several studies have revealed that heat stress induced by challenges such as testicular insulation can elicit a marked negative effect on the male reproductive system, and particularly the production of spermatozoa, less is known about the immediate impact on male reproductive function following subchronic whole-body exposure to elevated ambient temperature. To address this knowledge gap, we exposed unrestrained male mice to heat stress conditions that emulate a heat wave (daily cycle of 8 h at 35 °C followed by 16 h at 25 °C) for a period of 7 d. Neither the testes or epididymides of heat-exposed male mice exhibited evidence of gross histological change, and similarly, spermatozoa of exposed males retained their functionality and ability to support embryonic development. However, the embryos generated from heat-exposed spermatozoa experienced pronounced changes in gene expression linked to acceleration of early embryo development, aberrant blastocyst hatching, and increased fetal:placental weight ratio. Such changes were causally associated with an altered sperm small noncoding RNA (sncRNA) profile, such that these developmental phenotypes were recapitulated by microinjection of wild-type embryos sired by control spermatozoa with RNAs extracted from heat-exposed spermatozoa. Such data highlight that even relatively modest excursions in ambient temperature can affect male reproductive function and identify the sperm sncRNA profile as a particular point of vulnerability to this imposed environmental stress.
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Affiliation(s)
- Natalie Trigg
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
- Department of Genetics Epigenetics Institute, Institute of Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA19104
- Department of Pediatrics Epigenetics Institute, Institute of Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA19104
- Center for Reproductive and Women’s Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA19104
- Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - John E. Schjenken
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - Jacinta H. Martin
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - David A. Skerrett-Byrne
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg85764, Germany
- German Center for Diabetes Research, Deutsche Zentrum für Diabetesforschung, Neuherberg85764, Germany
| | - Shannon P. Smyth
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
- School of BioSciences Bio21 Molecular Sciences and Biotechnology Institute, Faculty of Science, University of Melbourne, Parkville, VIC3010, Australia
| | - Ilana R. Bernstein
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - Amanda L. Anderson
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - Simone J. Stanger
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - Ewan N. A. Simpson
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - Archana Tomar
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg85764, Germany
- German Center for Diabetes Research, Deutsche Zentrum für Diabetesforschung, Neuherberg85764, Germany
| | - Raffaele Teperino
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg85764, Germany
- German Center for Diabetes Research, Deutsche Zentrum für Diabetesforschung, Neuherberg85764, Germany
| | - Colin C. Conine
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Department of Pediatrics Epigenetics Institute, Institute of Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA19104
- Center for Reproductive and Women’s Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA19104
- Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Geoffry N. De Iuliis
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - Shaun D. Roman
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
- NSW Health Pathology, Newcastle, NSW2300, Australia
| | - Elizabeth G. Bromfield
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
- School of BioSciences Bio21 Molecular Sciences and Biotechnology Institute, Faculty of Science, University of Melbourne, Parkville, VIC3010, Australia
| | - Matthew D. Dun
- Cancer Signaling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
| | - Andrew L. Eamens
- School of Health, University of the Sunshine Coast, Maroochydore, QLD4558, Australia
| | - Brett Nixon
- School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW2308, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW2305, Australia
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9
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Trigg NA, Conine CC. Epididymal acquired sperm microRNAs modify post-fertilization embryonic gene expression. Cell Rep 2024; 43:114698. [PMID: 39226174 DOI: 10.1016/j.celrep.2024.114698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 06/18/2024] [Accepted: 08/14/2024] [Indexed: 09/05/2024] Open
Abstract
Sperm small RNAs have emerged as important non-genetic contributors to embryogenesis and offspring health. A subset of sperm small RNAs is thought to be acquired during epididymal transit. However, the identity of the specific small RNAs transferred remains unclear. Here, we employ Cre/Lox genetics to generate germline- and epididymal-specific Dgcr8 knockout (KO) mice to investigate the dynamics of sperm microRNAs (miRNAs) and their functions post-fertilization. Testicular sperm from germline Dgcr8 KO mice has reduced levels of 116 miRNAs. Enthrallingly, following epididymal transit, the abundance of 72% of these miRNAs is restored. Conversely, sperm from epididymal Dgcr8 KO mice displayed reduced levels of 27 miRNAs. This loss of epididymal miRNAs in sperm was accompanied by transcriptomic changes in embryos fertilized by this sperm, which was rescued by microinjection of epididymal miRNAs. These findings ultimately demonstrate the acquisition of miRNAs from the soma by sperm during epididymal transit and their subsequent regulation of embryonic gene expression.
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Affiliation(s)
- Natalie A Trigg
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Departments of Genetics and Pediatrics - Penn Epigenetics Institute, Institute of Regenerative Medicine, and Center for Women's Health and Reproductive Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Colin C Conine
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Departments of Genetics and Pediatrics - Penn Epigenetics Institute, Institute of Regenerative Medicine, and Center for Women's Health and Reproductive Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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10
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Chang WC, Li SH, Tsai PS. Seminal Vesicle-Derived Exosomes for the Regulation of Sperm Activity. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2024. [PMID: 39287631 DOI: 10.1007/102_2024_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The seminal vesicle contributes to a large extent of the semen volume and composition. Removal of seminal vesicle or lack of seminal vesicle proteins leads to decreased fertility. Seminal plasma proteome revealed that seminal fluid contained a wide diversity of proteins. Many of them are known to modulate sperm capacitation and serve as capacitation inhibitors or decapacitation factors. Despite identifying secretory vesicles from the male reproductive tract, such as epididymosomes or prostasomes, isolation, identification, and characterization of seminal vesicle-derived exosomes are still unknown. This chapter aims to review the current understanding of the function of seminal vesicles on sperm physiology and male reproduction and provide ultracentrifugation-based isolation protocols for the isolation of seminal vesicle exosomes. Moreover, via proteomic analysis and functional categorization, a total of 726 proteins IDs were identified in the purified seminal vesicle exosomes fraction. Preliminary data showed seminal vesicle-derived exosomes inhibited sperm capacitation; however, more studies will be needed to reveal other functional involvements of seminal vesicle-derived exosomes on the sperm physiology and, more importantly, how these exosomes interact with sperm membrane to achieve their biological effects.
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Affiliation(s)
- Wei-Chao Chang
- Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Sheng-Hsiang Li
- Department of Medical Research, MacKay Memorial Hospital, Tamsui, Taiwan.
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
| | - Pei-Shiue Tsai
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan.
- Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan.
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
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11
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Moon N, Morgan CP, Marx-Rattner R, Jeng A, Johnson RL, Chikezie I, Mannella C, Sammel MD, Epperson CN, Bale TL. Stress increases sperm respiration and motility in mice and men. Nat Commun 2024; 15:7900. [PMID: 39261485 PMCID: PMC11391062 DOI: 10.1038/s41467-024-52319-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 09/02/2024] [Indexed: 09/13/2024] Open
Abstract
Semen quality and fertility has declined over the last 50 years, corresponding to ever-increasing environmental stressors. However, the cellular mechanisms involved and their impact on sperm functions remain unknown. In a repeated sampling human cohort study, we identify a significant effect of prior perceived stress to increase sperm motility 2-3 months following stress, timing that expands upon our previous studies revealing significant stress-associated changes in sperm RNA important for fertility. We mechanistically examine this post-stress timing in mice using an in vitro stress model in the epididymal epithelial cells responsible for sperm maturation and find 7282 differentially H3K27me3 bound DNA regions involving genes critical for mitochondrial and metabolic pathways. Further, prior stress exposure significantly changes the composition and size of epithelial cell-secreted extracellular vesicles that when incubated with mouse sperm, increase mitochondrial respiration and sperm motility, adding to our prior work showing impacts on embryo development. Together, these studies identify a time-dependent, translational signaling pathway that communicates stress experience to sperm, ultimately affecting reproductive functions.
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Affiliation(s)
- Nickole Moon
- Department of Psychiatry, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, 80045, USA
- Department of Pharmacology, University of Maryland Baltimore, Baltimore, MD, 21201, USA
| | - Christopher P Morgan
- Department of Pharmacology, University of Maryland Baltimore, Baltimore, MD, 21201, USA
| | - Ruth Marx-Rattner
- Department of Pharmacology, University of Maryland Baltimore, Baltimore, MD, 21201, USA
| | - Alyssa Jeng
- Department of Psychiatry, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, 80045, USA
| | - Rachel L Johnson
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Ijeoma Chikezie
- Department of Pharmacology, University of Maryland Baltimore, Baltimore, MD, 21201, USA
| | - Carmen Mannella
- Department of Physiology, University of Maryland Baltimore, Baltimore, MD, 21201, USA
| | - Mary D Sammel
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - C Neill Epperson
- Department of Psychiatry, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, 80045, USA
| | - Tracy L Bale
- Department of Psychiatry, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, 80045, USA.
- Department of Pharmacology, University of Maryland Baltimore, Baltimore, MD, 21201, USA.
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12
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Champroux A, Sadat-Shirazi M, Chen X, Hacker J, Yang Y, Feig LA. Astrocyte-Derived Exosomes Regulate Sperm miR-34c Levels to Mediate the Transgenerational Effects of Paternal Chronic Social Instability Stress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.04.21.537854. [PMID: 37786715 PMCID: PMC10541588 DOI: 10.1101/2023.04.21.537854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induce stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here we describe evidence that a strocyte-derived exos omes ( A-Exos ) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.
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13
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Ma Z, Tang N, Zhang R, Deng H, Chen K, Liu Y, Ding Z. Ribonuclease Inhibitor 1 (RNH1) Regulates Sperm tsRNA Generation for Paternal Inheritance through Interacting with Angiogenin in the Caput Epididymis. Antioxidants (Basel) 2024; 13:1020. [PMID: 39199264 PMCID: PMC11351606 DOI: 10.3390/antiox13081020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
Environmental stressors can induce paternal epigenetic modifications that are a key determinant of the intergenerational inheritance of acquired phenotypes in mammals. Some of them can affect phenotypic expression through inducing changes in tRNA-derived small RNAs (tsRNAs), which modify paternal epigenetic regulation in sperm. However, it is unclear how these stressors can affect changes in the expression levels of tsRNAs and their related endonucleases in the male reproductive organs. We found that Ribonuclease inhibitor 1 (RNH1), an oxidation responder, interacts with ANG to regulate sperm tsRNA generation in the mouse caput epididymis. On the other hand, inflammation and oxidative stress induced by either lipopolysaccharide (LPS) or palmitate (PA) treatments weakened the RNH1-ANG interaction in the epididymal epithelial cells (EEC). Accordingly, ANG translocation increased from the nucleus to the cytoplasm, which led to ANG upregulation and increases in cytoplasmic tsRNA expression levels. In conclusion, as an antioxidant, RNH1 regulates tsRNA generation through targeting ANG in the mouse caput epididymis. Moreover, the tsRNA is an epigenetic factor in sperm that modulates paternal inheritance in offspring via the fertilization process.
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Affiliation(s)
- Zhuoyao Ma
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Z.M.); (N.T.)
- Department of Teaching Laboratory Center for Basic Medicine, Chengdu Medical College, Chengdu 610500, China
| | - Ningyuan Tang
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Z.M.); (N.T.)
| | - Ruiyan Zhang
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (R.Z.); (H.D.); (K.C.)
| | - Hanyu Deng
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (R.Z.); (H.D.); (K.C.)
| | - Kexin Chen
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (R.Z.); (H.D.); (K.C.)
| | - Yue Liu
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Z.M.); (N.T.)
| | - Zhide Ding
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Z.M.); (N.T.)
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14
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Kilama J, Dahlen CR, Reynolds LP, Amat S. Contribution of the seminal microbiome to paternal programming. Biol Reprod 2024; 111:242-268. [PMID: 38696371 PMCID: PMC11327320 DOI: 10.1093/biolre/ioae068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 04/18/2024] [Accepted: 04/22/2024] [Indexed: 05/04/2024] Open
Abstract
The field of Developmental Origins of Health and Disease has primarily focused on maternal programming of offspring health. However, emerging evidence suggests that paternal factors, including the seminal microbiome, could potentially play important roles in shaping the developmental trajectory and long-term offspring health outcomes. Historically, the microbes present in the semen were regarded as inherently pathogenic agents. However, this dogma has recently been challenged by the discovery of a diverse commensal microbial community within the semen of healthy males. In addition, recent studies suggest that the transmission of semen-associated microbes into the female reproductive tract during mating has potentials to not only influence female fertility and embryo development but could also contribute to paternal programming in the offspring. In this review, we summarize the current knowledge on the seminal microbiota in both humans and animals followed by discussing their potential involvement in paternal programming of offspring health. We also propose and discuss potential mechanisms through which paternal influences are transmitted to offspring via the seminal microbiome. Overall, this review provides insights into the seminal microbiome-based paternal programing, which will expand our understanding of the potential paternal programming mechanisms which are currently focused primarily on the epigenetic modifications, oxidative stresses, and cytokines.
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Affiliation(s)
- Justine Kilama
- Department of Microbiological Sciences, North Dakota State University, NDSU Department 7520, Fargo, ND 58108-6050, USA
| | - Carl R Dahlen
- Department of Animal Sciences, and Center for Nutrition and Pregnancy, North Dakota State University, NDSU Department 7630, Fargo, ND 58108-6050, USA
| | - Lawrence P Reynolds
- Department of Animal Sciences, and Center for Nutrition and Pregnancy, North Dakota State University, NDSU Department 7630, Fargo, ND 58108-6050, USA
| | - Samat Amat
- Department of Microbiological Sciences, North Dakota State University, NDSU Department 7520, Fargo, ND 58108-6050, USA
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15
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Carrageta DF, Pereira SC, Ferreira R, Monteiro MP, Oliveira PF, Alves MG. Signatures of metabolic diseases on spermatogenesis and testicular metabolism. Nat Rev Urol 2024; 21:477-494. [PMID: 38528255 DOI: 10.1038/s41585-024-00866-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2024] [Indexed: 03/27/2024]
Abstract
Diets leading to caloric overload are linked to metabolic disorders and reproductive function impairment. Metabolic and hormonal abnormalities stand out as defining features of metabolic disorders, and substantially affect the functionality of the testis. Metabolic disorders induce testicular metabolic dysfunction, chronic inflammation and oxidative stress. The disruption of gastrointestinal, pancreatic, adipose tissue and testicular hormonal regulation induced by metabolic disorders can also contribute to a state of compromised fertility. In this Review, we will delve into the effects of high-fat diets and metabolic disorders on testicular metabolism and spermatogenesis, which are crucial elements for male reproductive function. Moreover, metabolic disorders have been shown to influence the epigenome of male gametes and might have a potential role in transmitting phenotype traits across generations. However, the existing evidence strongly underscores the unmet need to understand the mechanisms responsible for transgenerational paternal inheritance of male reproductive function impairment related to metabolic disorders. This knowledge could be useful for developing targeted interventions to prevent, counteract, and most of all break the perpetuation chain of male reproductive dysfunction associated with metabolic disorders across generations.
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Affiliation(s)
- David F Carrageta
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, Porto, Portugal
| | - Sara C Pereira
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
- LAQV-REQUIMTE & Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Rita Ferreira
- LAQV-REQUIMTE & Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Mariana P Monteiro
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
- Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, Porto, Portugal
| | - Pedro F Oliveira
- LAQV-REQUIMTE & Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Marco G Alves
- Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Campus de Santiago Agra do Crasto, Aveiro, Portugal.
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16
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Phillips D, Noble D. Bubbling beyond the barrier: exosomal RNA as a vehicle for soma-germline communication. J Physiol 2024; 602:2547-2563. [PMID: 37936475 DOI: 10.1113/jp284420] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 10/27/2023] [Indexed: 11/09/2023] Open
Abstract
'Weismann's barrier' has restricted theories of heredity to the transmission of genomic variation for the better part of a century. However, the discovery and elucidation of epigenetic mechanisms of gene regulation such as DNA methylation and histone modifications has renewed interest in studies on the inheritance of acquired traits and given them mechanistic plausibility. Although it is now clear that these mechanisms allow many environmentally acquired traits to be transmitted to the offspring, how phenotypic information is communicated from the body to its gametes has remained a mystery. Here, we discuss recent evidence that such communication is mediated by somatic RNAs that travel inside extracellular vesicles to the gametes where they reprogram the offspring epigenome and phenotype. How gametes learn about bodily changes has implications not only for the clinic, but also for evolutionary theory by bringing together intra- and intergenerational mechanisms of phenotypic plasticity and adaptation.
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Affiliation(s)
- Daniel Phillips
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Denis Noble
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK
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17
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Tomar A, Gomez-Velazquez M, Gerlini R, Comas-Armangué G, Makharadze L, Kolbe T, Boersma A, Dahlhoff M, Burgstaller JP, Lassi M, Darr J, Toppari J, Virtanen H, Kühnapfel A, Scholz M, Landgraf K, Kiess W, Vogel M, Gailus-Durner V, Fuchs H, Marschall S, Hrabě de Angelis M, Kotaja N, Körner A, Teperino R. Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature 2024; 630:720-727. [PMID: 38839949 PMCID: PMC11186758 DOI: 10.1038/s41586-024-07472-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 04/26/2024] [Indexed: 06/07/2024]
Abstract
Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.
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MESH Headings
- Animals
- Female
- Humans
- Male
- Mice
- Body Mass Index
- Diet, High-Fat/adverse effects
- Embryo, Mammalian/cytology
- Embryo, Mammalian/embryology
- Embryo, Mammalian/metabolism
- Epididymis/cytology
- Epigenesis, Genetic/genetics
- Fertilization/genetics
- Gene Expression Profiling
- Gene Expression Regulation, Developmental
- Mice, Inbred C57BL
- Mitochondria/genetics
- Mitochondria/metabolism
- Mitochondria/pathology
- Obesity/genetics
- Obesity/metabolism
- Obesity/etiology
- Oocytes/metabolism
- Overweight/genetics
- Overweight/metabolism
- Paternal Inheritance/genetics
- RNA, Mitochondrial/genetics
- RNA, Mitochondrial/metabolism
- RNA, Small Untranslated/genetics
- RNA, Small Untranslated/metabolism
- RNA, Transfer/genetics
- RNA, Transfer/metabolism
- Spermatozoa/metabolism
- Testis/cytology
- Transcription, Genetic
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Affiliation(s)
- A Tomar
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - M Gomez-Velazquez
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - R Gerlini
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - G Comas-Armangué
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - L Makharadze
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - T Kolbe
- Unit of in vivo and in vitro Models, Center for Biological Sciences, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
- IFA-Tulln, University of Natural Resources and Life Sciences, Vienna, Austria
| | - A Boersma
- Unit of in vivo and in vitro Models, Center for Biological Sciences, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - M Dahlhoff
- Unit of in vivo and in vitro Models, Center for Biological Sciences, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - J P Burgstaller
- Institute of Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
- Group Molecular Reproduction, IFA-Tulln, Tulln, Austria
| | - M Lassi
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - J Darr
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - J Toppari
- Institute of Biomedicine, Integrative Physiology and Pharmacology Unit, University of Turku, Turku, Finland
- Center for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - H Virtanen
- Institute of Biomedicine, Integrative Physiology and Pharmacology Unit, University of Turku, Turku, Finland
- Center for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - A Kühnapfel
- University of Leipzig, Medical Faculty, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany
| | - M Scholz
- University of Leipzig, Medical Faculty, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany
| | - K Landgraf
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
| | - W Kiess
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
- LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
| | - M Vogel
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
- LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
| | - V Gailus-Durner
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - H Fuchs
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - S Marschall
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - M Hrabě de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, Germany
| | - N Kotaja
- Institute of Biomedicine, Integrative Physiology and Pharmacology Unit, University of Turku, Turku, Finland
| | - A Körner
- Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany
- LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
- Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - R Teperino
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
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18
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Hamada H, Casciaro C, Moisiadis VG, Constantinof A, Kostaki A, Matthews SG. Prenatal maternal glucocorticoid exposure modifies sperm miRNA profiles across multiple generations in the guinea-pig. J Physiol 2024; 602:2127-2139. [PMID: 38285002 DOI: 10.1113/jp284942] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/11/2024] [Indexed: 01/30/2024] Open
Abstract
Maternal stress and glucocorticoid exposure during pregnancy have multigenerational effects on neuroendocrine function and behaviours in offspring. Importantly, effects are transmitted through the paternal lineage. Altered phenotypes are associated with profound differences in transcription and DNA methylation in the brain. In the present study, we hypothesized that maternal prenatal synthetic glucocorticoid (sGC) exposure in the F0 pregnancy will result in differences in miRNA levels in testes germ cells and sperm across multiple generations, and that these changes will associate with modified microRNA (miRNA) profiles and gene expression in the prefrontal cortex (PFC) of subsequent generations. Pregnant guinea-pigs (F0) were treated with multiple courses of the sGC betamethasone (Beta) (1 mg kg-1; gestational days 40, 41, 50, 51, 60 and 61) in late gestation. miRNA levels were assessed in testes germ cells and in F2 PFC using the GeneChip miRNA 4.0 Array and candidate miRNA measured in epididymal sperm by quantitative real-time PCR. Maternal Beta exposure did not alter miRNA levels in germ cells derived from the testes of adult male offspring. However, there were significant differences in the levels of four candidate miRNAs in the sperm of F1 and F2 adult males. There were no changes in miRNA levels in the PFC of juvenile F2 female offspring. The present study has identified that maternal Beta exposure leads to altered miRNA levels in sperm that are apparent for at least two generations. The fact that differences were confined to epididymal sperm suggests that the intergenerational effects of Beta may target the epididymis. KEY POINTS: Paternal glucocorticoid exposure prior to conception leads to profound epigenetic changes in the brain and somatic tissues in offspring, and microRNAs (miRNAs) in sperm may mediate these changes. We show that there were significant differences in the miRNA profile of epididymal sperm in two generations following prenatal glucocorticoid exposure that were not observed in germ cells derived from the testes. The epididymis is a probable target for intergenerational programming. The effects of prenatal glucocorticoid treatment may span multiple generations.
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Affiliation(s)
- Hirotaka Hamada
- Departments of Physiology, Obstetrics and Gynaecology and Medicine, University of Toronto, Toronto, ON, Canada
- Department of Gynecology and Obstetrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Christopher Casciaro
- Departments of Physiology, Obstetrics and Gynaecology and Medicine, University of Toronto, Toronto, ON, Canada
| | - Vasilis G Moisiadis
- Departments of Physiology, Obstetrics and Gynaecology and Medicine, University of Toronto, Toronto, ON, Canada
| | - Andrea Constantinof
- Departments of Physiology, Obstetrics and Gynaecology and Medicine, University of Toronto, Toronto, ON, Canada
| | - Alisa Kostaki
- Departments of Physiology, Obstetrics and Gynaecology and Medicine, University of Toronto, Toronto, ON, Canada
| | - Stephen G Matthews
- Departments of Physiology, Obstetrics and Gynaecology and Medicine, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health Systems, Toronto, ON, Canada
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19
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Rice RC, Gil DV, Baratta AM, Frawley RR, Hill SY, Farris SP, Homanics GE. Inter- and transgenerational heritability of preconception chronic stress or alcohol exposure: Translational outcomes in brain and behavior. Neurobiol Stress 2024; 29:100603. [PMID: 38234394 PMCID: PMC10792982 DOI: 10.1016/j.ynstr.2023.100603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 01/19/2024] Open
Abstract
Chronic stress and alcohol (ethanol) use are highly interrelated and can change an individual's behavior through molecular adaptations that do not change the DNA sequence, but instead change gene expression. A recent wealth of research has found that these nongenomic changes can be transmitted across generations, which could partially account for the "missing heritability" observed in genome-wide association studies of alcohol use disorder and other stress-related neuropsychiatric disorders. In this review, we summarize the molecular and behavioral outcomes of nongenomic inheritance of chronic stress and ethanol exposure and the germline mechanisms that could give rise to this heritability. In doing so, we outline the need for further research to: (1) Investigate individual germline mechanisms of paternal, maternal, and biparental nongenomic chronic stress- and ethanol-related inheritance; (2) Synthesize and dissect cross-generational chronic stress and ethanol exposure; (3) Determine cross-generational molecular outcomes of preconception ethanol exposure that contribute to alcohol-related disease risk, using cancer as an example. A detailed understanding of the cross-generational nongenomic effects of stress and/or ethanol will yield novel insight into the impact of ancestral perturbations on disease risk across generations and uncover actionable targets to improve human health.
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Affiliation(s)
- Rachel C. Rice
- Center for Neuroscience at the University of Pittsburgh, Pittsburgh, PA, USA
| | - Daniela V. Gil
- Center for Neuroscience at the University of Pittsburgh, Pittsburgh, PA, USA
| | - Annalisa M. Baratta
- Center for Neuroscience at the University of Pittsburgh, Pittsburgh, PA, USA
| | - Remy R. Frawley
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Shirley Y. Hill
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sean P. Farris
- Center for Neuroscience at the University of Pittsburgh, Pittsburgh, PA, USA
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Gregg E. Homanics
- Center for Neuroscience at the University of Pittsburgh, Pittsburgh, PA, USA
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
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20
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Li H, Wang Z, Zhao B, Zhang H, Fan D, Ma H, Zhang Y, Wang Y. Sperm-borne lncRNA loc100847420 improves development of early bovine embryos. Anim Reprod Sci 2023; 257:107333. [PMID: 37729849 DOI: 10.1016/j.anireprosci.2023.107333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/01/2023] [Accepted: 09/14/2023] [Indexed: 09/22/2023]
Abstract
Long non-coding RNAs (lncRNAs) act as competing endogenous RNAs (ceRNAs) that play a significant role in bovine embryo development; but the influence of sperm-borne lncRNA on the preimplantation development of bovine embryos has not been reported in detail. In this study, we aimed to clarify how sperm-borne lncRNAs can act to regulate early development of bovine embryos. Utilizing high-throughput sequencing technology and quantitative real-time PCR (qPCR), we found that the lncRNA, loc100847420, was highly enriched in bovine sperm and was carried into the oocyte during fertilization. Introduction of wild-type loc100847420 had no effect on cleavage rate of parthenogenetic embryos compared with injection of mutant loc100847420 (70.58 ± 2.85% vs 70.46 ± 1.98%, p > 0.05), but significantly improved the blastocyst rate (33.67 ± 2.40% vs 28.35 ± 3.06%, p < 0.05), total numbers of cells (p < 0.05), numbers of inner cell mass (ICM) cells (p < 0.05) and numbers of trophoblast (TE) cells (p < 0.05). In summary, the sperm-borne lncRNA, loc100847420, can improve the developmental potential of early bovine embryos.
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Affiliation(s)
- Heqiang Li
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi 712100, PR China; College of Veterinary Medicine, Northwest A&F University, Ministry of Agriculture and Rural Affairs, Northwest A&∼F University, Yangling, Shaanxi, 712100, PR China
| | - Zheng Wang
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi 712100, PR China; College of Veterinary Medicine, Northwest A&F University, Ministry of Agriculture and Rural Affairs, Northwest A&∼F University, Yangling, Shaanxi, 712100, PR China
| | - Baobao Zhao
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi 712100, PR China; College of Veterinary Medicine, Northwest A&F University, Ministry of Agriculture and Rural Affairs, Northwest A&∼F University, Yangling, Shaanxi, 712100, PR China
| | - Han Zhang
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi 712100, PR China; College of Veterinary Medicine, Northwest A&F University, Ministry of Agriculture and Rural Affairs, Northwest A&∼F University, Yangling, Shaanxi, 712100, PR China
| | - Dexiang Fan
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi 712100, PR China; College of Veterinary Medicine, Northwest A&F University, Ministry of Agriculture and Rural Affairs, Northwest A&∼F University, Yangling, Shaanxi, 712100, PR China
| | - Huiming Ma
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, Ningxia Medical University, Yinchuan 750004, PR China
| | - Yong Zhang
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi 712100, PR China; College of Veterinary Medicine, Northwest A&F University, Ministry of Agriculture and Rural Affairs, Northwest A&∼F University, Yangling, Shaanxi, 712100, PR China.
| | - Yongsheng Wang
- Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi 712100, PR China; College of Veterinary Medicine, Northwest A&F University, Ministry of Agriculture and Rural Affairs, Northwest A&∼F University, Yangling, Shaanxi, 712100, PR China.
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21
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Alagundagi DB, Ghate SD, Shetty P, Gollapalli P, Shetty P, Patil P. Integrated molecular-network analysis reveals infertility-associated key genes and transcription factors in the non-obstructive azoospermia. Eur J Obstet Gynecol Reprod Biol 2023; 288:183-190. [PMID: 37549510 DOI: 10.1016/j.ejogrb.2023.07.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 06/05/2023] [Accepted: 07/31/2023] [Indexed: 08/09/2023]
Abstract
BACKGROUND Male infertility is a multifactorial reproductive health problem with complex causes. Non-obstructive azoospermia (NOA) is characterized by failure of spermatogenesis, leading to the absence of spermatozoa in ejaculates. The molecular mechanism underlying the NOA is still not well understood. OBJECTIVES This study aims to identify the key genes involved in male infertility that could be a potential biomarker in the diagnosis and prognosis of azoospermia. STUDY DESIGN The microarray expression profiles dataset GSE45885 and GSE45887 were downloaded from the NCBI's Gene Expression Omnibus (GEO) database and analyzed for male infertility-associated differentially expressed genes (DEGs) using the GEO2R tool. The common DEGs between the two datasets were combined and their protein-protein interaction (PPI) network was constructed using Cytoscape to reveal the hub genes by topology and module analysis. In addition, transcription factors (TFs) and protein kinases regulating the hub genes were identified using the X2K tool. Then, the expression of the hub genes was validated by analyzing the GSE190752 microarray dataset. Further, the PPI network was screened for biological roles and enriched pathways using DAVID software. RESULTS About 256 DEGs associated with NOA were identified and constructed the PPI network to find the infertility-associated proteins. The biological processes linked with these proteins were spermatogenesis, cell differentiation, flagellated sperm motility, and spermatid development. The topology and module analysis of the infertility-associated protein network identified the hub genes TEX38, FAM71F, PRR30, FAM166A, LYZL6, TPPP2, ARMC12, SPACA4, and FAM205A, which were found to be upregulated in the non-obstructive azoospermia. In addition, a total of 23 transcription factors and 3 protein kinases that are regulating these key hub genes were identified. Further these hub genes expression was validated using the microarray data and found that their expression was increased in the testicular biopsies obtained from NOA subjects, compared to healthy individuals. CONCLUSION The identified key genes and its associated transcription factors are known to regulate the infertility-related processes in the non-obstructive azoospermia. Also, the clinical sample-based microarray data validation for the expression of these key hub genes indicates their potentiality to develop them as diagnostic or prognostic biomarkers for NOA.
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Affiliation(s)
- Dhananjay B Alagundagi
- Central Research Laboratory, K S Hegde Medical Academy, NITTE (Deemed to be University), Mangaluru 575018, Karnataka, India.
| | - Sudeep D Ghate
- Center for Bioinformatics and Biostatistics, NITTE (Deemed to be University), Mangaluru 575018, Karnataka, India.
| | - Prasannakumar Shetty
- Department of Obstetrics and Gynecology, Justice K S Hegde Charitable Hospital, K S Hegde Medical Academy, NITTE (Deemed to be University), Mangaluru 575018, Karnataka, India.
| | - Pavan Gollapalli
- Center for Bioinformatics and Biostatistics, NITTE (Deemed to be University), Mangaluru 575018, Karnataka, India.
| | - Praveenkumar Shetty
- Central Research Laboratory, K S Hegde Medical Academy, NITTE (Deemed to be University), Mangaluru 575018, Karnataka, India; Department of Biochemistry, K S Hegde Medical Academy, NITTE (Deemed to be University), Mangaluru 575018, Karnataka, India.
| | - Prakash Patil
- Central Research Laboratory, K S Hegde Medical Academy, NITTE (Deemed to be University), Mangaluru 575018, Karnataka, India.
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22
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Ali W, Deng K, Bian Y, Liu Z, Zou H. Spectacular role of epididymis and bio-active cargo of nano-scale exosome in sperm maturation: A review. Biomed Pharmacother 2023; 164:114889. [PMID: 37209627 DOI: 10.1016/j.biopha.2023.114889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/30/2023] [Accepted: 05/12/2023] [Indexed: 05/22/2023] Open
Abstract
The epididymis is responsible for post-testicular sperm maturation as it provides a favorable environment for spermatozoa to gain the ability for movement and fertilization. The recent evidence has shown that, the spermatozoa are vulnerable to dynamic variations driven by various cellular exposure mechanisms mediated by epididymosomes. Exosomes provide new insight into a mechanism of intercellular communication because they provide direct evidence for the transfer of several important bio-active cargo elements (proteins, lipid, DNA, mRNA, microRNA, circular RNA, long noncoding RNA) between epididymis and spermatozoa. In broad sense, proteomic analysis of exosomes from epididymis indicates number of proteins that are involved in sperm motility, acrosomal reaction, prevent pre-mature sperm capacitation and male infertility. Pinpointing, how reproductive disorders are associated with bio-active cargo elements of nano-scale exosome in the male reproductive tract. Therefore, the current review presents evidence regarding the distinctive characteristics and functions of nano-scale exosome in the male reproductive tract in both pathological and physiological developments, and argue that these vesicles serve as an important regulator of male reproduction, fertility, and disease susceptibility.
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Affiliation(s)
- Waseem Ali
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Kai Deng
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Yusheng Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.
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23
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Liu S, Sharma U. Sperm RNA Payload: Implications for Intergenerational Epigenetic Inheritance. Int J Mol Sci 2023; 24:5889. [PMID: 36982962 PMCID: PMC10052761 DOI: 10.3390/ijms24065889] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 03/03/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
There is mounting evidence that ancestral life experiences and environment can influence phenotypes in descendants. The parental environment regulates offspring phenotypes potentially via modulating epigenetic marks in the gametes. Here, we review examples of across-generational inheritance of paternal environmental effects and the current understanding of the role of small RNAs in such inheritance. We discuss recent advances in revealing the small RNA payload of sperm and how environmental conditions modulate sperm small RNAs. Further, we discuss the potential mechanism of inheritance of paternal environmental effects by focusing on sperm small RNA-mediated regulation of early embryonic gene expression and its role in influencing offspring phenotypes.
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Affiliation(s)
| | - Upasna Sharma
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA
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24
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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:ijms24065447. [PMID: 36982521 PMCID: PMC10051672 DOI: 10.3390/ijms24065447] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/14/2023] Open
Abstract
Reproductive dysfunction and urogenital malignancies represent a serious health concern in men. This is in part as a result of the absence of reliable non-invasive tests of diagnosis/prognosis. Optimizing diagnosis and predicting the patient’s prognosis will affect the choice of the most appropriate treatment and therefore increase the chances of success and the result of therapy, that is, it will lead to a more personalized treatment of the patient. This review aims firstly to critically summarize the current knowledge of the reproductive roles played by extracellular vesicle small RNA components, which are typically altered in diseases affecting the male reproductive tract. Secondly, it aims to describe the use of semen extracellular vesicles as a non-invasive source of sncRNA-based biomarkers for urogenital diseases.
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25
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Ma Y, Ma QW, Sun Y, Chen XF. The emerging role of extracellular vesicles in the testis. Hum Reprod 2023; 38:334-351. [PMID: 36728671 DOI: 10.1093/humrep/dead015] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/07/2022] [Indexed: 02/03/2023] Open
Abstract
Extracellular vesicles (EVs) are nano-sized membrane-bounded particles, released by all cells and capable of transporting bioactive cargoes, proteins, lipids, and nucleic acids, to regulate a variety of biological functions. Seminal plasma is enriched in EVs, and extensive evidence has revealed the role of EVs (e.g. prostasomes and epididymosomes) in the male genital tract. Recently, EVs released from testicular cells have been isolated and identified, and some new insights have been generated on their role in maintaining normal spermatogenesis and steroidogenesis in the testis. In the seminiferous tubules, Sertoli cell-derived EVs can promote the differentiation of spermatogonial stem cells (SSCs), and EVs secreted from undifferentiated A spermatogonia can inhibit the proliferation of SSCs. In the testicular interstitium, EVs have been identified in endothelial cells, macrophages, telocytes, and Leydig cells, although their roles are still elusive. Testicular EVs can also pass through the blood-testis barrier and mediate inter-compartment communication between the seminiferous tubules and the interstitium. Immature Sertoli cell-derived EVs can promote survival and suppress the steroidogenesis of Leydig cells. Exosomes isolated from macrophages can protect spermatogonia from radiation-induced injury. In addition to their role in intercellular communication, testicular EVs may also participate in the removal of aberrant proteins and the delivery of antigens for immune tolerance. EVs released from testicular cells can be detected in seminal plasma, which makes them potential biomarkers reflecting testicular function and disease status. The testicular EVs in seminal plasma may also affect the female reproductive tract to facilitate conception and may even affect early embryogenesis through modulating sperm RNA. EVs represent a new type of intercellular messenger in the testis. A detailed understanding of the role of testicular EV may contribute to the discovery of new mechanisms causing male infertility and enable the development of new diagnostic and therapeutic strategies for the treatment of infertile men.
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Affiliation(s)
- Yi Ma
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Qin-Wen Ma
- Shanghai Xinzhu Middle School, Shanghai, China
| | - Yun Sun
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Xiang-Feng Chen
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.,Shanghai Human Sperm Bank, Shanghai, China
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26
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Transfer of Galectin-3-Binding Protein via Epididymal Extracellular Vesicles Promotes Sperm Fertilizing Ability and Developmental Potential in the Domestic Cat Model. Int J Mol Sci 2023; 24:ijms24043077. [PMID: 36834494 PMCID: PMC9966717 DOI: 10.3390/ijms24043077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/03/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Key proteins transferred by epididymal extracellular vesicles (EVs) to the transiting sperm cells contribute to their centrosomal maturation and developmental potential. Although not reported in sperm cells yet, galectin-3-binding protein (LGALS3BP) is known to regulate centrosomal functions in somatic cells. Using the domestic cat model, the objectives of this study were to (1) detect the presence and characterize the transfer of LGALS3BP via EVs between the epididymis and the maturing sperm cells and (2) demonstrate the impact of LGALS3BP transfer on sperm fertilizing ability and developmental potential. Testicular tissues, epididymides, EVs, and spermatozoa were isolated from adult individuals. For the first time, this protein was detected in EVs secreted by the epididymal epithelium. The percentage of spermatozoa with LGALS3BP in the centrosome region increased as cells progressively incorporated EVs during the epididymal transit. When LGALS3BP was inhibited during in vitro fertilization with mature sperm cells, less fertilized oocytes and slower first cell cycles were observed. When the protein was inhibited in epididymal EVs prior to incubation with sperm cells, poor fertilization success further demonstrated the role of EVs in the transfer of LGALS3BP to the spermatozoa. The key roles of this protein could lead to new approaches to enhance or control fertility in clinical settings.
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27
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Barbero G, de Sousa Serro MG, Perez Lujan C, Vitullo AD, González CR, González B. Transcriptome profiling of histone writers/erasers enzymes across spermatogenesis, mature sperm and pre-cleavage embryo: Implications in paternal epigenome transitions and inheritance mechanisms. Front Cell Dev Biol 2023; 11:1086573. [PMID: 36776561 PMCID: PMC9911891 DOI: 10.3389/fcell.2023.1086573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/04/2023] [Indexed: 01/28/2023] Open
Abstract
Accumulating evidence points out that sperm carry epigenetic instructions to embryo in the form of retained histones marks and RNA cargo that can transmit metabolic and behavioral traits to offspring. However, the mechanisms behind epigenetic inheritance of paternal environment are still poorly understood. Here, we curated male germ cells RNA-seq data and analyzed the expression profile of all known histone lysine writers and erasers enzymes across spermatogenesis, unraveling the developmental windows at which they are upregulated, and the specific activity related to canonical and non-canonical histone marks deposition and removal. We also characterized the epigenetic enzymes signature in the mature sperm RNA cargo, showing most of them positive translation at pre-cleavage zygote, suggesting that paternally-derived enzymes mRNA cooperate with maternal factors to embryo chromatin assembly. Our study shows several histone modifying enzymes not described yet in spermatogenesis and even more, important mechanistic aspects behind transgenerational epigenetics. Epigenetic enzymes not only can respond to environmental stressors, but could function as vectors of epigenetic information and participate in chromatin organization during maternal-to-zygote transition.
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Affiliation(s)
- Gastón Barbero
- Centro de Estudios Biomédicos Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Maximiliano G. de Sousa Serro
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires–Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Camila Perez Lujan
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires–Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Alfredo D. Vitullo
- Centro de Estudios Biomédicos Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Candela R. González
- Centro de Estudios Biomédicos Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Betina González
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires–Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina,*Correspondence: Betina González,
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28
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Morgan CP, Meadows VE, Marx-Rattner R, Cisse YM, Bale TL. HA-tag CD63 is a novel conditional transgenic approach to track extracellular vesicle interactions with sperm and their transfer at conception. Sci Rep 2023; 13:707. [PMID: 36639735 PMCID: PMC9839718 DOI: 10.1038/s41598-023-27898-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Extracellular vesicles (EVs) are a unique mode of intercellular communication capable of specificity in transmitting signals and cargo to coordinate local and distant cellular functions. A key example of this is the essential role that EVs secreted by epithelial cells lining the lumen of the male reproductive tract play in post-spermatogenic sperm maturation. We recently showed in a preclinical mouse model that this fundamental process had a causal role in somatic-to-germline transmission of biological information regarding prior stress experience capable of altering the rate of fetal development. However, critical mechanistic questions remain unanswered as to the processes by which signaling occurs between EVs and sperm, and whether EVs or their cargo are delivered at conception and are detectable in the early embryo. Unfortunately, notable methodological limitations shared across EV biology, particularly in the isolation and labeling of EVs, complicate efforts to answer these important questions as well as questions on EV targeting specificity and mechanisms. In our current studies, we developed a novel approach to track EVs using a conditional transgenic construct designed to label EVs via conditional Cre-induced hemagglutinin (HA) tagging of the EV endogenous tetraspanin, CD63. In our exhaustive validation steps, this internal small molecular weight tag did not affect EV secretion or functionality, a common problem found in the previous design of EV tags using larger molecular weight proteins, including fluorescent proteins. Utilizing a stably transfected immortalized epididymal epithelial cell line, we first validated key parameters of the conditional HA-tagged protein packaged into secreted EVs. Importantly, we systematically confirmed that expression of the CD63-HA had no impact on the production, size distribution, or surface charge of secreted EVs, nor did it alter the tetraspanin or miRNA composition of these EVs. We also utilized the CD63-HA EVs to verify physical interactions with sperm. Finally, using in vitro fertilization we produced some of the first images confirming sperm delivered EV cargo at conception and still detectable in the early-stage embryo. As such, this construct serves as a methodological advance and as a valuable tool, with applications in the study of EV function across biomedical research areas.
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Affiliation(s)
- Christopher P Morgan
- Department of Pharmacology and Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Victoria E Meadows
- Department of Pharmacology and Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Ruth Marx-Rattner
- Department of Pharmacology and Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Yasmine M Cisse
- Department of Pharmacology and Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Tracy L Bale
- Department of Pharmacology and Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
- Department of Psychiatry, University of Colorado School of Medicine, CU Anschutz Medical Campus, 12800 E. 19th Avenue, Aurora, CO, 80045, USA.
- The Anschutz Foundation Endowed Chair in Women's Integrated Mental and Physical Health Research at the Ludeman Center, Aurora, USA.
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29
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Nixon B, Schjenken JE, Burke ND, Skerrett-Byrne DA, Hart HM, De Iuliis GN, Martin JH, Lord T, Bromfield EG. New horizons in human sperm selection for assisted reproduction. Front Endocrinol (Lausanne) 2023; 14:1145533. [PMID: 36909306 PMCID: PMC9992892 DOI: 10.3389/fendo.2023.1145533] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/08/2023] [Indexed: 02/24/2023] Open
Abstract
Male infertility is a commonly encountered pathology that is estimated to be a contributory factor in approximately 50% of couples seeking recourse to assisted reproductive technologies. Upon clinical presentation, such males are commonly subjected to conventional diagnostic andrological practices that rely on descriptive criteria to define their fertility based on the number of morphologically normal, motile spermatozoa encountered within their ejaculate. Despite the virtual ubiquitous adoption of such diagnostic practices, they are not without their limitations and accordingly, there is now increasing awareness of the importance of assessing sperm quality in order to more accurately predict a male's fertility status. This realization raises the important question of which characteristics signify a high-quality, fertilization competent sperm cell. In this review, we reflect on recent advances in our mechanistic understanding of sperm biology and function, which are contributing to a growing armory of innovative approaches to diagnose and treat male infertility. In particular we review progress toward the implementation of precision medicine; the robust clinical adoption of which in the setting of fertility, currently lags well behind that of other fields of medicine. Despite this, research shows that the application of advanced technology platforms such as whole exome sequencing and proteomic analyses hold considerable promise in optimizing outcomes for the management of male infertility by uncovering and expanding our inventory of candidate infertility biomarkers, as well as those associated with recurrent pregnancy loss. Similarly, the development of advanced imaging technologies in tandem with machine learning artificial intelligence are poised to disrupt the fertility care paradigm by advancing our understanding of the molecular and biological causes of infertility to provide novel avenues for future diagnostics and treatments.
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Affiliation(s)
- Brett Nixon
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- *Correspondence: Brett Nixon,
| | - John E. Schjenken
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Nathan D. Burke
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - David A. Skerrett-Byrne
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Hanah M. Hart
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Geoffry N. De Iuliis
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Jacinta H. Martin
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Tessa Lord
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Elizabeth G. Bromfield
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
- Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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30
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Li HM, Wan XY, Zhao JY, Liang XM, Dai Y, Li HG. Promising novel biomarkers and therapy targets: The application of cell-free seminal nucleotides in male reproduction research. Transl Res 2022; 256:73-86. [PMID: 36586533 DOI: 10.1016/j.trsl.2022.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/10/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022]
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.
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Affiliation(s)
- Hui-Min Li
- Guilin Medical University, Guilin, 541004, P. R. China
| | - Xiao-Yan Wan
- Department of Obstetrics and gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510620, P. R. China
| | - Jie-Yi Zhao
- Institute of Reproductive Health/Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P. R. China
| | - Xu-Ming Liang
- Affiliated Hospital of Guilin Medical University, Guilin, 541001, P. R. China
| | - Yun Dai
- Affiliated Hospital of Guilin Medical University, Guilin, 541001, P. R. China
| | - Hong-Gang Li
- Institute of Reproductive Health/Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P. R. China; Wuhan Tongji Reproductive Medicine Hospital, Wuhan, 430030, P. R. China.
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31
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Tarín JJ, García-Pérez MA, Cano A. It Is Premature to Use Postmortem Sperm for Reproductive Purposes: a Data-Driven Opinion. Reprod Sci 2022; 29:3387-3393. [PMID: 35146695 PMCID: PMC9734227 DOI: 10.1007/s43032-022-00874-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/31/2022] [Indexed: 12/14/2022]
Abstract
Postmortem sperm retrieval for reproductive purposes is an assisted reproduction procedure that offers women an opportunity to have a child using sperm retrieved from their deceased partners. The ethical issues of this procedure have been discussed in previous works. However, an assessment of the procedure using a scientific perspective is still lacking. Here, we aim to ascertain, using a biological standpoint, whether postmortem sperm should be rescued for reproductive purposes. Data suggest that it is premature to use postmortem sperm for reproductive purposes. This procedure should not be clinically applied until appropriate and comprehensive analyses have been completed. Such analyses should be focused not only on fertilization, embryo development, and pregnancy outcomes, but also on potential postmortem alterations of sperm DNA, RNAs, and proteins. In addition, genetic and epigenetic analyses of sperm, pre-implantation embryos, and newborns, as well as mental and physical health follow-up of the resulting offspring during a whole life cycle, using appropriate non-human mammalian models, are warranted.
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Affiliation(s)
- Juan J Tarín
- Department of Cellular Biology, Functional Biology and Physical Anthropology, Faculty of Biological Sciences, University of Valencia, Dr. Moliner 50, 46100, Burjassot, Valencia, Spain.
- Institute of Health Research INCLIVA, Valencia, Spain.
| | - Miguel A García-Pérez
- Institute of Health Research INCLIVA, Valencia, Spain
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Dr. Moliner 50, 46100, Burjassot, Valencia, Spain
| | - Antonio Cano
- Institute of Health Research INCLIVA, Valencia, Spain
- Service of Obstetrics and Gynecology, University Clinic Hospital, Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Av. Blasco Ibañez 17, 46010, Valencia, Spain
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32
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Jiang Z, El-Brolosy MA, Serobyan V, Welker JM, Retzer N, Dooley CM, Jakutis G, Juan T, Fukuda N, Maischein HM, Balciunas D, Stainier DY. Parental mutations influence wild-type offspring via transcriptional adaptation. SCIENCE ADVANCES 2022; 8:eabj2029. [PMID: 36427314 PMCID: PMC9699682 DOI: 10.1126/sciadv.abj2029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 10/12/2022] [Indexed: 06/16/2023]
Abstract
Transgenerational epigenetic inheritance (TEI) is mostly discussed in the context of physiological or environmental factors. Here, we show intergenerational and transgenerational inheritance of transcriptional adaptation (TA), a process whereby mutant messenger RNA (mRNA) degradation affects gene expression, in nematodes and zebrafish. Wild-type offspring of animals heterozygous for mRNA-destabilizing alleles display increased expression of adapting genes. Notably, offspring of animals heterozygous for nontranscribing alleles do not display this response. Germline-specific mutations are sufficient to induce TA in wild-type offspring, indicating that, at least for some genes, mutations in somatic tissues are not necessary for this process. Microinjecting total RNA from germ cells of TA-displaying heterozygous zebrafish can trigger TA in wild-type embryos and in their progeny, suggesting a model whereby mutant mRNAs in the germline trigger a TA response that can be epigenetically inherited. In sum, this previously unidentified mode of TEI reveals a means by which parental mutations can modulate the offspring's transcriptome.
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Affiliation(s)
- Zhen Jiang
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
| | - Mohamed A. El-Brolosy
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Vahan Serobyan
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
| | - Jordan M. Welker
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Nicholas Retzer
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Christopher M. Dooley
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Gabrielius Jakutis
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Thomas Juan
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Nana Fukuda
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Hans-Martin Maischein
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
| | - Darius Balciunas
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
- Life Sciences Centre, Vilnius University, Vilnius, Lithuania
| | - Didier Y.R. Stainier
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany
- Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
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33
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Hamilton M, Russell S, Menezes K, Moskovtsev SI, Librach C. Assessing spermatozoal small ribonucleic acids and their relationship to blastocyst development in idiopathic infertile males. Sci Rep 2022; 12:20010. [PMID: 36411317 PMCID: PMC9678953 DOI: 10.1038/s41598-022-24568-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022] Open
Abstract
Clinical testing strategies for diagnosing male factor infertility are limited. A deeper analysis of spermatozoa-derived factors could potentially diagnose some cases of 'unexplained infertility'. Spermatozoa carry a rich and dynamic profile of small RNAs, which have demonstrated potential developmental importance and association with fertility status. We used next-generation sequencing to correlate sperm small RNA profiles of normozoospermic males (n = 54) with differing blastocyst development rates, when using young donor oocytes. While ribosomal RNAs accounted for the highest number of sequencing reads, transfer RNA fragments of tRNAGly/GCC and tRNAVal-CAC were the most abundant sequences across all sperm samples. A total of 324 small RNAs were differentially expressed between samples with high (n = 18) and low (n = 14) blastocyst rates (p-adj < 0.05). Ninety three miRNAs were differentially expressed between these groups (p-adj < 0.05). Differentially expressed transfer RNA fragments included: 5'-tRF-Asp-GTC; 5'-tRF-Phe-GAA; and 3'-tRF-Ser-GCA. Differentially expressed miRNAs included: let-7f-2-5p; miR-4755-3p; and miR-92a-3p. This study provides the foundation on which to validate a clinical panel of fertility-related sperm small RNAs, as well as to pursue potential mechanisms through which they alter blastocyst development.
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Affiliation(s)
| | | | - Karen Menezes
- grid.490031.fCReATe Fertility Centre, Toronto, ON Canada
| | - Sergey I. Moskovtsev
- grid.490031.fCReATe Fertility Centre, Toronto, ON Canada ,grid.17063.330000 0001 2157 2938Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada
| | - Clifford Librach
- grid.490031.fCReATe Fertility Centre, Toronto, ON Canada ,grid.17063.330000 0001 2157 2938Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON Canada ,grid.17063.330000 0001 2157 2938Department of Physiology and Institute of Medical Sciences, University of Toronto, Toronto, ON Canada ,grid.17063.330000 0001 2157 2938Sunnybrook Research Institute, Toronto, ON Canada
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34
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Maitan P, Bromfield EG, Stout TAE, Gadella BM, Leemans B. A stallion spermatozoon's journey through the mare's genital tract: In vivo and in vitro aspects of sperm capacitation. Anim Reprod Sci 2022; 246:106848. [PMID: 34556396 DOI: 10.1016/j.anireprosci.2021.106848] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/03/2021] [Accepted: 09/04/2021] [Indexed: 12/14/2022]
Abstract
Conventional in vitro fertilization is not efficacious when working with equine gametes. Although stallion spermatozoa bind to the zona pellucida in vitro, these gametes fail to initiate the acrosome reaction in the vicinity of the oocyte and cannot, therefore, penetrate into the perivitelline space. Failure of sperm penetration most likely relates to the absence of optimized in vitro fertilization media containing molecules essential to support stallion sperm capacitation. In vivo, the female reproductive tract, especially the oviductal lumen, provides an environmental milieu that appropriately regulates interactions between the gametes and promotes fertilization. Identifying these 'fertilization supporting factors' would be a great contribution for development of equine in vitro fertilization media. In this review, a description of the current understanding of the interactions stallion spermatozoa undergo during passage through the female genital tract, and related specific molecular changes that occur at the sperm plasma membrane is provided. Understanding these molecular changes may hold essential clues to achieving successful in vitro fertilization with equine gametes.
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Affiliation(s)
- Paula Maitan
- Departments of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands; Department of Veterinary Sciences, Universidade Federal de Viçosa, Viçosa, MG, Brazil
| | - Elizabeth G Bromfield
- Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, The Netherlands; Priority Research Centre for Reproductive Science, College of Engineering, Science and Environment, University of Newcastle, Australia
| | - Tom A E Stout
- Departments of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands
| | - Bart M Gadella
- Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, The Netherlands; Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, The Netherlands
| | - Bart Leemans
- Departments of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 112, 3584 CM Utrecht, The Netherlands.
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35
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Roca J, Rodriguez-Martinez H, Padilla L, Lucas X, Barranco I. Extracellular vesicles in seminal fluid and effects on male reproduction. An overview in farm animals and pets. Anim Reprod Sci 2022; 246:106853. [PMID: 34556398 DOI: 10.1016/j.anireprosci.2021.106853] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 09/09/2021] [Accepted: 09/11/2021] [Indexed: 02/08/2023]
Abstract
Extracellular vesicles (EVs) are lipid bilayer nanovesicles released by most functional cells to body fluids, containing bioactive molecules, mainly proteins, lipids, and nucleic acids having actions at target cells. The EVs have essential functions in cell-to-cell communication by regulating different biological processes in target cells. Fluids from the male reproductive tract, including seminal plasma, contain many extracellular vesicles (sEVs), which have been evaluated to a lesser extent than those of other body fluids, particularly in farm animals and pets. Results from the few studies that have been conducted indicated epithelial cells of the testis, epididymis, ampulla of ductus deferens and many accessory sex glands release sEVs mainly via apocrine mechanisms. The sEVs are morphologically heterogeneous and bind to functional cells of the male reproductive tract, spermatozoa, and cells of the functional tissues of the female reproductive tract after mating or insemination. The sEVs encapsulate proteins and miRNAs that modulate sperm functions and male fertility. The sEVs, therefore, could be important as reproductive biomarkers in breeding sires. Many of the current findings regarding sEV functions, however, need experimental confirmation. Further studies are particularly needed to characterize both membranes and contents of sEVs, as well as the interaction between sEVs and target cells (spermatozoa and functional cells of the internal female reproductive tract). A priority for conducting these studies is development of methods that can be standardized and that are scalable, cost-effective and time-saving for isolation of different subtypes of EVs present in the entire population of sEVs.
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Affiliation(s)
- Jordi Roca
- Department of Medicine and Animal Surgery, Faculty of Veterinary Medicine, International Excellence Campus for Higher Education and Research "Campus Mare Nostrum", University of Murcia, 30100 Murcia, Spain.
| | - Heriberto Rodriguez-Martinez
- Department of Biomedical & Clinical Sciences (BKV), BKH/Obstetrics & Gynaecology, Faculty of Medicine and Health Sciences, Linköping University, SE-58185 Linköping, Sweden
| | - Lorena Padilla
- Department of Medicine and Animal Surgery, Faculty of Veterinary Medicine, International Excellence Campus for Higher Education and Research "Campus Mare Nostrum", University of Murcia, 30100 Murcia, Spain
| | - Xiomara Lucas
- Department of Medicine and Animal Surgery, Faculty of Veterinary Medicine, International Excellence Campus for Higher Education and Research "Campus Mare Nostrum", University of Murcia, 30100 Murcia, Spain
| | - Isabel Barranco
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell'Emilia, IT-40064 Bologna, Italy
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36
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Skerrett-Byrne DA, Anderson AL, Bromfield EG, Bernstein IR, Mulhall JE, Schjenken JE, Dun MD, Humphrey SJ, Nixon B. Global profiling of the proteomic changes associated with the post-testicular maturation of mouse spermatozoa. Cell Rep 2022; 41:111655. [DOI: 10.1016/j.celrep.2022.111655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 06/15/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
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Rodriguez-Martinez H, Roca J, Alvarez-Rodriguez M, Martinez-Serrano CA. How does the boar epididymis regulate the emission of fertile spermatozoa? Anim Reprod Sci 2022; 246:106829. [PMID: 34452796 DOI: 10.1016/j.anireprosci.2021.106829] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 02/07/2023]
Abstract
The epididymis is responsible for peripheral immune tolerance of maturing spermatozoa even though these have xeno-antigens foreign to the male and female immune system. The epididymis also produces factors required for fertilization and serves as a sperm repository until the time of ejaculation. These reproduction-relevant epididymal functions occur in the mesonephros-derived duct-system that is composed of absorptive and secretory epithelial cells with the capacity for merocrine and apocrine secretion of proteins, antioxidative- and electrolyte/pH-regulating enzymes and small, non-coding RNAs (sncRNAs), many stored in epididymosomes for sperm adhesion and long-lasting modifications of sperm functions. This paper provides a review summary of current and new knowledge of how the boar epididymis affects the quality of spermatozoa in the ejaculate of breeding boars. There is a particular focus on sperm maturation, survival, function and the role of signaling to the female immune system in fertility modulation. Furthermore, aspects related to the ductus epithelial contributions regarding electrolyte control, protein production, release of epididymosomes that contain sncRNAs are emphasized as are novel associations with fertility of the male, sperm quiescence during storage in the cauda epididymis, and on changes occurring in sperm subsequent to ejaculation.
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Affiliation(s)
- Heriberto Rodriguez-Martinez
- Department of Biomedical & Clinical Sciences (BKV), BKH/Obstetrics & Gynecology, Faculty of Medicine and Health Sciences, Linköping University, SE-58185, Linköping, Sweden.
| | - Jordi Roca
- Department of Medicine and Animal Surgery, Faculty of Veterinary Medicine, International Excellence Campus for Higher Education and Research "Campus Mare Nostrum", University of Murcia, Murcia, Spain
| | - Manuel Alvarez-Rodriguez
- Department of Biomedical & Clinical Sciences (BKV), BKH/Obstetrics & Gynecology, Faculty of Medicine and Health Sciences, Linköping University, SE-58185, Linköping, Sweden
| | - Cristina A Martinez-Serrano
- Department of Biomedical & Clinical Sciences (BKV), BKH/Obstetrics & Gynecology, Faculty of Medicine and Health Sciences, Linköping University, SE-58185, Linköping, Sweden
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38
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Comas-Armangue G, Makharadze L, Gomez-Velazquez M, Teperino R. The Legacy of Parental Obesity: Mechanisms of Non-Genetic Transmission and Reversibility. Biomedicines 2022; 10:biomedicines10102461. [PMID: 36289722 PMCID: PMC9599218 DOI: 10.3390/biomedicines10102461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 11/27/2022] Open
Abstract
While a dramatic increase in obesity and related comorbidities is being witnessed, the underlying mechanisms of their spread remain unresolved. Epigenetic and other non-genetic mechanisms tend to be prominent candidates involved in the establishment and transmission of obesity and associated metabolic disorders to offspring. Here, we review recent findings addressing those candidates, in the context of maternal and paternal influences, and discuss the effectiveness of preventive measures.
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Affiliation(s)
- Gemma Comas-Armangue
- German Research Center for Environmental Health Neuherberg, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD) Neuherberg, 85764 Neuherberg, Germany
| | - Lela Makharadze
- German Research Center for Environmental Health Neuherberg, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD) Neuherberg, 85764 Neuherberg, Germany
| | - Melisa Gomez-Velazquez
- German Research Center for Environmental Health Neuherberg, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD) Neuherberg, 85764 Neuherberg, Germany
- Correspondence: (M.G.-V.); (R.T.)
| | - Raffaele Teperino
- German Research Center for Environmental Health Neuherberg, Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD) Neuherberg, 85764 Neuherberg, Germany
- Correspondence: (M.G.-V.); (R.T.)
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39
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sncRNAs in Epididymosomes: The Contribution to Embryonic Development and Offspring Health. Int J Mol Sci 2022; 23:ijms231810851. [PMID: 36142765 PMCID: PMC9501405 DOI: 10.3390/ijms231810851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/30/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Much progress has been made in determining that paternal environmental exposures can remodel their spermatozoa small noncoding RNAs (sncRANs) and, in turn, affect the phenotypes of their offspring. Studies have shown that changes in the spermatozoa sncRNAs profile occur during passing through the epididymis. Due to the absence of transcription and translation in the epididymis, spermatozoa remodel their sncRNAs profile through communication with the epididymal microenvironment. Since epididymosomes contribute to the process of spermatozoa maturation by mediating the crosstalk between the epididymis and the passing spermatozoa, they are considered to be the leading candidate to mediate these changes. Previous studies and reviews on the role of epididymal transfer proteins in sperm maturation and function are myriad. This review focuses on the role and mechanisms of epididymosome-mediated transfer of sncRNAs cargoes onembryonic development and offspring health.
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40
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Parental competition for the regulators of chromatin dynamics in mouse zygotes. Commun Biol 2022; 5:699. [PMID: 35835981 PMCID: PMC9283401 DOI: 10.1038/s42003-022-03623-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 06/22/2022] [Indexed: 11/08/2022] Open
Abstract
The underlying mechanism for parental asymmetric chromatin dynamics is still unclear. To reveal this, we investigate chromatin dynamics in parthenogenetic, androgenic, and several types of male germ cells-fertilized zygotes. Here we illustrate that parental conflicting role mediates the regulation of chromatin dynamics. Sperm reduces chromatin dynamics in both parental pronuclei (PNs). During spermiogenesis, male germ cells acquire this reducing ability and its resistance. On the other hand, oocytes can increase chromatin dynamics. Notably, the oocytes-derived chromatin dynamics enhancing ability is dominant for the sperm-derived opposing one. This maternal enhancing ability is competed between parental pronuclei. Delayed fertilization timing is critical for this competition and compromises parental asymmetric chromatin dynamics and zygotic transcription. Together, parental competition for the maternal factor enhancing chromatin dynamics is a determinant to establish parental asymmetry, and paternal repressive effects have supporting roles to enhance asymmetry.
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Morphological, morphometric, ultrastructural, and functional evaluation of red-rumped agouti (Dasyprocta leporina) sperm during epididymal transit. Anim Reprod Sci 2022; 243:107029. [PMID: 35752031 DOI: 10.1016/j.anireprosci.2022.107029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 11/23/2022]
Abstract
The red-rumped agouti (Dasyprocta leporina) is a hystricognath rodent with reproductive anatomical peculiarities presenting as an intra-abdominal testes-epididymis complex. This study was carried out to describe, for the first time, details related to the morphological and functional changes in sperm along the epididymal transit in agoutis. The testes-epididymal complexes were sampled from seven sexually mature agoutis. Sperm from different epididymal regions (caput, corpus, and cauda) were collected using the floating technique, and their morphology, morphometry, ultrastructure, mitochondrial activity, membrane structural integrity, and kinetic parameters were determined. The number of sperm collected (823.5 ×106 sperm) was higher in the epididymis cauda. No significant differences in normal sperm morphology among the different epididymal regions (caput, 82.42%; corpus, 86.71%; and cauda, 88.86 %) were observed. The mean head length, head width, and tail length were highest in the caput (5.15 µm, 3.44 µm, and 32.04 µm, respectively), decreasing along the epididymal transit. Ultrastructure by scanning electron microscopy (SEM) revealed agglomeration of spermatozoa from caput and corpus, thus, enabling analysis of the gametes from only the epididymal cauda with clarity. Sperm from epididymis cauda showed the greatest proportion of membrane integrity and mitochondrial activity, followed by those from corpus and caput (79.71 %, 58.9 %, 47.7 %, respectively). Significant increase in total motility, progressive motility, velocity average pathway -VAP, velocity straightline - VSL, velocity curvilinear - VCL, and rapid sperm in the caput-corpus-cauda direction were observed. These novel data contribute to the knowledge of sperm maturation in the red-rumped agouti.
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Gurunathan S, Kang MH, Song H, Kim NH, Kim JH. The role of extracellular vesicles in animal reproduction and diseases. J Anim Sci Biotechnol 2022; 13:62. [PMID: 35681164 PMCID: PMC9185900 DOI: 10.1186/s40104-022-00715-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/05/2022] [Indexed: 02/08/2023] Open
Abstract
Extracellular vesicles (EVs) are nanosized membrane-enclosed compartments that serve as messengers in cell-to-cell communication, both in normal physiology and in pathological conditions. EVs can transfer functional proteins and genetic information to alter the phenotype and function of recipient cells, which undergo different changes that positively affect their structural and functional integrity. Biological fluids are enriched with several subpopulations of EVs, including exosomes, microvesicles (MVs), and apoptotic bodies carrying several cargoes, such as lipids, proteins, and nucleic acids. EVs associated with the reproductive system are actively involved in the regulation of different physiological events, including gamete maturation, fertilization, and embryo and fetal development. EVs can influence follicle development, oocyte maturation, embryo production, and endometrial-conceptus communication. EVs loaded with cargoes are used to diagnose various diseases, including pregnancy disorders; however, these are dependent on the type of cell of origin and pathological characteristics. EV-derived microRNAs (miRNAs) and proteins in the placenta regulate inflammatory responses and trophoblast invasion through intercellular delivery in the placental microenvironment. This review presents evidence regarding the types of extracellular vesicles, and general aspects of isolation, purification, and characterization of EVs, particularly from various types of embryos. Further, we discuss EVs as mediators and messengers in reproductive biology, the effects of EVs on placentation and pregnancy disorders, the role of EVs in animal reproduction, in the male reproductive system, and mother and embryo cross-communication. In addition, we emphasize the role of microRNAs in embryo implantation and the role of EVs in reproductive and therapeutic medicine. Finally, we discuss the future perspectives of EVs in reproductive biology.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Hyuk Song
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Nam Hyung Kim
- Guangdong Provincial Key Laboratory of Large Animal models for Biomedicine, Wuyi University, Jiangmen, 529020, China
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea.
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Choy KHK, Chan SY, Lam W, Jin J, Zheng T, Law TYS, Yu SS, Wang W, Li L, Xie G, Yim HCH, Chen H, Fok EKL. The repertoire of testicular extracellular vesicle cargoes and their involvement in inter-compartmental communication associated with spermatogenesis. BMC Biol 2022; 20:78. [PMID: 35351114 PMCID: PMC8966158 DOI: 10.1186/s12915-022-01268-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/03/2022] [Indexed: 12/04/2022] Open
Abstract
Background Spermatogenesis is regulated by a complex network of intercellular communication processes. Extracellular vesicles (EVs) are one of the important mediators in intercellular communication. Previous reports have demonstrated the involvement of EVs from the epididymis and prostate in sperm maturation and function. However, the presence of EVs in the testis and their potential involvement in spermatogenesis has not been explored. Here, we have established a testis dissociation protocol that allows the isolation and characterization of testicular EVs. Results We show that testicular EVs are specifically and efficiently taken up by somatic cells and germ cells, including the spermatozoa in the interstitial space and the seminiferous tubule compartments. We profiled the proteome of testicular EVs and probed the cell types that release them, revealing the potential contributions from the Leydig cells and testicular macrophages. Moreover, we sequenced the small RNA cargoes of testicular EVs and identified sets of small non-coding RNAs that were overlooked in the testis transcriptome. Selected miRNA candidates in testicular EVs were found in sperm RNA payload and demonstrated specific resistance towards ribonuclease A independent of the vesicle membrane. Small molecule inhibition of EV secretion perturbed spermatogenesis via inter-compartmental communication. Conclusions Together, our study provides a valuable resource on the repertoire of cargoes carried by testicular EVs and uncovers a physiological function of testicular EVs in inter-compartmental communication associated to spermatogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-022-01268-5.
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Affiliation(s)
- Kathleen Hoi Kei Choy
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Sze Yan Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - William Lam
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Jing Jin
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Tingting Zheng
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Tin Yu Samuel Law
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Sidney Siubun Yu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Weiping Wang
- Dr. Li Dak-Sum Research Centre, University of Hong Kong, Hong Kong, SAR, China
| | - Linxian Li
- Ming Wai Lau Centre for Reparative Medicine, Karolinska Institute, Hong Kong, SAR, China
| | - Gangcai Xie
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, People's Republic of China
| | - Howard Chi Ho Yim
- Microbiome Research Centre, St George and Sutherland Clinical School, The University of New South Wales, Sydney, Australia
| | - Hao Chen
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, People's Republic of China.
| | - Ellis Kin Lam Fok
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China. .,Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, People's Republic of China.
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Quarato P, Singh M, Bourdon L, Cecere G. Inheritance and maintenance of small RNA-mediated epigenetic effects. Bioessays 2022; 44:e2100284. [PMID: 35338497 DOI: 10.1002/bies.202100284] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/04/2022] [Accepted: 03/15/2022] [Indexed: 11/08/2022]
Abstract
Heritable traits are predominantly encoded within genomic DNA, but it is now appreciated that epigenetic information is also inherited through DNA methylation, histone modifications, and small RNAs. Several examples of transgenerational epigenetic inheritance of traits have been documented in plants and animals. These include even the inheritance of traits acquired through the soma during the life of an organism, implicating the transfer of epigenetic information via the germline to the next generation. Small RNAs appear to play a significant role in carrying epigenetic information across generations. This review focuses on how epigenetic information in the form of small RNAs is transmitted from the germline to the embryos through the gametes. We also consider how inherited epigenetic information is maintained across generations in a small RNA-dependent and independent manner. Finally, we discuss how epigenetic traits acquired from the soma can be inherited through small RNAs.
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Affiliation(s)
- Piergiuseppe Quarato
- Department of Developmental and Stem Cell Biology, Institut Pasteur, Université de Paris, CNRS UMR3738, Mechanisms of Epigenetic Inheritance, Paris, France
| | - Meetali Singh
- Department of Developmental and Stem Cell Biology, Institut Pasteur, Université de Paris, CNRS UMR3738, Mechanisms of Epigenetic Inheritance, Paris, France
| | - Loan Bourdon
- Department of Developmental and Stem Cell Biology, Institut Pasteur, Université de Paris, CNRS UMR3738, Mechanisms of Epigenetic Inheritance, Paris, France
| | - Germano Cecere
- Department of Developmental and Stem Cell Biology, Institut Pasteur, Université de Paris, CNRS UMR3738, Mechanisms of Epigenetic Inheritance, Paris, France
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Abumaghaid MM, Abdelazim AM, Belali TM, Alhujaily M, Saadeldin IM. Shuttle Transfer of mRNA Transcripts via Extracellular Vesicles From Male Reproductive Tract Cells to the Cumulus–Oocyte Complex in Rabbits (Oryctolagus cuniculus). Front Vet Sci 2022; 9:816080. [PMID: 35372562 PMCID: PMC8968341 DOI: 10.3389/fvets.2022.816080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/17/2022] [Indexed: 12/21/2022] Open
Abstract
Semen is known to contain an ovulation-inducing factor (identified as a nerve growth factor, NGF) that shows a significant increase in ovulation after semen deposition in induced ovulatory species. However, the interplay between the male reproductive tract cells and oocyte maturation through messenger RNA (mRNA) cargo is yet to be investigated. Extracellular vesicles (EVs) from the primary culture of rabbit prostate (pEVs), epididymis (eEVs), and testis (tEVs) were isolated to examine their contents for several mRNA transcripts through relative quantitative PCR (RT-qPCR). The expressions of NGF, neurotrophin (NTF3), vascular endothelial growth factor A (VEGFA), A disintegrin and metalloprotease 17 (ADAM17), midkine (MDK), kisspeptin (KISS1), and gonadotrophin-releasing hormone (GNRH1) were examined in isolated EVs. EVs were characterized through transmission electron microscopy. EV uptake by cumulus cell culture was confirmed through microscopic detection of PKH26-stained EVs. Furthermore, the effects of pEVs, eEVs, and tEVs were compared with NGF (10, 20, and 30 ng/ml) supplementation on oocyte in vitro maturation (IVM) and transcript expression. KISS1, NTF3, MDK, ADAM17, GAPDH, and ACTB were detected in all EV types. GNRH1 was detected in tEVs. NGF was detected in pEVs, whereas VEGFA was detected in eEVs. pEVs, eEVs, and 20 ng/ml NGF showed the highest grade of cumulus expansion, followed by tEVs and 10 ng/ml NGF. Control groups and 30 ng/ml NGF showed the least grade of cumulus expansion. Similarly, first polar body (PB) extrusion was significantly increased in oocytes matured with eEVs, pEVs, tEVs, NGF20 (20 ng/ml NGF), NGF10 (10 ng/ml NGF), control, and NGF30 (30 ng/ml NGF). Additionally, the expression of NGFR showed a 1.5-fold increase in cumulus cells supplemented with eEVs compared with the control group, while the expression of PTGS2 (COX2) and NTRK showed 3-fold and 5-fold increase in NGF20-supplemented cumulus-oocyte complexes (COCs), respectively. Oocyte PMP15 expression showed a 1.8-fold increase in IVM medium supplemented with eEVs. Additionally, oocyte NGFR and NTRK expressions were drastically increased in IVM medium supplemented with pEVS (3.2- and 1.6-fold, respectively) and tEVs (4- and 1.7-fold, respectively). This is the first report to examine the presence of mRNA cargo in the EVs of male rabbit reproductive tract cells that provides a model for the stimulation of female rabbits after semen deposition.
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Affiliation(s)
- Mosleh M. Abumaghaid
- Department of Laboratory Medical Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia
- *Correspondence: Mosleh M. Abumaghaid
| | - Aaser M. Abdelazim
- Department of Basic Medical Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia
| | - Tareg M. Belali
- Department of Laboratory Medical Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia
| | - Muhanad Alhujaily
- Department of Laboratory Medical Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia
| | - Islam M. Saadeldin
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
- Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, South Korea
- Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
- Islam M. Saadeldin
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Skakkebæk NE, Lindahl-Jacobsen R, Levine H, Andersson AM, Jørgensen N, Main KM, Lidegaard Ø, Priskorn L, Holmboe SA, Bräuner EV, Almstrup K, Franca LR, Znaor A, Kortenkamp A, Hart RJ, Juul A. Environmental factors in declining human fertility. Nat Rev Endocrinol 2022; 18:139-157. [PMID: 34912078 DOI: 10.1038/s41574-021-00598-8] [Citation(s) in RCA: 167] [Impact Index Per Article: 55.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/03/2021] [Indexed: 12/14/2022]
Abstract
A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.
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Affiliation(s)
- Niels E Skakkebæk
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | | | - Hagai Levine
- School of Public Health, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Anna-Maria Andersson
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Niels Jørgensen
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Katharina M Main
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Øjvind Lidegaard
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lærke Priskorn
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Stine A Holmboe
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Elvira V Bräuner
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Kristian Almstrup
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Luiz R Franca
- Department of Morphology, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Ariana Znaor
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
| | - Andreas Kortenkamp
- Division of Environmental Sciences, Brunel University London, Uxbridge, UK
| | - Roger J Hart
- Division of Obstetrics and Gynaecology, University of Western Australia, Perth, Western Australia, Australia
- Fertility Specialists of Western Australia, Bethesda Hospital, Claremont, Western Australia, Australia
| | - Anders Juul
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Diet and Male Fertility: The Impact of Nutrients and Antioxidants on Sperm Energetic Metabolism. Int J Mol Sci 2022; 23:ijms23052542. [PMID: 35269682 PMCID: PMC8910394 DOI: 10.3390/ijms23052542] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 12/12/2022] Open
Abstract
Diet might affect male reproductive potential, but the biochemical mechanisms involved in the modulation of sperm quality remain poorly understood. While a Western diet is considered a risk factor for male infertility, the Mediterranean diet seems to protect against male infertility; moreover, the role of a vegetarian habitus in the preservation of sperm quality is controversial. The aim of this review is to analyze the molecular effects of single nutrients on sperm quality, focusing on their involvement in biochemical mechanisms related to sperm bioenergetics. It appears that diets rich in saturated fatty acids (SFA) and low in polyunsaturated fatty acids (PUFA) negatively affect sperm quality, whereas unsaturated fatty acids supplementation ameliorates sperm quality. In fact, the administration of PUFA, especially omega-3 PUFA, determined an increase in mitochondrial energetic metabolism and a reduction in oxidative damage. Carbohydrates and proteins are also nutritional modulators of oxidative stress and testosterone levels, which are strictly linked to sperm mitochondrial function, a key element for sperm quality. Moreover, many dietary natural polyphenols differentially affect (positively or negatively) the mitochondrial function, depending on their concentration. We believe that an understanding of the biochemical mechanisms responsible for sperm quality will lead to more targeted and effective therapeutics for male infertility.
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WEI YS, LIN WZ, WANG TE, LEE WY, LI SH, LIN FJ, NIXON B, SIPILÄ P, TSAI PS. Polarized epithelium-sperm co-culture system reveals stimulatory factors for the secretion of mouse epididymal quiescin sulfhydryl oxidase 1. J Reprod Dev 2022; 68:198-208. [PMID: 35228412 PMCID: PMC9184822 DOI: 10.1262/jrd.2021-128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Spermatozoa acquire fertilization ability through post-translational modifications. These membrane surface alterations occur in various segments of the epididymis. Quiescin sulfhydryl
oxidases, which catalyze thiol-oxidation reactions, are involved in disulfide bond formation, which is essential for sperm maturation, upon transition and migration in the epididymis. Using
castration and azoospermia transgenic mouse models, in the present study, we showed that quiescin sulfhydryl oxidase 1 (QSOX1) protein expression and secretion are positively correlated with
the presence of testosterone and sperm cells. A two-dimensional in vitro epithelium-sperm co-culture system provided further evidence in support of the notion that both
testosterone and its dominant metabolite, 5α-dihydrotestosterone, promote epididymal QSOX1 secretion. We also demonstrated that immature caput spermatozoa, but not mature cauda sperm cells,
exhibited great potential to stimulate QSOX1 secretion in vitro, suggesting that sperm maturation is a key regulatory factor for mouse epididymal QSOX1 secretion. Proteomic
analysis identified 582 secretory proteins from the co-culture supernatant, of which 258 were sperm-specific and 154 were of epididymal epithelium-origin. Gene Ontology analysis indicated
that these secreted proteins exhibit functions known to facilitate sperm membrane organization, cellular activity, and sperm-egg recognition. Taken together, our data demonstrated that
testosterone and sperm maturation status are key regulators of mouse epididymal QSOX1 protein expression and secretion.
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Affiliation(s)
- Yu-Syuan WEI
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Wan-Zhen LIN
- Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Tse-En WANG
- Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Wei-Yun LEE
- Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Sheng-Hsiang LI
- Department of Medical Research, Mackay Memorial Hospital, Tamshui 25160, Taiwan
| | - Fu-Jung LIN
- Department of Biochemical Science and Technology, National Taiwan University, Taipei 10617, Taiwan
| | - Brett NIXON
- Priority Research Centre for Reproduction, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia
| | - Petra SIPILÄ
- Department of Physiology, Institute of Biomedicine, University of Turku, Turku 20520, Finland
| | - Pei-Shiue TSAI
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan
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Fraser B, Peters AE, Sutherland JM, Liang M, Rebourcet D, Nixon B, Aitken RJ. Biocompatible Nanomaterials as an Emerging Technology in Reproductive Health; a Focus on the Male. Front Physiol 2021; 12:753686. [PMID: 34858208 PMCID: PMC8632065 DOI: 10.3389/fphys.2021.753686] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 10/06/2021] [Indexed: 12/24/2022] Open
Abstract
A growing body of research has confirmed that nanoparticle (NP) systems can enhance delivery of therapeutic and imaging agents as well as prevent potentially damaging systemic exposure to these agents by modifying the kinetics of their release. With a wide choice of NP materials possessing different properties and surface modification options with unique targeting agents, bespoke nanosystems have been developed for applications varying from cancer therapeutics and genetic modification to cell imaging. Although there remain many challenges for the clinical application of nanoparticles, including toxicity within the reproductive system, some of these may be overcome with the recent development of biodegradable nanoparticles that offer increased biocompatibility. In recognition of this potential, this review seeks to present recent NP research with a focus on the exciting possibilities posed by the application of biocompatible nanomaterials within the fields of male reproductive medicine, health, and research.
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Affiliation(s)
- Barbara Fraser
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW, Australia.,Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Alexandra E Peters
- Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Reproductive Science, School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
| | - Jessie M Sutherland
- Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Reproductive Science, School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
| | - Mingtao Liang
- Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Reproductive Science, School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
| | - Diane Rebourcet
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW, Australia.,Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Brett Nixon
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW, Australia.,Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Robert J Aitken
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW, Australia.,Pregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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50
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Sellem E, Jammes H, Schibler L. Sperm-borne sncRNAs: potential biomarkers for semen fertility? Reprod Fertil Dev 2021; 34:160-173. [PMID: 35231268 DOI: 10.1071/rd21276] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Semen infertility or sub-fertility, whether in humans or livestock species, remains a major concern for clinicians and technicians involved in reproduction. Indeed, they can cause tragedies in human relationships or have a dramatic overall negative impact on the sustainability of livestock breeding. Understanding and predicting semen fertility issues is therefore crucial and quality control procedures as well as biomarkers have been proposed to ensure sperm fertility. However, their predictive values appeared to be too limited and additional relevant biomarkers are still required to diagnose sub-fertility efficiently. During the last decade, the study of molecular mechanisms involved in spermatogenesis and sperm maturation highlighted the regulatory role of a variety of small non-coding RNAs (sncRNAs) and led to the discovery that sperm sncRNAs comprise both remnants from spermatogenesis and post-testicular sncRNAs acquired through interactions with extracellular vesicles along epididymis. This has led to the hypothesis that sncRNAs may be a source of relevant biomarkers, associated either with sperm functionality or embryo development. This review aims at providing a synthetic overview of the current state of knowledge regarding implication of sncRNA in spermatogenesis defects and their putative roles in sperm maturation and embryo development, as well as exploring their use as fertility biomarkers.
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Affiliation(s)
- Eli Sellem
- R&D Department, ALLICE, 149 rue de Bercy, 75012 Paris, France
| | - Hélène Jammes
- Université Paris Saclay, UVSQ, INRAE, BREED, 78350 Jouy en Josas, France; and Ecole Nationale Vétérinaire d'Alfort, BREED, 94700 Maisons-Alfort, France
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