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Special Issue "Molecular Biology of Spermatozoa"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2019).

Special Issue Editor

Prof. Dr. Fernando Juan Peña Vega
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Guest Editor
Laboratory of Equine Reproduction, Department of Medicine, Faculty of Veterinary Medicine, University of Extremadura, Avd de la Universidad s/n, 10003 Cáceres, Spain
Interests: flow cytometry applied to sperm analysis; redox regulation of sperm function; cryopreservation; impact of sperm in early embryo
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The spermatozoon is a very special cell; it is generated in the male reproductive tract, and has to travel to the female reproductive tract, of another individual, to fertilize an egg. This amazing journey, however, has to be able to respond and adapt to dramatically changing environments. The last decade has witnessed huge advances in the understanding of the molecular biology of this particular cell; these findings have provided new clues to understand male infertility and the impact of reproductive technologies in sperm function. Thus, empirical approaches for sperm conservation are being substituted by approaches based in translational research. As a transcriptionally-silent cell, spermatozoa largely depend on post-translational modifications of proteins to regulate their functions; among these regulatory mechanisms, redox regulation plays a relevant role, and deregulation of redox homeostasis is behind male factor infertility. With the incorporation of “omics”, lipidomics, epigenomics proteomics, and metabolomics to the study of the spermatozoa, the knowledge of sperm function has increased significantly in the last decade; developments in image analysis and advanced flow cytometry have also significantly contributed to this advance.

Prof. Fernando Juan Peña Vega
Guest Editor

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Keywords

  • sperm
  • flow cytometry
  • proteomics
  • epigenomics
  • redox regulation
  • lipidomics

Published Papers (12 papers)

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Editorial

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Open AccessEditorial
Molecular Biology of Spermatozoa
Int. J. Mol. Sci. 2020, 21(9), 3060; https://doi.org/10.3390/ijms21093060 - 26 Apr 2020
Viewed by 705
Abstract
The spermatozoon is a very special cell; it is generated in the male reproductive tract and has to travel to the female reproductive tract, of another individual, to fertilize an egg [...] Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)

Research

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Open AccessArticle
Cryopreservation Differentially Alters the Proteome of Epididymal and Ejaculated Pig Spermatozoa
Int. J. Mol. Sci. 2019, 20(7), 1791; https://doi.org/10.3390/ijms20071791 - 11 Apr 2019
Cited by 14 | Viewed by 1662
Abstract
Cryopreservation induces differential remodeling of the proteome in mammalian spermatozoa. How these proteome changes relate to the loss of sperm function during cryopreservation remains unsolved. The present study aimed to clarify this issue evaluating differential changes in the proteome of fresh and frozen-thawed [...] Read more.
Cryopreservation induces differential remodeling of the proteome in mammalian spermatozoa. How these proteome changes relate to the loss of sperm function during cryopreservation remains unsolved. The present study aimed to clarify this issue evaluating differential changes in the proteome of fresh and frozen-thawed pig spermatozoa retrieved from the cauda epididymis and the ejaculate of the same boars, with clear differences in cryotolerance. Spermatozoa were collected from 10 healthy, sexually mature, and fertile boars, and cryopreserved using a standard 0.5 mL-straw protocol. Total and progressive motility, viability, and mitochondria membrane potential were higher and membrane fluidity and reactive oxygen species generation lower in frozen-thawed (FT) epididymal than ejaculated spermatozoa. Quantitative proteomics of fresh and FT spermatozoa were analyzed using a LC-ESI-MS/MS-based Sequential Window Acquisition of All Theoretical Spectra approach. Cryopreservation quantitatively altered more proteins in ejaculated than cauda epididymal spermatozoa. Differential protein–protein networks highlighted a set of proteins quantitatively altered in ejaculated spermatozoa, directly involved in mitochondrial functionality which would explain why ejaculated spermatozoa deteriorate during cryopreservation. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessArticle
Addressing the Compartmentalization of Specific Integrin Heterodimers in Mouse Sperm
Int. J. Mol. Sci. 2019, 20(5), 1004; https://doi.org/10.3390/ijms20051004 - 26 Feb 2019
Cited by 6 | Viewed by 1367
Abstract
Integrins are transmembrane cell receptors involved in two crucial mechanisms for successful fertilization, namely, mammalian intracellular signaling and cell adhesion. Integrins α6β4, α3β1 and α6β1 are three major laminin receptors expressed on the surface of mammalian cells including gametes, and the presence of [...] Read more.
Integrins are transmembrane cell receptors involved in two crucial mechanisms for successful fertilization, namely, mammalian intracellular signaling and cell adhesion. Integrins α6β4, α3β1 and α6β1 are three major laminin receptors expressed on the surface of mammalian cells including gametes, and the presence of individual integrin subunits α3, α6, β1 and β4 has been previously detected in mammalian sperm. However, to date, proof of the existence of individual heterodimer pairs in sperm and their detailed localization is missing. The major conclusion of this study is evidence that the β4 integrin subunit is expressed in mouse sperm and that it pairs with subunit α6; additionally, there is a detailed identification of integrin heterodimer pairs across individual membranes in an intact mouse sperm head. We also demonstrate the existence of β4 integrin mRNAs in round spermatids and spermatogonia by q-RT-PCR, which was further supported by sequencing the PCR products. Using super-resolution microscopy accompanied by colocalization analysis, we located integrin subunits as follows: α6/β4-inner apical acrosomal membrane and equatorial segment; α3, α6/β1, β4-plasma membrane overlaying the apical acrosome; and α3/β1-outer acrosomal membrane. The existence of α6β4, α3β1 and α6β1 heterodimers was further confirmed by proximity ligation assay (PLA). In conclusion, we delivered detailed characterization of α3, α6, β1 and β4 integrin subunits, showing their presence in distinct compartments of the intact mouse sperm head. Moreover, we identified sperm-specific localization for heterodimers α6β4, α3β1 and α6β1, and their membrane compartmentalization and the presented data show a complexity of membranes overlaying specialized microdomain structures in the sperm head. Their different protein compositions of these individual membrane rafts may play a specialized role, based on their involvement in sperm-epithelium and sperm-egg interaction. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessArticle
Expression of Immune Regulatory Genes in the Porcine Internal Genital Tract Is Differentially Triggered by Spermatozoa and Seminal Plasma
Int. J. Mol. Sci. 2019, 20(3), 513; https://doi.org/10.3390/ijms20030513 - 25 Jan 2019
Cited by 30 | Viewed by 1710
Abstract
Mating or cervical deposition of spermatozoa or seminal plasma (SP) modifies the expression of genes affecting local immune defense processes at the oviductal sperm reservoir in animals with internal fertilization, frequently by down-regulation. Such responses may occur alongside sperm transport to or even [...] Read more.
Mating or cervical deposition of spermatozoa or seminal plasma (SP) modifies the expression of genes affecting local immune defense processes at the oviductal sperm reservoir in animals with internal fertilization, frequently by down-regulation. Such responses may occur alongside sperm transport to or even beyond the reservoir. Here, immune-related gene expression was explored with cDNA microarrays on porcine cervix-to-infundibulum tissues, pre-/peri-ovulation. Samples were collected 24 h post-mating or cervical deposition of sperm-peak spermatozoa or SP (from the sperm-peak fraction or the whole ejaculate). All treatments of this interventional study affected gene expression. The concerted action of spermatozoa and SP down-regulated chemokine and cytokine (P00031), interferon-gamma signaling (P00035), and JAK/STAT (P00038) pathways in segments up to the sperm reservoir (utero-tubal junction (UTJ)/isthmus). Spermatozoa in the vanguard sperm-peak fraction (P1-AI), uniquely displayed an up-regulatory effect on these pathways in the ampulla and infundibulum. Sperm-free SP, on the other hand, did not lead to major effects on gene expression, despite the clinical notion that SP mitigates reactivity by the female immune system after mating or artificial insemination. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessArticle
Acute Myeloid Leukemia Affects Mouse Sperm Parameters, Spontaneous Acrosome Reaction, and Fertility Capacity
Int. J. Mol. Sci. 2019, 20(1), 219; https://doi.org/10.3390/ijms20010219 - 08 Jan 2019
Cited by 4 | Viewed by 1545
Abstract
Leukemia is one of the most common cancers in patients of reproductive age. It is well known that chemotherapy, used as anti-cancer therapy, adversely affects male fertility. Moreover, the negative effect of leukemia on sperm quality, even before chemotherapy treatment, has been reported. [...] Read more.
Leukemia is one of the most common cancers in patients of reproductive age. It is well known that chemotherapy, used as anti-cancer therapy, adversely affects male fertility. Moreover, the negative effect of leukemia on sperm quality, even before chemotherapy treatment, has been reported. However, the mechanisms behind this disease’s effect on sperm quality remains unknown. In this study, we examine the direct effect of leukemia and chemotherapy alone and in combination on sperm parameters and male fertility. For this, we developed an acute myeloid leukemia (AML) mouse model (mice were treated with AML cells C1498 and developed leukemia); these mice then received cytarabine chemotherapy. Our findings reveal a significant reduction in sperm concentration and motility and a significant increase in abnormal morphology and spontaneous acrosome reaction of the sperm following AML and chemotherapy treatment, alone and in combination. We also found a reduction in male fertility and the number of delivered offspring. Our results support previous findings that AML impairs sperm parameters and show for the first time that AML increases spontaneous acrosome reaction and decreases male fertility capacity and number of offspring. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessCommunication
Ethanol-Induced Autophagy in Sertoli Cells Is Specifically Marked at Androgen-Dependent Stages of the Spermatogenic Cycle: Potential Mechanisms and Implications
Int. J. Mol. Sci. 2019, 20(1), 184; https://doi.org/10.3390/ijms20010184 - 06 Jan 2019
Cited by 11 | Viewed by 1570
Abstract
In a recent study, we reported that acute ethanol exposure enhanced autophagy in Sertoli cells (SCs) of adult rats. However, further research is needed to clarify the specific spermatogenic stage exhibiting the highest autophagic response, the mechanisms behind such specificity, and the related [...] Read more.
In a recent study, we reported that acute ethanol exposure enhanced autophagy in Sertoli cells (SCs) of adult rats. However, further research is needed to clarify the specific spermatogenic stage exhibiting the highest autophagic response, the mechanisms behind such specificity, and the related relevance to sperm. This brief report provides results indicating that stages VII–VIII (androgen-dependent or spermiation stages) of the spermatogenic cycle exhibited more marked autophagic response in acute-ethanol treated rats (ETRs) than other stages based on suppression of androgen receptor (AR), analysis of microtubule-associated protein 1 light chain 3 (LC3) (an autophagosomal marker) immunostaining in SCs, double labeling of LC3 and lysosomal proteins and electron microscopy. Ultrastructural observations and TUNEL method revealed a notable presence of phagocytosed apoptotic germ cells and retained sperm in SCs of ETRs at these specific stages—a finding rarely observed in control testes. In addition, PTEN-induced putative kinase 1 ( PINK1) (a sensor of mitochondrial damage and mitophagy) and giant lipid droplets were found to have accumulated in SCs of ETRs at same stages. Our data show novel findings indicating that stages VII–VIII of the spermatogenic cycle exhibit high levels of autophagy, specifically under stress conditions, as expressed by the term autophagic stages. This stage-specific upregulation of autophagy in SCs may be related to AR suppression, mitochondrial damage, lipid accumulation, and phagocytosis of apoptotic cells. The phenomenon may be an essential part of ensuring the viability of SCs and supporting germ cells in toxic environments. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessArticle
New Insight into Sperm Capacitation: A Novel Mechanism of 17β-Estradiol Signalling
Int. J. Mol. Sci. 2018, 19(12), 4011; https://doi.org/10.3390/ijms19124011 - 12 Dec 2018
Cited by 5 | Viewed by 3891
Abstract
17β-estradiol (estradiol) is a natural estrogen regulating reproduction including sperm and egg development, sperm maturation—called capacitation—and sperm–egg communication. High doses can increase germ cell apoptosis and decrease sperm count. Our aim was to answer the biological relevance of estradiol in sperm capacitation and [...] Read more.
17β-estradiol (estradiol) is a natural estrogen regulating reproduction including sperm and egg development, sperm maturation—called capacitation—and sperm–egg communication. High doses can increase germ cell apoptosis and decrease sperm count. Our aim was to answer the biological relevance of estradiol in sperm capacitation and its effect on motility and acrosome reaction to quantify its interaction with estrogen receptors and propose a model of estradiol action during capacitation using kinetic analysis. Estradiol increased protein tyrosine phosphorylation, elevated rate of spontaneous acrosome reaction, and altered motility parameters measured Hamilton-Thorne Computer Assisted Semen Analyzer (CASA) in capacitating sperm. To monitor time and concentration dependent binding dynamics of extracellular estradiol, high-performance liquid chromatography with tandem mass spectrometry was used to measure sperm response and data was subjected to kinetic analysis. The kinetic model of estradiol action during sperm maturation shows that estradiol adsorption onto a plasma membrane surface is controlled by Langmuir isotherm. After, when estradiol passes into the cytoplasm, it forms an unstable adduct with cytoplasmic receptors, which display a signalling autocatalytic pattern. This autocatalytic reaction suggests crosstalk between receptor and non-receptor pathways utilized by sperm prior to fertilization. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessArticle
Development of Spermatogenesis In Vitro in Three-Dimensional Culture from Spermatogonial Cells of Busulfan-Treated Immature Mice
Int. J. Mol. Sci. 2018, 19(12), 3804; https://doi.org/10.3390/ijms19123804 - 29 Nov 2018
Cited by 16 | Viewed by 1874
Abstract
Aggressive chemotherapy may lead to permanent male infertility. Prepubertal males do not generate sperm, but their testes do contain spermatogonial cells (SPGCs) that could be used for fertility preservation. In the present study, we examined the effect of busulfan (BU) on the SPGCs [...] Read more.
Aggressive chemotherapy may lead to permanent male infertility. Prepubertal males do not generate sperm, but their testes do contain spermatogonial cells (SPGCs) that could be used for fertility preservation. In the present study, we examined the effect of busulfan (BU) on the SPGCs of immature mice, and the possible induction of the survivor SPGCs to develop spermatogenesis in 3D in-vitro culture. Immature mice were injected with BU, and after 0.5–12 weeks, their testes were weighed and evaluated histologically compared to the control mice. The spermatogonial cells [Sal-like protein 4 (SALL4) and VASA (a member of the DEAD box protein family) in the testicular tissue were counted/seminiferous tubule (ST). The cells from the STs were enzymatically isolated and cultured in vitro. Our results showed a significant decrease in the testicular weight of the BU-treated mice compared to the control. This was in parallel to a significant increase in the number of severely damaged STs, and a decrease in the number of SALL4 and VASA/STs compared to the control. The cultures of the isolated cells from the STs of the BU-treated mice showed a development of colonies and meiotic and post-meiotic cells after four weeks of culture. The addition of homogenates from adult GFP mice to those cultures induced the development of sperm-like cells after four weeks of culture. This is the first study demonstrating the presence of biologically active spermatogonial cells in the testicular tissue of BU-treated immature mice, and their capacity to develop sperm-like cells in vitro. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessArticle
Expression of the O-Glycosylation Enzyme GalNAc-T3 in the Equatorial Segment Correlates with the Quality of Spermatozoa
Int. J. Mol. Sci. 2018, 19(10), 2949; https://doi.org/10.3390/ijms19102949 - 27 Sep 2018
Cited by 2 | Viewed by 1416
Abstract
We question whether the expression of GalNAc-T3, the only known O-GalNAc-transferase present in germ cells, is correlated with qualitative and functional parameters of spermatozoa. We investigated the expression of GalNAc-T3 in ejaculated spermatozoa with immunocytochemistry in swim-up purified and acrosome-reacted spermatozoa from [...] Read more.
We question whether the expression of GalNAc-T3, the only known O-GalNAc-transferase present in germ cells, is correlated with qualitative and functional parameters of spermatozoa. We investigated the expression of GalNAc-T3 in ejaculated spermatozoa with immunocytochemistry in swim-up purified and acrosome-reacted spermatozoa from quality-control semen donors and in semen samples from 206 randomly selected men representing a broad spectrum of semen quality. Using donor ejaculates and immunofluorescence detection we found that expression of GalNAc-T3 and the presence of the immature O-glycans Tn and T localized to the equatorial segment of spermatozoa. The proportion of GalNAc-T3-positive spermatozoa in the ejaculate increased after swim-up and appeared unaffected by induction of acrosomal exocytosis. The fraction of spermatozoa with equatorial expression of GalNAc-T3 correlated with classical semen parameters (concentration p = 9 × 10−6, morphology p = 7 × 10−8, and motility p = 1.8 × 10−5) and was significantly lower in men with oligoteratoasthenozoospermia (p = 0.0048). In conclusion, GalNAc-T3 was highly expressed by motile spermatozoa and the expression correlated positively with the classical semen parameters. Therefore, GalNAc-T3 expression seems related to the quality of the spermatozoa, and we propose that reduced expression of GalNAc-T3 may lead to impaired O-glycosylation of proteins and thereby abnormal maturation and reduced functionality of the spermatozoa. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Review

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Open AccessReview
Taste Receptors: New Players in Sperm Biology
Int. J. Mol. Sci. 2019, 20(4), 967; https://doi.org/10.3390/ijms20040967 - 22 Feb 2019
Cited by 9 | Viewed by 3845
Abstract
Taste receptors were first described as sensory receptors located on the tongue, where they are expressed in small clusters of specialized epithelial cells. However, more studies were published in recent years pointing to an expression of these proteins not only in the oral [...] Read more.
Taste receptors were first described as sensory receptors located on the tongue, where they are expressed in small clusters of specialized epithelial cells. However, more studies were published in recent years pointing to an expression of these proteins not only in the oral cavity but throughout the body and thus to a physiological role beyond the tongue. The recent observation that taste receptors and components of the coupled taste transduction cascade are also expressed during the different phases of spermatogenesis as well as in mature spermatozoa from mouse to humans and the overlap between the ligand spectrum of taste receptors with compounds in the male and female reproductive organs makes it reasonable to assume that sperm “taste” these different cues in their natural microenvironments. This assumption is assisted by the recent observations of a reproductive phenotype of different mouse lines carrying a targeted deletion of a taste receptor gene as well as the finding of a significant correlation between human male infertility and some polymorphisms in taste receptors genes. In this review, we depict recent findings on the role of taste receptors in male fertility, especially focusing on their possible involvement in mechanisms underlying spermatogenesis and post testicular sperm maturation. We also highlight the impact of genetic deletions of taste receptors, as well as their polymorphisms on male reproduction. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessReview
DNA Damage and Repair in Human Reproductive Cells
Int. J. Mol. Sci. 2019, 20(1), 31; https://doi.org/10.3390/ijms20010031 - 21 Dec 2018
Cited by 23 | Viewed by 2444
Abstract
The fundamental underlying paradigm of sexual reproduction is the production of male and female gametes of sufficient genetic difference and quality that, following syngamy, they result in embryos with genomic potential to allow for future adaptive change and the ability to respond to [...] Read more.
The fundamental underlying paradigm of sexual reproduction is the production of male and female gametes of sufficient genetic difference and quality that, following syngamy, they result in embryos with genomic potential to allow for future adaptive change and the ability to respond to selective pressure. The fusion of dissimilar gametes resulting in the formation of a normal and viable embryo is known as anisogamy, and is concomitant with precise structural, physiological, and molecular control of gamete function for species survival. However, along the reproductive life cycle of all organisms, both male and female gametes can be exposed to an array of “stressors” that may adversely affect the composition and biological integrity of their proteins, lipids and nucleic acids, that may consequently compromise their capacity to produce normal embryos. The aim of this review is to highlight gamete genome organization, differences in the chronology of gamete production between the male and female, the inherent DNA protective mechanisms in these reproductive cells, the aetiology of DNA damage in germ cells, and the remarkable DNA repair mechanisms, pre- and post-syngamy, that function to maintain genome integrity. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessReview
Zinc: A Necessary Ion for Mammalian Sperm Fertilization Competency
Int. J. Mol. Sci. 2018, 19(12), 4097; https://doi.org/10.3390/ijms19124097 - 18 Dec 2018
Cited by 26 | Viewed by 2893
Abstract
The importance of zinc for male fertility only emerged recently, being propelled in part by consumer interest in nutritional supplements containing ionic trace minerals. Here, we review the properties, biological roles and cellular mechanisms that are relevant to zinc function in the male [...] Read more.
The importance of zinc for male fertility only emerged recently, being propelled in part by consumer interest in nutritional supplements containing ionic trace minerals. Here, we review the properties, biological roles and cellular mechanisms that are relevant to zinc function in the male reproductive system, survey available peer-reviewed data on nutritional zinc supplementation for fertility improvement in livestock animals and infertility therapy in men, and discuss the recently discovered signaling pathways involving zinc in sperm maturation and fertilization. Emphasis is on the zinc-interacting sperm proteome and its involvement in the regulation of sperm structure and function, from spermatogenesis and epididymal sperm maturation to sperm interactions with the female reproductive tract, capacitation, fertilization, and embryo development. Merits of dietary zinc supplementation and zinc inclusion into semen processing media are considered with livestock artificial insemination (AI) and human assisted reproductive therapy (ART) in mind. Collectively, the currently available data underline the importance of zinc ions for male fertility, which could be harnessed to improve human reproductive health and reproductive efficiency in agriculturally important livestock species. Further research will advance the field of sperm and fertilization biology, provide new research tools, and ultimately optimize semen processing procedures for human infertility therapy and livestock AI. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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