Molecular Regulation of Spermatozoa

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 9829

Special Issue Editor


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Guest Editor
Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada
Interests: reproduction; female fertility preservation; male fertility preservation; female infertility; male infertility; oocyte; sperm; embryo; ovarian tissue; spermatogonial stem cell; testicular tissue; reproductive cells and tissues culture; reproductive cells and tissues cryopreservation; apoptosis; oxidative stress; antioxidant therapy

Special Issue Information

Dear Colleagues,

Infertility is a common problem affecting many couples worldwide. In approximately 50% of cases, the male factor is the primary or contributing cause. In most infertility cases, adequate numbers of spermatozoa are produced, and, in fact, these numbers are sufficient to induce pregnancy; however, the biological functions such as capacitation, hyperactivation, acrosome reaction, and fertilizing ability of those spermatozoa have been compromised, which is considered the most frequent cause of human infertility. A dynamic interplay between spermatozoa and a constantly changing environment is necessary to activate the underlying molecular events and signaling pathways which lead to the regulation of sperm functions. In fact, various signaling molecules, such as hormones, immune regulatory molecules, neurotransmitters, ions, proteins, growth factors, and free radicals are involved in the regulation of sperm functions, mainly through post-translational modifications of proteins. Therefore, the deregulation of those interactions can be behind male factor infertility.

For this Special Issue of ”Biomedicines”, we invite you to contribute either an original research article or a review article on the topic “Molecular Regulation of Spermatozoa.” The scope includes in vitro and in vivo research on molecular mechanisms and signaling pathways that regulate spermatozoa function in physiological conditions, as well as under different special conditions, such as those causing male infertility or subfertility. Additionally, any paper related to the redox regulation role in sperm function is welcome.

Dr. Atefeh Najafi
Guest Editor

Manuscript Submission Information

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Keywords

  • Spermatogenesis;
  • Spermiogenesis;
  • Sperm;
  • Capacitation;
  • Acrosome reaction;
  • Hyperactivation;
  • Fertilization;
  • Male infertility;
  • Antioxidants;
  • Redox regulation

Published Papers (7 papers)

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15 pages, 1760 KiB  
Article
Can Microfluidics Improve Sperm Quality? A Prospective Functional Study
by Fernando Meseguer, Carla Giménez Rodríguez, Rocío Rivera Egea, Laura Carrión Sisternas, Jose A. Remohí and Marcos Meseguer
Biomedicines 2024, 12(5), 1131; https://doi.org/10.3390/biomedicines12051131 - 20 May 2024
Viewed by 956
Abstract
The same sperm selection techniques in assisted reproduction clinics have remained largely unchanged despite their weaknesses. Recently, microfluidic devices have emerged as a novel methodology that facilitates the sperm selection process with promising results. A prospective case-control study was conducted in two phases: [...] Read more.
The same sperm selection techniques in assisted reproduction clinics have remained largely unchanged despite their weaknesses. Recently, microfluidic devices have emerged as a novel methodology that facilitates the sperm selection process with promising results. A prospective case-control study was conducted in two phases: 100 samples were used to compare the microfluidic device with Density Gradient, and another 100 samples were used to compare the device with the Swim-up. In the initial phase, a significant enhancement in progressive motility, total progressive motile sperm count, vitality, morphology, and sperm DNA fragmentation were obtained for the microfluidic group compared to Density Gradient. Nevertheless, no statistically significant differences were observed in sperm concentration and chromatin structure stability. In the subsequent phase, the microfluidic group exhibited significant increases in sperm concentration, total progressive motile sperm count, and vitality compared to Swim-up. However, non-significant differences were seen for progressive motility, morphology, DNA structure stability, and DNA fragmentation. Similar trends were observed when results were stratified into quartiles. In conclusion, in a comparison of microfluidics with standard techniques, an improvement in sperm quality parameters was observed for the microfluidic group. However, this improvement was not significant for all parameters. Full article
(This article belongs to the Special Issue Molecular Regulation of Spermatozoa)
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22 pages, 10574 KiB  
Article
Rats Orally Administered with Ethyl Alcohol for a Prolonged Time Show Histopathology of the Epididymis and Seminal Vesicle Together with Changes in the Luminal Metabolite Composition
by Chayakorn Taoto, Nareelak Tangsrisakda, Wipawee Thukhammee, Jutarop Phetcharaburanin, Sitthichai Iamsaard and Nongnuj Tanphaichitr
Biomedicines 2024, 12(5), 1010; https://doi.org/10.3390/biomedicines12051010 - 3 May 2024
Viewed by 787
Abstract
Prolonged ethanol (EtOH) consumption is associated with male infertility, with a decreased spermatogenesis rate as one cause. The defective maturation and development of sperm during their storage in the cauda epididymis and transit in the seminal vesicle can be another cause, possibly occurring [...] Read more.
Prolonged ethanol (EtOH) consumption is associated with male infertility, with a decreased spermatogenesis rate as one cause. The defective maturation and development of sperm during their storage in the cauda epididymis and transit in the seminal vesicle can be another cause, possibly occurring before the drastic spermatogenesis disruption. Herein, we demonstrated that the cauda epididymis and seminal vesicle of rats, orally administered with EtOH under a regimen in which spermatogenesis was still ongoing, showed histological damage, including lesions, a decreased height of the epithelial cells and increased collagen fibers in the muscle layer, which implicated fibrosis. Lipid peroxidation (shown by malondialdehyde (MDA) levels) was observed, indicating that reactive oxygen species (ROS) were produced along with acetaldehyde during EtOH metabolism by CYP2E1. MDA, acetaldehyde and other lipid peroxidation products could further damage cellular components of the cauda epididymis and seminal vesicle, and this was supported by increased apoptosis (shown by a TUNEL assay and caspase 9/caspase 3 expression) in these two tissues of EtOH-treated rats. Consequently, the functionality of the cauda epididymis and seminal vesicle in EtOH-treated rats was impaired, as demonstrated by a decreases in 1H NMR-analyzed metabolites (e.g., carnitine, fructose), which were important for sperm development, metabolism and survival in their lumen. Full article
(This article belongs to the Special Issue Molecular Regulation of Spermatozoa)
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14 pages, 4976 KiB  
Article
The Role of Chorein Deficiency in Late Spermatogenesis
by Kaoru Arai, Yoshiaki Nishizawa, Omi Nagata, Hitoshi Sakimoto, Natsuki Sasaki, Akira Sano and Masayuki Nakamura
Biomedicines 2024, 12(1), 240; https://doi.org/10.3390/biomedicines12010240 - 22 Jan 2024
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Abstract
VPS13A, also known as chorein, whose loss of function causes chorea-acanthocytosis (ChAc), is characterized by Huntington’s-disease-like neurodegeneration and neuropsychiatric symptoms in addition to acanthocytosis in red blood cells. We previously reported that ChAc-model mice with a loss of chorein function exhibited male infertility, [...] Read more.
VPS13A, also known as chorein, whose loss of function causes chorea-acanthocytosis (ChAc), is characterized by Huntington’s-disease-like neurodegeneration and neuropsychiatric symptoms in addition to acanthocytosis in red blood cells. We previously reported that ChAc-model mice with a loss of chorein function exhibited male infertility, with asthenozoospermia and mitochondrial dysmorphology in the spermatozoa. Here, we report a novel aspect of chorein dysfunction in male fertility, particularly its role in spermatogenesis and mitochondrial integrity. An increase in anti-malondialdehyde antibody immunoreaction within the testes, predominantly observed at the advanced stages of sperm formation in chorein-deficient mice, suggests oxidative stress as a contributing factor to mitochondrial dysfunction and impaired sperm maturation. The chorein immunoreactivity in spermatids of wild-type mice accentuates its significance in sperm development. ChAc-model mice exhibit mitochondrial ultrastructural abnormalities, specifically during the late stages of sperm maturation, suggesting a critical timeframe for chorein’s action in spermiogenesis. We observed an increase in TOM20 protein levels, indicative of disrupted mitochondrial import mechanisms. The concurrent decrease in metabolic enzymes such as IDH3A, LDHC, PGK2, and ACAT1 suggests a complex chorein-mediated metabolic network that is essential for sperm vitality. Additionally, heightened separation of cytoplasmic droplets from sperm highlights the potential membrane instability in chorein-deficient spermatozoa. Metabolomic profiling further suggests a compensatory metabolic shift, with elevated glycolytic and TCA-cycle substrates. Our findings suggest that chorein is involved in anti-ferroptosis and the maturation of mitochondrial morphology in the late stages of spermatogenesis, and its deficiency leads to asthenozoospermia characterized by membrane instability, abnormal cytosolic glycolysis, abnormal mitochondrial function, and a disrupted TCA cycle. Further analyses are required to unravel the molecular mechanisms that directly link these findings and to elucidate the role of chorein in spermatogenesis as well as its broader implications. Full article
(This article belongs to the Special Issue Molecular Regulation of Spermatozoa)
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14 pages, 3202 KiB  
Article
A Possible Role for Nerve Growth Factor and Its Receptors in Human Sperm Pathology
by Anna Maria Stabile, Alessandra Pistilli, Elena Moretti, Desirée Bartolini, Mariangela Ruggirello, Mario Rende, Cesare Castellini, Simona Mattioli, Rosetta Ponchia, Sergio Antonio Tripodi and Giulia Collodel
Biomedicines 2023, 11(12), 3345; https://doi.org/10.3390/biomedicines11123345 - 18 Dec 2023
Cited by 2 | Viewed by 1107
Abstract
Nerve growth factor (NGF) signalling affects spermatogenesis and mature sperm traits. In this paper, we aimed to evaluate the distribution and the role of NGF and its receptors (p75NTR and TrKA) on the reproductive apparatus (testis and epididymis) and sperm of fertile [...] Read more.
Nerve growth factor (NGF) signalling affects spermatogenesis and mature sperm traits. In this paper, we aimed to evaluate the distribution and the role of NGF and its receptors (p75NTR and TrKA) on the reproductive apparatus (testis and epididymis) and sperm of fertile men (F) and men with different pathologies, namely varicocele (V) and urogenital infections (UGIs). We collected semen samples from 21 individuals (31–40 years old) subdivided as follows: V (n = 7), UGIs (n = 7), and F (n = 7). We submitted the semen samples to bacteriological analysis, leucocyte identification, and analysis of sperm parameters (concentration, motility, morphology, and viability). We determined the seminal plasma levels of NGF, interleukin 1β (IL-1β), and F2-isoprostanes (F2-IsoPs), and the gene and protein expression of NGF receptors on sperm. We also used immunofluorescence to examine NGF receptors on ejaculated sperm, testis, and epididymis. As expected, fertile men showed better sperm parameters as well as lower levels of NGF, F2-IsoPs, and IL-1β compared with men with infertility. Notably, in normal sperm, p75NTR and TrKA were localised throughout the entire tail. TrKA was also found in the post-acrosomal sheath. This localisation appeared different in patients with infertility: in particular, there was a strong p75NTR signal in the midpiece and the cytoplasmic residue or coiled tails of altered ejaculated sperm. In line with these findings, NGF receptors were intensely expressed in the epididymis and interstitial tissue of the testis. These data suggest the distinctive involvement of NGF and its receptors in the physiology of sperm from fertile men and men with infertility, indicating a possible role for new targeted treatment strategies. Full article
(This article belongs to the Special Issue Molecular Regulation of Spermatozoa)
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14 pages, 2430 KiB  
Article
Stain-Free Sperm Analysis and Selection for Intracytoplasmic Sperm Injection Complying with WHO Strict Normal Criteria
by Yulia Michailov, Luba Nemerovsky, Yehudith Ghetler, Maya Finkelstein, Oshrat Schonberger, Amir Wiser, Arie Raziel, Bozhena Saar-Ryss, Ido Ben-Ami, Olga Kaplanski, Netanella Miller, Einat Haikin Herzberger, Yardena Mashiach Friedler, Tali Levitas-Djerbi, Eden Amsalem, Natalia Umanski, Valeria Tamadaev, Yaniv S. Ovadia, Aharon Peretz, Gilat Sacks, Nava Dekel, Odelya Zaken and Mattan Leviadd Show full author list remove Hide full author list
Biomedicines 2023, 11(10), 2614; https://doi.org/10.3390/biomedicines11102614 - 23 Sep 2023
Viewed by 1098
Abstract
This multi-center study evaluated a novel microscope system capable of quantitative phase microscopy (QPM) for label-free sperm-cell selection for intracytoplasmic sperm injection (ICSI). Seventy-three patients were enrolled in four in vitro fertilization (IVF) units, where senior embryologists were asked to select 11 apparently [...] Read more.
This multi-center study evaluated a novel microscope system capable of quantitative phase microscopy (QPM) for label-free sperm-cell selection for intracytoplasmic sperm injection (ICSI). Seventy-three patients were enrolled in four in vitro fertilization (IVF) units, where senior embryologists were asked to select 11 apparently normal and 11 overtly abnormal sperm cells, in accordance with current clinical practice, using a micromanipulator and 60× bright field microscopy. Following sperm selection and imaging via QPM, the individual sperm cell was chemically stained per World Health Organization (WHO) 2021 protocols and imaged via bright field microscopy for subsequent manual measurements by embryologists who were blinded to the QPM measurements. A comparison of the two modalities resulted in mean differences of 0.18 µm (CI −0.442–0.808 µm, 95%, STD—0.32 µm) for head length, −0.26 µm (CI −0.86–0.33 µm, 95%, STD—0.29 µm) for head width, 0.17 (CI −0.12–0.478, 95%, STD—0.15) for length–width ratio and 5.7 for acrosome–head area ratio (CI −12.81–24.33, 95%, STD—9.6). The repeatability of the measurements was significantly higher in the QPM modality. Surprisingly, only 19% of the subjectively pre-selected normal cells were found to be normal according to the WHO2021 criteria. The measurements of cells imaged stain-free through QPM were found to be in good agreement with the measurements performed on the reference method of stained cells imaged through bright field microscopy. QPM is non-toxic and non-invasive and can improve the clinical effectiveness of ICSI by choosing sperm cells that meet the strict criteria of the WHO2021. Full article
(This article belongs to the Special Issue Molecular Regulation of Spermatozoa)
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12 pages, 1843 KiB  
Systematic Review
Does Sperm SNRPN Methylation Change with Fertility Status and Age? A Systematic Review and Meta-Regression Analysis
by Claudia Leanza, Rossella Cannarella, Federica Barbagallo, Carmelo Gusmano and Aldo E. Calogero
Biomedicines 2024, 12(2), 445; https://doi.org/10.3390/biomedicines12020445 - 16 Feb 2024
Viewed by 1302
Abstract
Background: The Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) gene is a paternally expressed imprinted gene, whose abnormal methylation appears to be associated with syndromes associated with the use of assisted reproductive techniques (ART), such as Angelman and Prader–Willi. Data present in [...] Read more.
Background: The Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) gene is a paternally expressed imprinted gene, whose abnormal methylation appears to be associated with syndromes associated with the use of assisted reproductive techniques (ART), such as Angelman and Prader–Willi. Data present in the literature suggest the association between aberrant sperm SNRPN gene methylation and abnormal sperm parameters. The latest meta-analysis on the methylation pattern of this gene in spermatozoa of infertile patients published in 2017 reported a higher degree of methylation in the spermatozoa of infertile patients compared to fertile controls. Objectives: Here we provide an updated and comprehensive systematic review and meta-analysis of the sperm methylation pattern of the SNRPN gene in patients with abnormal sperm parameters/infertility compared to men with normal sperm parameters/fertile. For the first time in the literature, we performed a meta-regression analysis to evaluate whether age or sperm concentration could influence the methylation status of this gene at the sperm level. Methods: This meta-analysis was registered in PROSPERO (n. CRD42023397056). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) and the MOOSE guidelines for meta-analyses and systematic reviews of observational studies were strictly followed in our meta-analysis. According to our Population Exposure Comparison Outcome (PECO) question, we included data from original articles assessing the levels of SNRPN gene methylation at the sperm level in infertile patients or patients with abnormalities in one or more sperm parameters compared to fertile or normozoospermic men. Results: Only six of 354 screened studies were included in the quantitative synthesis. Our analysis showed significantly higher levels of SNRPN gene methylation in patients compared to controls. However, significant heterogeneity was found between studies. In sensitivity analysis, no studies were sensitive enough to skew the results. The Egger test showed no publication bias. In the meta-regression analysis, the results were independent of age and sperm concentration in the overall population. The same results were found in the control group. However, when analyzing the patient group, a direct correlation was found between SNRPN methylation and age, indicating that the degree of methylation of the SNRPN gene increases with advancing age. Conclusions: Fertility status or abnormality of sperm parameters is associated with a change in the methylation pattern of the SNRPN gene, with higher levels found in infertile patients or those with abnormal sperm parameters compared to fertile men or men with normal sperm parameters. In the group of infertile patients/patients with abnormal sperm parameters, age was directly correlated to the degree of SNRPN methylation, highlighting the presence of a mechanism that explains the age-related altered sperm quality and the risk of ART. Despite some limitations present in the analyzed studies, our results support the inclusion of SNRPN methylation in the genetic panel of prospective studies aimed at identifying the most representative and cost-effective genes to analyze in couples who want to undergo ART. Full article
(This article belongs to the Special Issue Molecular Regulation of Spermatozoa)
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14 pages, 2726 KiB  
Study Protocol
Sperm Mitochondrial Content and Mitochondrial DNA to Nuclear DNA Ratio Are Associated with Body Mass Index and Progressive Motility
by Efthalia Moustakli, Athanasios Zikopoulos, Charikleia Skentou, Ioanna Bouba, Georgia Tsirka, Sofoklis Stavros, Dionysios Vrachnis, Nikolaos Vrachnis, Anastasios Potiris, Ioannis Georgiou and Athanasios Zachariou
Biomedicines 2023, 11(11), 3014; https://doi.org/10.3390/biomedicines11113014 - 9 Nov 2023
Cited by 4 | Viewed by 1582
Abstract
Background: Mitochondrial dysfunction is a risk factor in the pathogenesis of metabolic disorders. According to the energy requirements, oxidative phosphorylation and the electron transport chain work together to produce ATP in sufficient quantities in the mitochondria of eukaryotic cells. Abnormal mitochondrial activity causes [...] Read more.
Background: Mitochondrial dysfunction is a risk factor in the pathogenesis of metabolic disorders. According to the energy requirements, oxidative phosphorylation and the electron transport chain work together to produce ATP in sufficient quantities in the mitochondria of eukaryotic cells. Abnormal mitochondrial activity causes fat accumulation and insulin resistance as cells require a balance between the production of ATP by oxidative phosphorylation (OXPHOS) in the mitochondria and the dissipation of the proton gradient to reduce damage from reactive oxygen species (ROS). This study aims to explore the relationship between the mitochondrial content of sperm and the ratio of mitochondrial DNA to nuclear DNA in relation to body mass index (BMI) and how it may affect the progressive motility of sperm cell. Understanding the relationships between these important variables will help us better understand the possible mechanisms that could connect sperm motility and quality to BMI, as well as further our understanding of male fertility and reproductive health. Methods: Data were collected from 100 men who underwent IVF/ICSI at the University Hospital of Ioannina’s IVF Unit in the Obstetrics and Gynecology Department. The body mass index (BMI) of the males tested was used to classify them as normal weight; overweight; and obese. Evaluations included sperm morphology; sperm count; sperm motility; and participant history. Results: In the group of men with normal BMI, both BMI and progressive motility displayed a statistically significant association (p < 0.05) with mitochondrial DNA content, relative mitochondrial DNA copy number, and the mtDNA/nDNA ratio. Similar to this, there was a positive association between BMI and motility in the groups of men who were overweight and obese, as well as between the expression of mitochondrial DNA and the mtDNA/nDNA ratio, with statistically significant differences (p < 0.05). There was not a statistically significant difference observed in the association between the relative mtDNA copy number and BMI or motility for the overweight group. Finally, the relative mtDNA copy number in the obese group was only associated with motility (p = 0.034) and not with BMI (p = 0.24). Conclusions: We found that in all three groups, BMI and progressive motility exhibited comparable relationships with mitochondrial DNA expression and the mtDNA/nDNA ratio. However, only in the normal group and in the obese group, the relative mitochondrial DNA copy number showed a positive association with BMI and progressive motility. Full article
(This article belongs to the Special Issue Molecular Regulation of Spermatozoa)
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