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Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 29345

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Dr. Manuel Álvarez-Rodríguez

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Department of Animal Health and Anatomy, Veterinary Faculty, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
Interests: animal reproduction and related biotechnologies; -omics in gametes and reproductive tissues; cryopreservation and in vitro procedures
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Dr. Jaime Catalan

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Department of Medicine and Animal Surgery, Autonomous University of Barcelona, Barcelona, Spain
Interests: equids reproduction; reproductive biology; cryopreservation, semen evaluation, semen preservation; sperm fertility; sperm biology, oxidative stress, seminal plasma
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Dear Colleagues,

The complex process of sperm development and maturation involves multiple interconnected steps that begin in the testis and result in fertility acquisition inside the male genital tract as well as the female genital tract. The sperm then has to cope with the active immune system and particular homeostasis of the tract. A special segment, the sperm reservoir, stores the sperm cells until they released and move towards the fertilization site.

This Special Issue aims to cover crucial molecular events and mechanisms in sperm development. The scope includes research on sperm cell physiology as well as on components in the seminal plasma and/or in the female allowing the realization of full fertilization of sperm, including extracellular vesicles. Thus, in vitro and in vitro studies aiming at unraveling new molecular determinants of the acquisition of full functionality in sperm are welcome.

Dr. Manuel Álvarez-Rodríguez
Dr. Jaime Catalan
Guest Editors

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Keywords

sperm physiology
seminal plasma
extracellular vesicles
reproduction
spermatogenesis
capacitation
fertility

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Related Special Issue

Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization 2.0 in International Journal of Molecular Sciences (12 articles)

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Research

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14 pages, 1979 KiB

Open AccessArticle

Characterization of Seminal Microbiome of Infertile Idiopathic Patients Using Third-Generation Sequencing Platform

by Sergio Garcia-Segura, Javier del Rey, Laia Closa, Iris Garcia-Martínez, Carlos Hobeich, Ana Belén Castel, Francisco Vidal, Jordi Benet and Maria Oliver-Bonet

Int. J. Mol. Sci. 2023, 24(9), 7867; https://doi.org/10.3390/ijms24097867 - 26 Apr 2023

Cited by 5 | Viewed by 2327

Abstract

Since the first description of a commensal seminal microbiome using sequencing, less than a decade ago, interest in the composition of this microbiome and its relationship with fertility has been growing. Articles using next-generation sequencing techniques agree on the identification of the most abundant bacterial phyla. However, at the genus level, there is still no consensus on which bacteria are most abundant in human seminal plasma. This discrepancy may be due to methodological variability such as sample collection, bacterial DNA extraction methodology, which hypervariable regions of 16S rRNA gene have been amplified, or bioinformatic analysis. In the present work, seminal microbiota of 14 control samples and 42 samples of idiopathic infertile patients were characterized based on full-length sequencing of the 16S rRNA gene using MinION platform from Oxford Nanopore. These same samples had been analyzed previously using Illumina’s MiSeq sequencing platform. Comparison between the results obtained with the two platforms has been used to analyze the impact of sequencing method on the study of the seminal microbiome’s composition. Seminal microbiota observed with MinION were mainly composed of the phyla Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria, with the most abundant genera being Peptoniphilus, Finegoldia, Staphylococcus, Anaerococcus, Campylobacter, Prevotella, Streptococcus, Lactobacillus, Ezakiella and Enterococcus. This composition was similar to that found by the Illumina platform, since these 10 most abundant genera were also among the most abundant genera detected by the Nanopore platform. In both cases, the top 10 genera represented more than 70% of the classified reads. However, relative abundance of each bacterium did not correlate between these two platforms, with intraindividual variations of up to 50 percentage points in some cases. Results suggest that the effect of the sequencing platform on the characterization of seminal microbiota is not very large at the phylum level, with slightly variances in Firmicutes and Actinobacteria, but presents differences at the genus level. These differences could alter the composition and diversity of bacterial profiles or posterior analyses. This indicates the importance of conducting multi-platform studies to better characterize seminal microbioma. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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17 pages, 4213 KiB

Open AccessArticle

The Mature COC Promotes the Ampullary NPPC Required for Sperm Release from Porcine Oviduct Cells

by Zhanying Wu, Biao Li, Kaiwei Yu, Nana Zheng, Feifei Yuan, Jingjing Miao, Meijia Zhang and Zhijuan Wang

Int. J. Mol. Sci. 2023, 24(4), 3118; https://doi.org/10.3390/ijms24043118 - 4 Feb 2023

Cited by 1 | Viewed by 1861

Abstract

Porcine spermatozoa are stored in the oviductal isthmus after natural mating, and the number of spermatozoa is increased in the oviductal ampulla when the mature cumulus-oocyte complexes (COCs) are transferred into the ampulla. However, the mechanism is unclear. Herein, natriuretic peptide type C (NPPC) was mainly expressed in porcine ampullary epithelial cells, whereas its cognate receptor natriuretic peptide receptor 2 (NPR2) was located on the neck and the midpiece of porcine spermatozoa. NPPC increased sperm motility and intracellular Ca²⁺ levels, and induced sperm release from oviduct isthmic cell aggregates. These actions of NPPC were blocked by the cyclic guanosine monophosphate (cGMP)-sensitive cyclic nucleotide-gated (CNG) channel inhibitor l-cis-Diltiazem. Moreover, porcine COCs acquired the ability to promote NPPC expression in the ampullary epithelial cells when the immature COCs were induced to maturation by epidermal growth factor (EGF). Simultaneously, transforming growth factor-β ligand 1 (TGFB1) levels were dramatically increased in the cumulus cells of the mature COCs. The addition of TGFB1 promoted NPPC expression in the ampullary epithelial cells, and the mature COC-induced NPPC was blocked by the transforming growth factor-β type 1 receptor (TGFBR1) inhibitor SD208. Taken together, the mature COCs promote NPPC expression in the ampullae via TGF-β signaling, and NPPC is required for the release of porcine spermatozoa from the oviduct isthmic cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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14 pages, 303 KiB

Open AccessArticle

Sperm Chromatin Condensation Defect Accelerates the Kinetics of Early Embryonic Development but Does Not Modify ICSI Outcome

by Fanny Jumeau, Nathalie Rives, Pauline Lechevallier, Coline Boniou, Maria Letailleur, Audrey Réal-Lhommet and Aurélie Feraille

Int. J. Mol. Sci. 2023, 24(1), 393; https://doi.org/10.3390/ijms24010393 - 26 Dec 2022

Cited by 5 | Viewed by 1944

Abstract

The origin and quality of gametes are likely to influence the kinetics of embryonic development. The purpose of the study was to assess the impact of sperm nuclear quality, and in particular sperm chromatin condensation, on the kinetics of early embryo development after intracytoplasmic sperm injection (ICSI). Our study included 157 couples who benefitted from ICSI for male factor infertility. Chromatin condensation and DNA fragmentation were assessed in spermatozoa prior to ICSI. Above the 20% threshold of sperm condensation defect, patients were included in the abnormal sperm chromatin condensation (ASCC) group; below the 20% threshold, patients were included in the normal sperm chromatin condensation (NSCC) group. After ICSI, the oocytes were placed in the time-lapse incubator. The kinetics of the cohort’s embryonic development have been modeled. The fading times of pronuclei and the time to two blastomeres (t2, first cleavage) and four blastomeres (t4, third cleavage) differed significantly between the NSCC and ASCC groups, with earlier events occurring in the ASCC group. On the other hand, the state of sperm chromatin condensation did not seem to have an impact on live birth rates or the occurrence of miscarriages. The kinetics of early embryonic development was accelerated in males with a sperm chromatin condensation defect without compromising the chances of pregnancy or promoting miscarriage. However, our study highlights the paternal contribution to early embryonic events and potentially to the future health of the conceptus. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

13 pages, 2208 KiB

Open AccessArticle

Dynamic Change of R-Loop Implicates in the Regulation of Zygotic Genome Activation in Mouse

by Hyeonji Lee, Seong-Yeob You, Dong Wook Han, Hyeonwoo La, Chanhyeok Park, Seonho Yoo, Kiye Kang, Min-Hee Kang, Youngsok Choi and Kwonho Hong

Int. J. Mol. Sci. 2022, 23(22), 14345; https://doi.org/10.3390/ijms232214345 - 18 Nov 2022

Cited by 2 | Viewed by 2518

Abstract

In mice, zygotic genome activation (ZGA) occurs in two steps: minor ZGA at the one–cell stage and major ZGA at the two–cell stage. Regarding the regulation of gene transcription, minor ZGA is known to have unique features, including a transcriptionally permissive state of chromatin and insufficient splicing processes. The molecular characteristics may originate from extremely open chromatin states in the one–cell stage zygotes, yet the precise underlying mechanism has not been well studied. Recently, the R-loop, a triple–stranded nucleic acid structure of the DNA/RNA hybrid, has been implicated in gene transcription and DNA replication. Therefore, in the present study, we examined the changes in R-loop dynamics during mouse zygotic development, and its roles in zygotic transcription or DNA replication. Our analysis revealed that R-loops persist in the genome of metaphase II oocytes and preimplantation embryos from the zygote to the blastocyst stage. In particular, zygotic R-loop levels dynamically change as development proceeds, showing that R-loop levels decrease as pronucleus maturation occurs. Mechanistically, R-loop dynamics are likely linked to ZGA, as inhibition of either DNA replication or transcription at the time of minor ZGA decreases R-loop levels in the pronuclei of zygotes. However, the induction of DNA damage by treatment with anticancer agents, including cisplatin or doxorubicin, does not elicit genome-wide changes in zygotic R-loop levels. Therefore, our study suggests that R-loop formation is mechanistically associated with the regulation of mouse ZGA, especially minor ZGA, by modulating gene transcription and DNA replication. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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12 pages, 2001 KiB

Open AccessArticle

Fertilization, but Not Post-Implantation Development, Can Occur in the Absence of Sperm and Oocyte Beta1 Integrin in Mice

by Nour El Houda Mimouni, Côme Ialy-Radio, Anne-Lyse Denizot, Isabelle Lagoutte, Michaela Frolikova, Katerina Komrskova, Sandrine Barbaux and Ahmed Ziyyat

Int. J. Mol. Sci. 2022, 23(22), 13812; https://doi.org/10.3390/ijms232213812 - 9 Nov 2022

Cited by 1 | Viewed by 2146

Abstract

Fertilization is a complex process that requires successive stages and culminates in the adhesion/fusion of gamete membranes. If the question of the involvement of oocyte integrins has been swept away by deletion experiments, that of the involvement of sperm integrins remains to be further characterized. In the present study, we addressed the question of the feasibility of sperm–oocyte adhesion/fusion and early implantation in the absence of sperm β1 integrin. Males and females with β1 integrin-depleted sperm and oocytes were mated, and fertilization outcome was monitored by a gestational ultrasound analysis. Results suggest that although the sperm β1 integrin participates in gamete adhesion/fusion, it is dispensable for fertilization in mice. However, sperm- and/or oocyte-originated integrin β1 is essential for post-implantation development. Redundancy phenomena could be at the origin of a compensatory expression or alternative dimerization pattern. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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14 pages, 1954 KiB

Open AccessArticle

Effects of Age and Lifelong Moderate-Intensity Exercise Training on Rats’ Testicular Function

by Joana V. Silva, Joana Santiago, Bárbara Matos, Magda C. Henriques, Daniela Patrício, Ana D. Martins, José A. Duarte, Rita Ferreira, Marco G. Alves, Paula Oliveira, Pedro F. Oliveira and Margarida Fardilha

Int. J. Mol. Sci. 2022, 23(19), 11619; https://doi.org/10.3390/ijms231911619 - 1 Oct 2022

Cited by 5 | Viewed by 3745

Abstract

Aging is associated with testicular morphological and functional alterations, but the underlying molecular mechanisms and the impact of physical exercise are poorly understood. In this study, we examined the effects of age and lifelong moderate-intensity exercise on rat testis. Mature adults (35 weeks) and middle-aged (61 weeks) Wistar Unilever male rats were maintained as sedentary or subjected to a lifelong moderate-intensity treadmill training protocol. Testis weight and histology, mitochondrial biogenesis and function, and proteins involved in protein synthesis and stress response were evaluated. Our results illustrate an age-induced testicular atrophy that was associated with alterations in stress response, and mitochondrial biogenesis and function. Aging was associated with increased testicular levels of heat shock protein beta-1 (HSP27) and antioxidant enzymes. Aging was also associated with decreased mRNA abundance of the nuclear respiratory factor 1 (Nrf1), a key transcription factor for mitochondrial biogenesis, which was accompanied by decreased protein levels of the oxidative phosphorylation system (OXPHOS) complexes subunits in the testes of older animals. On the other hand, exercise did not protect against age-induced testicular atrophy and led to deleterious effects on sperm morphology. Exercise led to an even more pronounced decrease in the Nrf1 mRNA levels in testes of both age groups and was associated with decreased mRNA abundance of other mitochondrial biogenesis markers and decreased protein levels of OXPHOS complexes subunits. Lifelong moderate-intensity exercise training was also associated with an increase in testicular oxidative stress markers and possibly with reduced translation. Together, our results indicate that exercise did not protect against age-induced testicular atrophy and was not associated with beneficial changes in mitochondria and stress response, further activating mechanisms of protein synthesis inhibition. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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Review

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14 pages, 1803 KiB

Open AccessReview

H19 Sperm Methylation in Male Infertility: A Systematic Review and Meta-Analysis

by Rossella Cannarella, Andrea Crafa, Federica Barbagallo, Scott D. Lundy, Sandro La Vignera, Rosita A. Condorelli and Aldo E. Calogero

Int. J. Mol. Sci. 2023, 24(8), 7224; https://doi.org/10.3390/ijms24087224 - 13 Apr 2023

Cited by 11 | Viewed by 2445

Abstract

This systematic review and meta-analysis summarize the difference in the methylation of the H19 gene in patients with abnormal versus normal conventional sperm parameters. It also evaluates the effects of age and sperm concentration on H19 methylation in spermatozoa using meta-regression analysis. It was performed according to the MOOSE guidelines for meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The quality of the evidence reported in the studies included was assessed using the Cambridge Quality Checklists. A total of 11 articles met our inclusion criteria. Quantitative analysis showed that H19 methylation levels were significantly lower in the group of infertile patients than in fertile controls. The reduction in methylation was much more pronounced in patients with oligozoospermia (alone or associated with other sperm parameter abnormalities) and in those with recurrent pregnancy loss. Meta-regression analysis showed the results to be independent of both patient age and sperm concentration. Therefore, the H19 methylation pattern should be evaluated among couples accessing assisted reproductive techniques (ART), in order to gain prognostic information on ART outcome and offspring health. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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18 pages, 1049 KiB

Open AccessReview

PP1, PP2A and PP2B Interplay in the Regulation of Sperm Motility: Lessons from Protein Phosphatase Inhibitors

by Ana F. Ferreira, Joana Santiago, Joana V. Silva, Pedro F. Oliveira and Margarida Fardilha

Int. J. Mol. Sci. 2022, 23(23), 15235; https://doi.org/10.3390/ijms232315235 - 3 Dec 2022

Cited by 6 | Viewed by 3407

Abstract

Male fertility relies on the ability of spermatozoa to fertilize the egg in the female reproductive tract (FRT). Spermatozoa acquire activated motility during epididymal maturation; however, to be capable of fertilization, they must achieve hyperactivated motility in the FRT. Extensive research found that three protein phosphatases (PPs) are crucial to sperm motility regulation, the sperm-specific protein phosphatase type 1 (PP1) isoform gamma 2 (PP1γ2), protein phosphatase type 2A (PP2A) and protein phosphatase type 2B (PP2B). Studies have reported that PP activity decreases during epididymal maturation, whereas protein kinase activity increases, which appears to be a requirement for motility acquisition. An interplay between these PPs has been extensively investigated; however, many specific interactions and some inconsistencies remain to be elucidated. The study of PPs significantly advanced following the identification of naturally occurring toxins, including calyculin A, okadaic acid, cyclosporin, endothall and deltamethrin, which are powerful and specific PP inhibitors. This review aims to overview the protein phosphorylation-dependent biochemical pathways underlying sperm motility acquisition and hyperactivation, followed by a discussion of the PP inhibitors that allowed advances in the current knowledge of these pathways. Since male infertility cases still attain alarming numbers, additional research on the topic is required, particularly using other PP inhibitors. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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32 pages, 2138 KiB

Open AccessReview

Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers

by Olatunbosun Arowolo, J. Richard Pilsner, Oleg Sergeyev and Alexander Suvorov

Int. J. Mol. Sci. 2022, 23(22), 14229; https://doi.org/10.3390/ijms232214229 - 17 Nov 2022

Cited by 16 | Viewed by 3641

Abstract

Polybrominated diphenyl ethers (PBDE) are a group of flame retardants used in a variety of artificial materials. Despite being phased out in most industrial countries, they remain in the environment and human tissues due to their persistence, lipophilicity, and bioaccumulation. Populational and experimental studies demonstrate the male reproductive toxicity of PBDEs including increased incidence of genital malformations (hypospadias and cryptorchidism), altered weight of testes and other reproductive tissues, altered testes histology and transcriptome, decreased sperm production and sperm quality, altered epigenetic regulation of developmental genes in spermatozoa, and altered secretion of reproductive hormones. A broad range of mechanistic hypotheses of PBDE reproductive toxicity has been suggested. Among these hypotheses, oxidative stress, the disruption of estrogenic signaling, and mitochondria disruption are affected by PBDE concentrations much higher than concentrations found in human tissues, making them unlikely links between exposures and adverse reproductive outcomes in the general population. Robust evidence suggests that at environmentally relevant doses, PBDEs and their metabolites may affect male reproductive health via mechanisms including AR antagonism and the disruption of a complex network of metabolic signaling. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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Other

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8 pages, 916 KiB

Open AccessOpinion

Cyclic Adenosine Monophosphate: A Central Player in Gamete Development and Fertilization, and Possible Target for Infertility Therapies

by Jan Tesarik and Raquel Mendoza-Tesarik

Int. J. Mol. Sci. 2022, 23(23), 15068; https://doi.org/10.3390/ijms232315068 - 1 Dec 2022

Cited by 4 | Viewed by 3783

Abstract

Human infertility, of both male and female origin, is often caused by the deficient response of the testis and the ovary to hormonal stimuli that govern sperm and oocyte development and fertilization. The effects of hormones and other extracellular ligands involved in these events are often mediated by G-protein-coupled receptors that employ cyclic adenosine monophosphate (cAMP) as the principal second messenger transducing the receptor-generated signal to downstream elements. This opinion article summarizes the actions of cAMP in sperm and oocyte development and fertilization, leading to therapeutic actions targeting cAMP metabolism to alleviate human male and female infertility. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization)

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