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International Journal of Molecular... Oct 2020Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn in spermatozoa,... (Review)
Review
Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn in spermatozoa, focusing on its involvement in sperm motility, capacitation and acrosomal exocytosis, three functions that are crucial for successful fertilization. The impact of zinc supplementation on assisted fertilization techniques is also described. The impact of zinc on sperm motility has been investigated in many vertebrate and invertebrate species. It has been reported that Zn in human seminal plasma decreases sperm motility and that Zn removal enhances motility. Reduction in the intracellular concentration of Zn during epididymal transit allows the development of progressive motility and the subsequent hyper activated motility during sperm capacitation. Extracellular Zn affects intracellular signaling pathways through its interaction with the Zn sensing receptor (ZnR), also named GPR39. This receptor was found in the sperm tail and the acrosome, suggesting the possible involvement of Zn in sperm motility and acrosomal exocytosis. Our studies showed that Zn stimulates bovine sperm acrosomal exocytosis, as well as human sperm hyper-activated motility, were both mediated by GPR39. Zn binds and activates GPR39, which activates the trans-membrane-adenylyl-cyclase (tmAC) to catalyze cAMP production. The NHE (Na/H-exchanger) is activated by cAMP, leading in increased pHi and activation of the sperm-specific Ca channel CatSper, resulting in an increase in [Ca], which, together with HCO, activates the soluble adenylyl-cyclase (sAC). The increase in [cAMP] activates protein kinase A (PKA), followed by activation of the Src-epidermal growth factor receptor-Pphospholipase C (Src-EGFR-PLC) cascade, resulting in inositol-triphosphate (IP) production, which mobilizes Ca from the acrosome, causing a further increase in [Ca] and the development of hyper-activated motility. PKA also activates phospholipase D1 (PLD1), leading to F-actin formation during capacitation. Prior to the acrosomal exocytosis, PLC induces phosphadidylinositol-4,5-bisphosphate (PIP) hydrolysis, leading to the release of the actin-severing protein gelsolin to the cytosol, which is activated by Ca, resulting in F-actin breakdown and the occurrence of acrosomal exocytosis.
Topics: Acrosome; Animals; Fertility; Humans; Male; Reproductive Techniques, Assisted; Sperm Capacitation; Sperm Motility; Spermatozoa; Zinc
PubMed: 33096823
DOI: 10.3390/ijms21207796 -
Advances in Anatomy, Embryology, and... 2016The acrosome, a single exocytotic vesicle on the head of sperm, has an essential role in fertilization, but the exact mechanisms by which it facilitates sperm-egg... (Review)
Review
The acrosome, a single exocytotic vesicle on the head of sperm, has an essential role in fertilization, but the exact mechanisms by which it facilitates sperm-egg interactions remain unresolved. The acrosome contains dozens of secretory proteins that are packaged into the forming structure during spermatogenesis; many of these proteins are localized into specific topographical areas of the acrosome, while others are more diffusely distributed. Acrosomal proteins can also be biochemically classified as components of the acrosomal matrix, a large, relatively insoluble complex, or as soluble proteins. This review focuses on recent findings using genetically modified mice (gene knockouts and transgenic "green acrosome" mice) to study the effects of eliminating acrosomal matrix-associated proteins on sperm structure and function. Some gene knockouts produce infertile phenotypes with obviously missing, specific activities that affect acrosome biogenesis during spermatogenesis or interfere with acrosome function in mature sperm. Mutations that delete some components produce fertile phenotypes with subtler effects that provide useful insights into acrosomal matrix function in fertilization. In general, these studies enable the reassessment of paradigms to explain acrosome formation and function and provide novel, objective insights into the roles of acrosomal matrix proteins in fertilization. The use of genetically engineered mouse models has yielded new mechanistic information that complements recent, important in vivo imaging studies.
Topics: Acrosome; Animals; Female; Fertilization; Gene Expression Regulation; Gene Knockout Techniques; Infertility, Male; Male; Membrane Fusion; Membrane Proteins; Mice; Mice, Transgenic; Mutation; Ovum; Peptide Hydrolases; Sperm Maturation
PubMed: 27194348
DOI: 10.1007/978-3-319-30567-7_2 -
Frontiers in Cell and Developmental... 2019During sexual reproduction, two haploid gametes fuse to form the zygote, and the acrosome is essential to this fusion process (fertilization) in animals. The acrosome is... (Review)
Review
During sexual reproduction, two haploid gametes fuse to form the zygote, and the acrosome is essential to this fusion process (fertilization) in animals. The acrosome is a special kind of organelle with a cap-like structure that covers the anterior portion of the head of the spermatozoon. The acrosome is derived from the Golgi apparatus and contains digestive enzymes. With the progress of our understanding of acrosome biogenesis, a number of models have been proposed to address the origin of the acrosome. The acrosome has been regarded as a lysosome-related organelle, and it has been proposed to have originated from the lysosome or the autolysosome. Our review will provide a brief historical overview and highlight recent findings on acrosome biogenesis in mammals.
PubMed: 31620437
DOI: 10.3389/fcell.2019.00195 -
Autophagy Jul 2021Spermiogenesis is the longest phase of spermatogenesis, with dramatic morphological changes and a final step of spermiation, which involves protein degradation and the...
Spermiogenesis is the longest phase of spermatogenesis, with dramatic morphological changes and a final step of spermiation, which involves protein degradation and the removal of excess cytoplasm; therefore, we hypothesized that macroautophagy/autophagy might be involved in the process. To test this hypothesis, we examined the function of ATG5, a core autophagy protein in male germ cell development. Floxed and mice were crossed to conditionally inactivate in male germ cells. In mutant mice, testicular expression of the autophagosome marker LC3A/B-II was significantly reduced, and expression of autophagy receptor SQSTM1/p62 was significantly increased, indicating a decrease in testicular autophagy activity. The fertility of mutant mice was dramatically reduced with about 70% being infertile. Sperm counts and motility were also significantly reduced compared to controls. Histological examination of the mutant testes revealed numerous, large residual bodies in the lumen of stages after their normal resorption within the seminiferous epithelium. The cauda epididymal lumen was filled with sloughed germ cells, large cytoplasmic bodies, and spermatozoa with disorganized heads and tails. Examination of cauda epididymal sperm by electron microscopy revealed misshapen sperm heads, a discontinuous accessory structure in the mid-piece and abnormal acrosome formation and loss of sperm individualization. Immunofluorescence staining of epididymal sperm showed abnormal mitochondria and acrosome distribution in the mutant mice. ATG5 was shown to induce autophagy by mediating multiple signals to maintain normal developmental processes. Our study demonstrated ATG5 is essential for male fertility and is involved in various aspects of spermiogenesis.: AKAP4: a-kinase anchoring protein 4; ATG5: autophagy-related 5; ATG7: autophagy-related 7; ATG10: autophagy-related 10; ATG12: autophagy-related 12; cKO: conditional knockout; DDX4: DEAD-box helicase 4; MAP1LC3/LC3/tg8: microtubule-associated protein 1 light chain 3; PBS: phosphate-buffered saline; PIWIL2/MILI: piwi like RNA-mediated gene silencing 2; RT-PCR: reverse transcription-polymerase chain reaction; SQSTM1/p62: sequestosome 1; TBC: tubulobulbar complexes; WT: wild type.
Topics: Acrosome; Animals; Autophagy; Autophagy-Related Protein 5; Blotting, Western; Epididymis; Fertility; Fluorescent Antibody Technique; Male; Mice; Mice, Knockout; Real-Time Polymerase Chain Reaction; Sperm Count; Spermatids; Spermatogenesis; Spermatozoa; Testis
PubMed: 32677505
DOI: 10.1080/15548627.2020.1783822 -
In Vivo (Athens, Greece) 2022The process of fertilization includes sperm capacitation, hyperactivation, an acrosome reaction and the release of acrosome enzymes, membrane fusion and channel... (Review)
Review
The process of fertilization includes sperm capacitation, hyperactivation, an acrosome reaction and the release of acrosome enzymes, membrane fusion and channel formation, the release of the sperm nucleus, and gamete fusion. This process is closely related to the shape and vitality of the sperm, acrosome enzyme release, and the zona pellucida structure of the egg, as well as the opening and closing of various ion (e.g., calcium) channels, the regulation of signaling pathways such as cyclic adenosine monophosphate-protein kinase A, the release of progesterone, and the coupling of G-proteins. The interaction among multiple factors and their precise regulation give rise to multiple cascading regulatory processes. Problems with any factor will affect the success rate of fertilization. Recent studies have shown that with rapid societal development, the incidence of male infertility is increasing and occurs at younger ages. According to World Health Organization statistics, 15% of couples of childbearing ages have infertility problems, of which 50% are caused by male factors. Additionally, the cause of infertility cannot be identified in as many as 60% to 75% of male infertility patients. In this article, we review the research progress on the microregulation of fertilization and mechanisms underlying this process to identify causes and develop novel prevention and treatment strategies for male infertility.
Topics: Acrosome Reaction; Humans; Infertility, Male; Male; Semen; Sperm Capacitation; Spermatozoa
PubMed: 36099087
DOI: 10.21873/invivo.12926 -
Journal of Human Reproductive Sciences 2015With absolute normal semen analysis parameters it may not be necessary to shift to specialized tests early but in cases with borderline parameters or with history of... (Review)
Review
With absolute normal semen analysis parameters it may not be necessary to shift to specialized tests early but in cases with borderline parameters or with history of fertilization failure in past it becomes necessary to do a battery of tests to evaluate different parameters of spermatozoa. Various sperm function tests are proposed and endorsed by different researchers in addition to the routine evaluation of fertility. These tests detect function of a certain part of spermatozoon and give insight on the events in fertilization of the oocyte. The sperms need to get nutrition from the seminal plasma in the form of fructose and citrate (this can be assessed by fructose qualitative and quantitative estimation, citrate estimation). They should be protected from the bad effects of pus cells and reactive oxygen species (ROS) (leukocyte detection test, ROS estimation). Their number should be in sufficient in terms of (count), structure normal to be able to fertilize eggs (semen morphology). Sperms should have intact and functioning membrane to survive harsh environment of vagina and uterine fluids (vitality and hypo-osmotic swelling test), should have good mitochondrial function to be able to provide energy (mitochondrial activity index test). They should also have satisfactory acrosome function to be able to burrow a hole in zona pellucida (acrosome intactness test, zona penetration test). Finally, they should have properly packed DNA in the nucleus to be able to transfer the male genes (nuclear chromatic decondensation test) to the oocyte during fertilization.
PubMed: 26157295
DOI: 10.4103/0974-1208.158588 -
Andrology Mar 2018To study apoptosis as a functional pathway in mature spermatozoa and apoptosis correlated to the acrosome reaction via the intracellular calcium concentration, semen...
To study apoptosis as a functional pathway in mature spermatozoa and apoptosis correlated to the acrosome reaction via the intracellular calcium concentration, semen samples from 27 healthy human donors were treated with inducers of apoptosis (betulinic acid, thapsigargin), inducers of the acrosome reaction (thapsigargin, calcium ionophore) or hydrogen peroxide to produce reactive oxygen species with and without prior incubation with a calcium chelator. Computer-assisted sperm analysis, flow cytometry, and transmission electron microscopy were performed to analyze changes in the acrosomal status and in apoptotic features. Betulinic acid, thapsigargin, and the calcium ionophore treatment resulted in an increased number of sperm cells with caspase 9 and caspase 3 activation, disrupted mitochondrial membrane potential, and a reacted acrosome. Sperm motility was decreased in all cases. Transmission electron analyses showed ultra-morphological changes, such as membrane integrity, membrane blebbing, the formation of head vacuoles, defects of the nuclear envelope, nuclear fragmentation, and the acrosome reaction. Acrosome reaction and apoptotic features decreased due to the reduction in intracellular calcium by the calcium chelator NP-EGTA, AM. Therefore, apoptotic cell death in acrosome-reacted sperm cells mediated by high intracellular calcium levels is possible.
Topics: Acrosome Reaction; Apoptosis; Calcium; Flow Cytometry; Humans; Male; Membrane Potential, Mitochondrial; Oxidative Stress; Pentacyclic Triterpenes; Sperm Motility; Spermatozoa; Thapsigargin; Triterpenes; Betulinic Acid
PubMed: 29438593
DOI: 10.1111/andr.12467 -
Environment International May 2022As a new widespread contaminant, nanoplastics (NPs) pose a potential risk to human health. Nevertheless, the adverse effects of NPs on the male reproductive system are...
As a new widespread contaminant, nanoplastics (NPs) pose a potential risk to human health. Nevertheless, the adverse effects of NPs on the male reproductive system are poorly understood. In this study, we aimed to determine the effects of polystyrene nanoplastics (PS-NPs) (50 nm) on sperm quality, with a focus on the acrosome defects. After 35 days of intragastric administration, sperm quality was decreased and testicular structures were impaired in mice exposed to PS-NPs in both the medium (1.0 mg/kg) and high dose (10 mg/kg) groups. No significant changes were observed in the low dose (0.2 mg/kg) group. Meanwhile, acrosome parameters including acrosome integrity and acrosome reaction were decreased after the administration of PS-NPs. These findings were consistent with the disruption of acrosome biogenesis, as identified by the changed testicular ultrastructure. Additionally, the findings were further validated using seven marker genes (Gba2, Pick1, Gopc, Hrb, Zpbp1, Spaca1 and Dpy19l2) essential for acrosome formation, which showed that two of these genes (Gopc and Dpy19l2) were significantly down-regulated. Moreover, repressed autophagy was observed in the testes of PS-NPs-exposed mice based on autophagy-related protein expression. This phenomenon was further verified in GC-2spd cells treated with PS-NPs (50 μg/mL, 100 μg/mL, 200 μg/mL for 24 h). The potential role of autophagy in such acrosome defects was explored by using the autophagy inhibitor 3-methyladenine (3-MA), autophagy activator rapamycin or beclin-1 siRNA. The results showed that Golgi-associated vesicle disorganization was exacerbated with the 3-MA and beclin-1 siRNA pretreatments, but decreased with the rapamycin pretreatment, and the expression of GOPC and DPY19L2 was also altered. These results indicated that autophagy might be involved in the PS-NPs-induced acrosome lesions based on the regulation of two key acrosome-formation proteins, GOPC and DPY19L2. Altogether, our results will provide new insights into the PS-NPs-induced male reproductive impairment.
Topics: Acrosome; Adaptor Proteins, Signal Transducing; Administration, Oral; Animals; Autophagy; Beclin-1; Golgi Matrix Proteins; Male; Mice; Microplastics; Nanoparticles; Polystyrenes; RNA, Small Interfering; Sirolimus
PubMed: 35381522
DOI: 10.1016/j.envint.2022.107220 -
Biosensors Aug 2022Microfluidics and lab-on-chip technologies have been used in a wide range of biomedical applications. They are known as versatile, rapid, and low-cost alternatives for...
Microfluidics and lab-on-chip technologies have been used in a wide range of biomedical applications. They are known as versatile, rapid, and low-cost alternatives for expensive equipment and time-intensive processing. The veterinary industry and human fertility clinics could greatly benefit from label-free and standardized methods for semen analysis. We developed a tool to determine the acrosome integrity of spermatozoa using microfluidic impedance cytometry. Spermatozoa from boars were treated with the calcium ionophore A23187 to induce acrosome reaction. The magnitude, phase and opacity of individual treated and non-treated (control) spermatozoa were analyzed and compared to conventional staining for acrosome integrity. The results show that the opacity at 19 MHz over 0.5 MHz is associated with acrosome integrity with a cut-off threshold at 0.86 (sensitivity 98%, specificity 97%). In short, we have demonstrated that acrosome integrity can be determined using opacity, illustrating that microfluidic impedance cytometers have the potential to become a versatile and efficient alternative in semen analysis and for fertility treatments in the veterinary industry and human fertility clinics.
Topics: Acrosome; Animals; Calcimycin; Calcium Ionophores; Electric Impedance; Humans; Male; Microfluidics; Spermatozoa; Swine
PubMed: 36140064
DOI: 10.3390/bios12090679 -
Cells Sep 2023Autophagy is critical to acrosome biogenesis and mitochondrial quality control, but the underlying mechanisms remain unclear. The ubiquitin ligase Nrdp1/RNF41 promotes...
Autophagy is critical to acrosome biogenesis and mitochondrial quality control, but the underlying mechanisms remain unclear. The ubiquitin ligase Nrdp1/RNF41 promotes ubiquitination of the mitophagy-associated Parkin and interacts with the pro-autophagic protein SIP/CacyBP. Here, we report that global deletion of Nrdp1 leads to formation of the round-headed sperm and male infertility by disrupting autophagy. Quantitative proteome analyses demonstrated that the expression of many proteins associated with mitochondria, lysosomes, and acrosomes was dysregulated in either spermatids or sperm of the Nrdp1-deficient mice. Deletion of Nrdp1 increased the levels of Parkin but decreased the levels of SIP, the mitochondrial fission protein Drp1 and the mitochondrial protein Tim23 in sperm, accompanied by the inhibition of autophagy, the impairment of acrosome biogenesis and the disruption of mitochondrial arrangement in sperm. Thus, our results uncover an essential role of Nrdp1 in spermiogenesis and male fertility by promoting autophagy, providing important clues to cope with the related male reproductive diseases.
Topics: Animals; Male; Mice; Acrosome; Autophagy; Mitochondria; Semen; Spermatogenesis; Ubiquitin-Protein Ligases
PubMed: 37759433
DOI: 10.3390/cells12182211