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Basic and Clinical Andrology Feb 2024Acephalic spermatozoa syndrome is a rare type of teratozoospermia causing male infertility due to detachment of the sperm head and flagellum, which precludes...
BACKGROUND
Acephalic spermatozoa syndrome is a rare type of teratozoospermia causing male infertility due to detachment of the sperm head and flagellum, which precludes fertilization potential. Although loss-of-function variations in several genes, including TSGA10, have been associated with acephalic spermatozoa syndrome, the genetic cause of many cases remains unclear.
RESULTS
We recruited a Pakistani family with two infertile brothers who suffered from acephalic spermatozoa syndrome. Through whole-exome sequencing (WES) followed by Sanger sequencing, we identified a novel missense variant in TSGA10 (c.1112T > C, p. Leu371Pro), which recessively co-segregated with the acephalic spermatozoa syndrome within this family. Ultrastructural analyses of spermatozoa from the patient revealed that 98% of flagellar cross-sections displayed abnormal axonemal ultrastructure, in addition to the head-flagellum detachment. Real-time quantitative PCR analysis revealed almost no detectable TSAG10 mRNA and western blot analysis also failed to detect TSAG10 protein in patient's sperm samples while TSGA10 expression was clearly detected in control samples. Consistently, immunofluorescence analysis demonstrated the presence of TSGA10 signal in the midpiece of sperm from the control but a complete absence of TSGA10 signal in sperm from the patient.
CONCLUSION
Altogether, our study identifies a novel TSGA10 pathogenic variant as a cause of acephalic spermatozoa syndrome in this family and provides information regarding the clinical manifestations associated with TSGA10 variants in human.
PubMed: 38317066
DOI: 10.1186/s12610-024-00220-7 -
Reproductive Biology and Endocrinology... Jan 2024Cyclophilin D (CypD) negatively regulates ATP production by opening of the mitochondrial permeability transition pore. This study aimed to understand the role of CypD in...
BACKGROUND
Cyclophilin D (CypD) negatively regulates ATP production by opening of the mitochondrial permeability transition pore. This study aimed to understand the role of CypD in sperm motility regulation.
METHODS
Changes in CypD during sperm capacitation and its interaction with glycogen synthase kinase 3α (GSK3α), a key kinase regulating sperm motility, were examined in mouse spermatozoa. The effects of CypD inhibitor cyclosporin A (CsA) and GSK3 inhibitor 6-bromo-indirubin-3'-oxime (BIO) on sperm motility, p-GSK3α(Ser21), mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (MMP), and ATP production were examined. The effect of proteasome inhibitor MG115 on the cellular levels of CypD was examined.
RESULTS
In cauda epididymal spermatozoa, GSK3α was found in both cytosolic and mitochondrial fractions whereas CypD was primarily found in the mitochondrial fraction together with ATP synthase F1 subunit alpha (ATP5A), a mitochondrial marker. GSK3α and CypD were co-localized in the sperm midpiece. Interaction between GSK3α and CypD was identified in co-immunoprecipitation. CsA, a CypD inhibitor, significantly increased sperm motility, tyrosine phosphorylation, mPTP closing, MMP, and ATP levels in spermatozoa, suggesting that CypD acts as a negative regulator of sperm function. Under capacitation condition, both GSK3α and CypD were decreased in spermatozoa but ATP5A was not. The GSK3 inhibitor BIO markedly increased p-GSK3α(Ser21) and decreased CypD but significantly increased mPTP closing, MMP, ATP production, and motility of spermatozoa. This suggests that inhibitory phosphorylation of GSK3α is coupled with degradation of CypD, potentiating the mitochondrial function. Degradation of CypD was attenuated by MG115, indicative of involvement of the ubiquitin proteasome system.
CONCLUSIONS
During sperm capacitation, CypD act as a downstream target of GSK3α can be degraded via the ubiquitin proteasome system, stimulating mitochondrial function and sperm motility.
Topics: Animals; Male; Mice; Adenosine Triphosphate; Cyclosporine; Glycogen Synthase Kinase 3; Peptidyl-Prolyl Isomerase F; Proteasome Endopeptidase Complex; Semen; Sperm Motility; Ubiquitins
PubMed: 38254112
DOI: 10.1186/s12958-024-01186-x -
BioRxiv : the Preprint Server For... Feb 2024Desmosterol and cholesterol are essential lipid components of the sperm plasma membrane. Cholesterol efflux is required for capacitation, a process through which sperm...
Desmosterol and cholesterol are essential lipid components of the sperm plasma membrane. Cholesterol efflux is required for capacitation, a process through which sperm acquire fertilizing ability. In this study, using a transgenic mouse model overexpressing 24-dehydrocholesterol reductase (DHCR24), an enzyme in the sterol biosynthesis pathway responsible for the conversion of desmosterol to cholesterol, we show that disruption of sterol homeostasis during spermatogenesis led to defective sperm morphology characterized by incomplete mitochondrial packing in the midpiece, reduced sperm count and motility, and a decline in male fertility with increasing paternal age, without changes in body fat composition. Sperm depleted of desmosterol exhibit inefficiency in the acrosome reaction, metabolic dysfunction, and an inability to fertilize the egg. These findings provide molecular insights into sterol homeostasis for sperm capacitation and its impact on male fertility.
PubMed: 38187697
DOI: 10.1101/2023.12.21.572851 -
Biomedicines Dec 2023Nerve 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...
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 (p75 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 ( = 7), UGIs ( = 7), and F ( = 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 F-isoprostanes (F-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, FIsoPs, and IL-1β compared with men with infertility. Notably, in normal sperm, p75 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 p75 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.
PubMed: 38137566
DOI: 10.3390/biomedicines11123345 -
Cureus Nov 2023The purpose of this study is to examine whether 5-hydroxytryptamine (5-HT, also known as serotonin) regulates human sperm motility, focusing on 5-HT receptors....
The purpose of this study is to examine whether 5-hydroxytryptamine (5-HT, also known as serotonin) regulates human sperm motility, focusing on 5-HT receptors. Immunofluorescent staining revealed the existence of seven types of 5-HT receptors with a heterogeneous pattern of reactive sites. In detail, 5-HT, 5-HT, and 5-HT were detected in the post-acrosomal and mid-piece regions. The 5-HT and 5-HT receptors were mainly localized in the equatorial segment. 5-HT and 5-HT receptors were present in the neck and post-acrosomal regions. When examining the effects of 5-HT receptor antagonists on sperm motility, only the 5-HT receptor antagonist significantly reduced sperm motility. This suggests that the 5-HT receptor may have a regulatory function in sperm motility. Eventually, progressive motility should be attenuated to penetrate the oocyte for fertilization. The current study indicated heterogenous expression patterns and plausible functions of 5-HT receptors in human sperm.
PubMed: 38033435
DOI: 10.7759/cureus.49530 -
Veterinary Sciences Nov 2023This study aimed to investigate the relationship between the sperm quality and the osteopontin (OPN) concentration in the prostates of Malakli shepherd dogs. Ejaculates...
This study aimed to investigate the relationship between the sperm quality and the osteopontin (OPN) concentration in the prostates of Malakli shepherd dogs. Ejaculates were collected once by digital manipulation from 39 male dogs aged between 2 and 4 years and older. The first and third fractions of the ejaculate were centrifuged at 5000× for 30 min, and supernatants were stored at -80 °C for further analysis of OPN using a double-antibody sandwich method (SEA899CA, Cloude-Clone Corp, Houston, TX, USA). Meanwhile, the second fractions were evaluated for sperm motility, concentration, viability, and rate of abnormal spermatozoa (head, acrosome, midpiece and tail abnormalities). The average concentration of OPN was 8.7 ± 5.2 ng/mL, and it differed significantly between the 1st 10.4 ± 5.3 ng/mL and 3rd 7.4 ± 5 ng/mL fractions. According to ROC (receiver operating characteristic curve) analysis, the OPN concentration had a better diagnostic ability for sperm motility ( < 0.001) than for the rate of abnormal spermatozoa ( < 0.05). Additionally, the OPN concentration was negatively correlated with poor sperm morphology and motility. In conclusion, the OPN concentration in prostate-derived secretions may be a possible marker of sperm quality in dogs. Further research could explore the involvement of OPN in sperm motility during cryopreservation and in vivo fertility.
PubMed: 37999469
DOI: 10.3390/vetsci10110646 -
Veterinary Research Communications Apr 2024Before fertilization of the oocyte, the spermatozoa must undergo through a series of biochemical changes in the female reproductive tract named sperm capacitation....
Before fertilization of the oocyte, the spermatozoa must undergo through a series of biochemical changes in the female reproductive tract named sperm capacitation. Spermatozoa regulates its functions by post-translational modifications, being historically the most studied protein phosphorylation. In addition to phosphorylation, recently, protein acetylation has been described as an important molecular mechanism with regulatory roles in several reproductive processes. However, its role on the mammal's sperm capacitation process remains unraveled. Sirtuins are a deacetylase protein family with 7 members that regulate protein acetylation. Here, we investigated the possible role of SIRT1 on pig sperm capacitation-related events by using YK 3-237, a commercial SIRT1 activator drug. SIRT1 is localized in the midpiece of pig spermatozoa. Protein tyrosine phosphorylation (focused at p32) is an event associated to pig sperm capacitation that increases when spermatozoa are in vitro capacitated in presence of YK 3-237. Eventually, YK 3-237 induces acrosome reaction in capacitated spermatozoa: YK 3-237 treatment tripled (3.40 ± 0.40 fold increase) the percentage of acrosome-reacted spermatozoa compared to the control. In addition, YK 3-237 induces sperm intracellular pH alkalinization and raises the intracellular calcium levels through a CatSper independent mechanism. YK 3-237 was not able to bypass sAC inhibition by LRE1. In summary, YK 3-237 promotes pig sperm capacitation by a mechanism upstream of sAC activation and independent of CatSper calcium channel.
Topics: Swine; Male; Female; Animals; Sperm Capacitation; Sirtuin 1; Semen; Spermatozoa; Acrosome Reaction; Mammals
PubMed: 37906355
DOI: 10.1007/s11259-023-10243-6 -
BioRxiv : the Preprint Server For... Oct 2023Mammalian sperm delve into the female reproductive tract to fertilize the female gamete. The available information about how sperm regulate their motility during the...
UNLABELLED
Mammalian sperm delve into the female reproductive tract to fertilize the female gamete. The available information about how sperm regulate their motility during the final journey to the fertilization site is extremely limited. In this work, we investigated the structural and functional changes in the sperm flagellum after acrosomal exocytosis and during the interaction with the eggs. The evidence demonstrates that the double helix actin network surrounding the mitochondrial sheath of the midpiece undergoes structural changes prior to the motility cessation. This structural modification is accompanied by a decrease in diameter of the midpiece and is driven by intracellular calcium changes that occur concomitant with a reorganization of the actin helicoidal cortex. Although midpiece contraction may occur in a subset of cells that undergo acrosomal exocytosis, live-cell imaging during in vitro fertilization showed that the midpiece contraction is required for motility cessation after fusion is initiated. These findings provide the first evidence of the F-actin network's role in regulating sperm motility, adapting its function to meet specific cellular requirements during fertilization, and highlighting the broader significance of understanding sperm motility.
SIGNIFICANT STATEMENT
In this work, we demonstrate that the helical structure of polymerized actin in the flagellum undergoes a rearrangement at the time of sperm-egg fusion. This process is driven by intracellular calcium and promotes a decrease in the sperm midpiece diameter as well as the arrest in motility, which is observed after the fusion process is initiated.
PubMed: 37904966
DOI: 10.1101/2023.06.22.546073 -
Human & Experimental Toxicology 20232,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a potential environmental toxin that has the ability to affect male reproductive tract. Rhamnazin is a naturally present...
Rhamnazin ameliorates 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin-evoked testicular toxicity by restoring biochemical, spermatogenic and histological profile in male albino rats.
2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a potential environmental toxin that has the ability to affect male reproductive tract. Rhamnazin is a naturally present flavone that displays multiple medicinal properties. Therefore, the current study was designed to determine the mitigative role of rhamnazin against TCDD induced reproductive damage. 48 adult male albino rats were randomly separated into four groups: control, TCDD (10 µgkg), TCDD + rhamnazin (10 µgkg + 5 mgkg respectively) and rhamnazin (5 mgkg). The trial was conducted for 56 days. TCDD intoxication notably affected superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GSR) and catalase (CAT) activities, besides reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations were augmented. TCDD administration also lowered sperm motility, viability, sperm number, while it augmented the sperm morphological (tail, neck/midpiece and head) anomalies. Moreover, it decreased the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma testosterone. Moreover, TCDD reduced steroidogenic enzymes i.e., 17-beta hydroxysteroid dehydrogenase (17β-HSD), steroidogenic acute regulatory protein (StAR) and 3-beta hydroxysteroid dehydrogenase (3β-HSD) as well as B-cell lymphoma 2 (Bcl-2) expressions, but increased the expressions of Bcl-2-associated X protein (Bax) and cysteine-aspartic acid protease (Caspase-3). Furthermore, TCDD exposure also induced histopathological anomalies in testicular tissues. However, the supplementation of rhamnazin recovered all the mentioned damages in the testicles. The outcomes revealed that rhamnazin can ameliorate TCDD induced reproductive toxicity due to its anti-oxidant, anti-apoptotic and androgenic nature.
Topics: Rats; Animals; Male; Testis; Polychlorinated Dibenzodioxins; Sperm Motility; Semen; Testosterone; Antioxidants; Hydroxysteroid Dehydrogenases; Oxidative Stress
PubMed: 37807851
DOI: 10.1177/09603271231205859 -
Frontiers in Bioscience (Scholar... Sep 2023Analysis of sperm morphology defects (amorphous heads, abnormal acrosome, etc.) is useful for estimating the efficiency of spermiogenesis and sperm maturation. An...
BACKGROUND
Analysis of sperm morphology defects (amorphous heads, abnormal acrosome, etc.) is useful for estimating the efficiency of spermiogenesis and sperm maturation. An advanced paternal age (more than 40 years) is associated with decreasing sperm count and reduced motility; however, there is little information on the effect of aging relating to sperm morphological defects. Moreover, searching for stable combinations of certain morphological defects in the same sperm can be useful for better understanding spermiogenesis. The aim of the study was to investigate age-related changes in sperm morphology and the prevalence of certain combinations of sperm morphological defects in men from the general population.
METHODS
Sperm morphology was assessed in 1266 volunteers from the Russian urban general population in different age groups (18-19, 20-24, 25-29, 30-34, 35-40, and over 40 years old). Two hundred sperm were evaluated from each semen sample (about 250 thousand spermatozoa in total). Sperm defects were classified according to the WHO laboratory manual (WHO, 2010). The total percentage of each sperm defect and the frequency of different combinations of sperm morphological anomalies for each age group were counted. Additionally, a similar analysis was performed for the groups of normospermia and pathozoospermia.
RESULTS
The frequency of coiled and short sperm tails increased in men over 40 years old compared to younger subjects; however, aging did not affect the percentage of morphologically normal sperm. It was shown that the combination of a misshaped head (amorphous, pyriform, and elongated) with a postacrosomal vacuole, acrosome defect, excess residual cytoplasm, or any anomaly of the midpiece or tail in the same spermatozoon were not random combinations of independent solitary defects. The increased frequency of combinations of coiled tails with amorphous, elongated, or vacuolated heads was observed in men older than 40 years. Sperm morphological defects, such as severely deformed heads (pyriform, elongated, and round) were more common in men with pathozoospermia compared to normospermic subjects.
CONCLUSIONS
An age-related impairment in sperm morphology was found. Stable combinations of head defects with anomalies in the acrosome, midpiece or tail suggest that these defects may be the result of a general violation in the morphogenetic mechanism.
Topics: Humans; Male; Adult; Semen; Spermatozoa; Acrosome; Sperm Tail; Semen Analysis
PubMed: 37806952
DOI: 10.31083/j.fbs1503012