Impaired Sperm Motility Research Articles

CCDC28A deficiency causes head-tail coupling defects and immotility in murine spermatozoa

Male infertility presents a substantial challenge in reproductive medicine, often attributed to impaired sperm motility. The present study investigates the role of CCDC28A, a protein expressed specifically in male germ cells, whose paralog CCDC28B has been implicated in ciliogenesis. We identify unique expression patterns for CCDC28A and CCDC28B within the mouse testes, where CCDC28A is expressed in germ cells, whereas CCDC28B is expressed in supporting somatic cells. Through knockout mouse models and histological analyses, we reveal that CCDC28A deficiency results in diminished sperm motility and structural aberrations in sperm tails, notably affecting the head-tail coupling apparatus (HTCA), thereby causing male infertility. Fine structural analyses by transmission electron microscopy reveal disruptions at the capitulum-basal plate junction of the HTCA in the CCDC28A mutants. This results in the bending of the head within the neck region, often accompanied by thickening of the tail midpiece. Our discovery demonstrates that CCDC28A plays an essential role in male fertility and sperm tail morphogenesis through the formation of HTCA.

Impact of Reductive Stress on Human Infertility: Underlying Mechanisms and Perspectives.

Antioxidants have a well-established effect on general health and are essential in preventing oxidative damage to cells by scavenging free radicals. Free radicals are thought to be neutralized by these substances, which include polyphenols, β-carotene, and vitamins C and E, reducing cellular damage. On the other hand, recent data indicates that consuming excessive amounts of antioxidants may have side effects. Apoptosis and cell signaling are two beneficial physiological processes that are affected by excessive supplementation. Other negative effects include paradoxical enhancement of oxidative stress and unbalanced cellular redox potential. Overdosing on particular antioxidants has been associated with increased medication interactions, cancer progression, and fatality risks. Additionally, the complex impacts they may have on fertility might be both useful and adverse, depending on the quantity and duration of usage. This review delves into the dual role of antioxidants and emphasizes the importance of employing antioxidants in moderation. Antioxidant overconsumption may disrupt the oxidative balance necessary for normal sperm and oocyte function, which is one of the potential negative effects of antioxidants on fertility in both males and females that are also investigated. Although modest usage of antioxidants is generally safe and useful, high levels of antioxidants can upset hormonal balance, impair sperm motility, and negatively impact the outcomes of assisted reproductive technologies (ART). The findings emphasize the need to use antioxidant supplements in a balanced way, the importance of further research to optimize their use in fertility treatments, and the importance of supporting reproductive health to avoid adverse effects.

Impacts of iodoacetic acid on reproduction: current evidence, underlying mechanisms, and future research directions.

In light of the undeniable and alarming fact that human fertility is declining, the harmful factors affecting reproductive health are garnering more and more attention. Iodoacetic acid (IAA), an emerging unregulated drinking water disinfection byproduct, derives from chlorine disinfection and is frequently detected in the environment and biological samples. Humans are ubiquitously exposed to IAA daily mainly through drinking water, consuming food and beverages made from disinfected water, contacting swimming pools and bath water, etc. Mounting evidence has indicated that IAA could act as a reproductive toxicant and bring about multifarious adverse reproductive damage. For instance, it can interfere with gonadal development, weaken ovarian function, impair sperm motility, trigger DNA damage to germ cells, perturb steroidogenesis, etc. The underlying mechanisms predominantly include cytotoxic and genotoxic effects on germ cells, disturbance of the hypothalamic-pituitary-gonadal axis, oxidative stress, inhibition of steroidogenic proteins or enzymes, and dysbiosis of gut microbiota. Nevertheless, there are still some knowledge gaps and limitations in studying the potential impact of IAA on reproduction, which urgently need to be addressed in the future. We suppose that necessary population epidemiological studies, more sensitive detection methods for internal exposure, and mechanism-based in-depth exploration will contribute to a more comprehensive understanding of characteristics and biological effects of IAA, thus providing an important scientific basis for revising sanitary standards for drinking water quality.

Kdm4d mutant mice show impaired sperm motility and subfertility.

Regulation of gene expression through histone modifications underlies cell homeostasis and differentiation. Kdm4d and Kdm4dl exhibit a high degree of similarity and demethylate H3K9me3. However, the physiological functions of these proteins remain unclear. In this study, we generated Kdm4dl mutant mice and found that Kdm4dl was dispensable for mouse development. However, through the generation of Kdm4d mutant mice, we unexpectedly found that Kdm4d mutant male mice were subfertile because of impaired sperm motility. The absence of Kdm4d was associated with an altered distribution of H3K9me3 in round spermatids, suggesting that the Kdm4d-mediated adjustment of H3K9me3 levels is required to generate motile sperm. Further analysis revealed that the absence of Kdm4d did not affect the functionality of sperm nuclei in generating offspring. As KDM4D is specifically expressed in the human testes, our results suggest that changes in KDM4D expression or its activity may be a risk factor for human infertility.

Ethanol-related transcriptomic changes in mouse testes

BackgroundAlcohol consumption is widely known to have detrimental effects on various organs and tissues. The effects of ethanol on male reproduction have been studied at the physiological and cellular levels, but no systematic study has examined the effects of ethanol on male reproduction-related gene expression.ResultsWe employed a model of chronic ethanol administration using the Lieber-DeCarli diet. Ethanol-fed mice showed normal testicular and epididymal integrity, and sperm morphology, but decreased sperm count. Total RNA sequencing analysis of testes from ethanol-fed mice showed that a small fraction (∼ 2%) of testicular genes were differentially expressed in ethanol-fed mice and that, of these genes, 28% were cell-type specific in the testis. Various in silico analyses were performed, and gene set enrichment analysis revealed that sperm tail structure-related genes, including forkhead box J1 (Foxj1), were down-regulated in testes of ethanol-fed mice. Consistent with this result, ethanol-fed mice exhibited decreased sperm motility.ConclusionThis study provides the first comprehensive transcriptomic profiling of ethanol-induced changes in the mouse testis, and suggests gene expression profile changes as a potential mechanism underlying ethanol-mediated reproductive dysfunction, such as impaired sperm motility.

FBXO24 deletion causes abnormal accumulation of membraneless electron-dense granules in sperm flagella and male infertility

Ribonucleoprotein (RNP) granules are membraneless electron-dense structures rich in RNAs and proteins, and involved in various cellular processes. Two RNP granules in male germ cells, intermitochondrial cement and the chromatoid body (CB), are associated with PIWI-interacting RNAs (piRNAs) and are required for transposon silencing and spermatogenesis. Other RNP granules in male germ cells, the reticulated body and CB remnants, are also essential for spermiogenesis. In this study, we disrupted FBXO24, a testis-enriched F-box protein, in mice and found numerous membraneless electron-dense granules accumulated in sperm flagella. Fbxo24 knockout (KO) mice exhibited malformed flagellar structures, impaired sperm motility, and male infertility, likely due to the accumulation of abnormal granules. The amount and localization of known RNP granule-related proteins were not disrupted in Fbxo24 KO mice, suggesting that the accumulated granules were distinct from known RNP granules. Further studies revealed that RNAs and two importins, IPO5 and KPNB1, abnormally accumulated in Fbxo24 KO spermatozoa and that FBXO24 could ubiquitinate IPO5. In addition, IPO5 and KPNB1 were recruited to stress granules, RNP complexes, when cells were treated with oxidative stress or a proteasome inhibitor. These results suggest that FBXO24 is involved in the degradation of IPO5, disruption of which may lead to the accumulation of abnormal RNP granules in sperm flagella.

FBXO24 deletion causes abnormal accumulation of membraneless electron-dense granules in sperm flagella and male infertility.

Ribonucleoprotein (RNP) granules are membraneless electron-dense structures rich in RNAs and proteins, and involved in various cellular processes. Two RNP granules in male germ cells, intermitochondrial cement and the chromatoid body (CB), are associated with PIWI-interacting RNAs (piRNAs) and are required for transposon silencing and spermatogenesis. Other RNP granules in male germ cells, the reticulated body and CB remnants, are also essential for spermiogenesis. In this study, we disrupted FBXO24, a testis-enriched F-box protein, in mice and found numerous membraneless electron-dense granules accumulated in sperm flagella. Fbxo24 knockout (KO) mice exhibited malformed flagellar structures, impaired sperm motility, and male infertility, likely due to the accumulation of abnormal granules. The amount and localization of known RNP granule-related proteins were not disrupted in Fbxo24 KO mice, suggesting that the accumulated granules were distinct from known RNP granules. Further studies revealed that RNAs and two importins, IPO5 and KPNB1, abnormally accumulated in Fbxo24 KO spermatozoa and that FBXO24 could ubiquitinate IPO5. In addition, IPO5 and KPNB1 were recruited to stress granules, RNP complexes, when cells were treated with oxidative stress or a proteasome inhibitor. These results suggest that FBXO24 is involved in the degradation of IPO5, disruption of which may lead to the accumulation of abnormal RNP granules in sperm flagella.

How exome sequencing improves the diagnostics and management of men with non-syndromic infertility.

Male infertility affects approximately 17% of all men and represents a complex disorder in which not only semen parameters such as sperm motility, morphology, and number of sperm are highly variable, but also testicular phenotypes range from normal spermatogenesis to complete absence of germ cells. Genetic factors significantly contribute to the disease but chromosomal aberrations, mostly Klinefelter syndrome, and microdeletions of the Y-chromosome have remained the only diagnostically and clinically considered genetic causes. Monogenic causes remain understudied and, thus, often unidentified, leaving the majority of the male factor couple infertility pathomechanistically unexplained. This has been changing mostly because of the introduction of exome sequencing that allows the analysis of multiple genes in large patient cohorts. As a result, pathogenic variants in single genes have been associated with non-syndromic forms of all aetiologic sub-categories in the last decade. This review highlights the contribution of exome sequencing to the identification of novel disease genes for isolated (non-syndromic) male infertility by presenting the results of a comprehensive literature search. Both, reduced sperm count in azoospermic and oligozoospermic patients, and impaired sperm motility and/or morphology, in asthenozoospermic and/or teratozoospermic patients are highly heterogeneous diseases with well over 100 different candidate genes described for each entity. Applying the standardized evaluation criteria of the ClinGen gene curation working group, 70 genes with at least moderate evidence to contribute to the disease are highlighted. The implementation of these valid disease genes in clinical exome sequencing is important to increase the diagnostic yield in male infertility and, thus, improve clinical decision-making and appropriate genetic counseling. Future advances in androgenetics will continue to depend on large-scale exome and genome sequencing studies of comprehensive international patient cohorts, which are the most promising approaches to identify additional disease genes and provide reliable data on the gene-disease relationship.

Impact of air pollution and heavy metal exposure on sperm quality: A clinical prospective research study

Exposure to air pollution poses significant risks to human health, including detrimental effects on the reproductive system, affecting both men and women. Our prospective clinical study aimed to assess the impact of prolonged air pollution exposure on sperm quality in male patients attending a fertility clinic. The current study was conducted at Sri Narayani Hospital and Research Centre in Vellore, Tamil Nadu, India, and the study examined sperm samples obtained from individuals with extended exposure to air pollution. Microscopic analysis, including scanning electron microscopy (SEM), was conducted to evaluate sperm morphology. At the same time, atomic absorption spectroscopy (AAS) determined the presence of heavy metals, including Zinc (Zn), Magnesium (Mg), Lead (Pb) and Cadmium (Cd), known to affect sperm production. Our findings revealed that long-term exposure to air pollution adversely affects sperm quality, manifesting in alterations during the spermatogenesis cycle, morphological abnormalities observed through SEM, and impaired sperm motility. Additionally, epidemiological evidence suggests that elevated levels of cadmium and lead in the environment induce oxidative stress, leading to sperm DNA damage and reduced sperm concentrations. These results underscore the urgent need for environmental interventions to mitigate air pollution and protect reproductive health.

Unveiling the crucial role of oxidative stress on steroid hormone receptors

ABSTRACT Oxidative stress is widely recognized as a major contributor to male infertility. Reactive oxygen species (ROS) can interact with various cellular components, causing irreversible damage to the male reproductive system. This damage results in several adverse effects, including impaired sperm motility, abnormal spermatogenesis, sperm deoxyribonucleic acid (DNA) damage, and altered steroidogenesis. Furthermore, oxidative damage to steroid hormone receptors contributes to their functional impairment. These factors, individually or collectively, lead to infertility or subfertility in men. ROS can damage proteins, lipids, and nucleic acids, with oxidative DNA damage potentially causing mutations, particularly in germ cells, as studies have shown. Such damage is also observed in steroid hormones and their receptors in men. Understanding the relationship between oxidative stress and its impact on genes is crucial for the accurate diagnosis, recognition, and treatment of male infertility. High-dose antioxidant supplementation, a beacon of hope, may eliminate, scavenge, or neutralize ROS, thereby mitigating ROS-induced genomic damage and oxidative harm to steroid hormones. Consequently, this approach may be considered the primary remedy against oxidative stress-induced male infertility.

Episodic ozone exposure in Long-Evans rats has limited effects on cauda sperm motility and non-coding RNA populations

Epidemiological evidence suggests the potential for air pollutants to induce male reproductive toxicity. In experimental studies, exposure to ozone during sensitive windows in the sperm lifecycle has been associated with impaired sperm motility. Subsequently, we sought to investigate the effects of episodic exposure to ozone during sperm maturation in the rat. Long-Evans rats were exposed to either filtered air or ozone (0.4 or 0.8 ppm) for five non-consecutive days over two weeks. Ozone exposure did not impact male reproductive organ weights or sperm motility ∼24 hours following the final exposure. Furthermore, circulating sex hormones remained unchanged despite increased T3 and T4 in the 0.8 ppm group. While there was indication of altered adrenergic signaling attributable to ozone exposure in the testis, there were minimal impacts on small non-coding RNAs detected in cauda sperm. Only two piwi-interacting RNAs (piRNAs) were altered in the mature sperm of ozone-exposed rats (piR-rno-346434 and piR-rno-227431). Data across all rats were next analyzed to identify any non-coding RNAs that may be correlated with reduced sperm motility. A total of 7 microRNAs (miRNAs), 8 RNA fragments, and 1682 piRNAs correlated well with sperm motility. Utilizing our exposure paradigm herein, we were unable to substantiate the relationship between ozone exposure during maturation with sperm motility. However, these approaches served to identify a suite of non-coding RNAs that were associated with sperm motility in rats. With additional investigation, these RNAs may prove to have functional roles in the acquisition of motility or be unique biomarkers for male reproductive toxicity.

How Per- and Poly-Fluoroalkyl Substances Affect Gamete Viability and Fertilization Capability: Insights from the Literature.

There has been emerging research linking per- and poly-fluoroalkyl substances (PFAS) to gamete viability and fertility. PFAS, prevalent in the environment and water supplies, undergo slow degradation due to their C-F bond and a long half-life (2.3-8.5 years). In females, PFAS inhibit the hypothalamic-pituitary-gonadal (HPG) axis, reducing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, leading to the inhibition of androgen and estradiol production. PFAS have been found to cause detrimental effects on egg quality through impairing folliculogenesis. In males, PFAS can impair sperm motility and morphology: two fundamental qualities of successful fertilization. PFAS exposure has been proven to inhibit testosterone production, sperm capacitation, and acrosomal reaction. After fertilization, the results of PFAS exposure to embryos have also been investigated, showing reduced development to the blastocyst stage. The aim of this review is to report the main findings in the literature on the impact of PFAS exposure to gamete competency and fertilization capability by highlighting key studies on both male and female fertility. We report that there is significant evidence demonstrating the negative impacts on fertility after PFAS exposure. At high doses, these environmentally abundant and widespread compounds can significantly affect human fertility.

Size-dependent deleterious effects of nano- and microplastics on sperm motility

IntroductionGrowing concerns regarding the reproductive toxicity associated with daily life exposure to micro-/nano-plastics (abbreviated as MNPs) have become increasingly prevalent. In reality, MNPs exposure involves a heterogeneous mixture of MNPs of different sizes rather than a single size. MethodsIn this study, an oral exposure mouse model was used to evaluate the effects of MNPs of four size ranges: 25–30 nm, 1–5 µm, 20–27 µm, and 125–150 µm. Adult male C57BL/6 J mice were administered environmentally relevant concentrations of 0.1 mg MNPs/day for 21 days. After that, open field test and computer assisted sperm assessment (CASA) were conducted. Immunohistochemical analyses of organ and cell type localization of MNPs were evaluated. Testicular transcriptome analysis was carried out to understand the molecular mechanisms. ResultsOur result showed that MNPs of different size ranges all impaired sperm motility, with a decrease in progressive sperm motility, linearity and straight-line velocity of sperm movement. Alterations did not manifest in animal locomotion, body weight, or sperm count. Noteworthy effects were most pronounced in the smaller MNPs size ranges (25–30 nm and 1–5 µm). Linear regression analysis substantiated a negative correlation between the size of MNPs and sperm curvilinear activity. Immunohistochemical analysis unveiled the intrusions of 1–5 µm MNPs, but not 20–27 µm and 125–150 µm MNPs, into Leydig cells and testicular macrophages. Further testicular transcriptomic analysis revealed perturbations in pathways related to spermatogenesis, oxidative stress, and inflammation. Particularly within the 1–5 µm MNPs group, a heightened perturbation in pathways linked to spermatogenesis and oxidative stress was observed. ConclusionsOur data support the size-dependent impairment of MNPs on sperm functionality, underscoring the pressing need for apprehensions about and interventions against the escalation of environmental micro-/nano-plastics contamination. This urgency is especially pertinent to small-sized MNPs.

A Biallelic Mutation in CCDC103 Impairs Sperm Motility due to the Absence of Dynein Arms

Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by destructive respiratory disease and laterality abnormalities due to randomized left–right body asymmetry. In men, PCD is also often associated with infertility due to immotile sperm owing to a malfunction of the sperm flagella. Pathogenic mutations have been found in more than 50 genes. Nonetheless, not all patients with PCD experience infertility. Therefore, to better understand the impact of PCD-associated mutations on male fertility, it is necessary to clarify the role of these genes in spermatogenesis. The CCDC103 p.His154Pro mutation has a high prevalence in PCD. Here, we present the identification and functional analysis of a biallelic mutation in CCDC103 identified in a familial case of PCD associated with male infertility. The biallelic CCDC103 mutations, NM_213607:c.161_162del(p.His55Serfs ∗9) and NM_213607:c.461A > C (p.His154Pro), were identified by whole-exome sequencing. Sanger sequencing validation was performed on all available family members, and the mutation was recessively separated with an infertility phenotype. The c.161_162del mutation breaks the reading frame of the protein and, therefore, is predicted to produce a nonfunctional protein. The tertiary structure of CCDC103-mutated protein indicated a significant conformational change that likely affected protein function. Transmission electron microscopy of spermatozoa showed that both the mid and principal regions of the flagellum lacked dynein arms, which was confirmed via immunofluorescence staining. Using the method of laser-assisted immotile sperm selection combined with intracytoplasmic sperm injection, the patient’s wife has a successful clinical pregnancy. These results extend the phenotype spectrum of the CCDC103 mutation in PCD.

Forkhead-associated phosphopeptide binding domain 1 (FHAD1) deficiency impaired murine sperm motility.

Genetic knockout-based studies conducted in mice provide a powerful means of assessing the significance of a gene for fertility. Forkhead-associated phosphopeptide binding domain 1 (FHAD1) contains a conserved FHA domain, that is present in many proteins with phospho-threonine reader activity. How FHAD1 functions in male fertility, however, remains uncertain. Fhad1-/- mice were generated by CRISPR/Cas9-mediated knockout, after which qPCR was used to evaluate changes in gene expression, with subsequent analyses of spermatogenesis and fertility. The testis phenotypes were also examined using immunofluorescence and histological staining, while sperm concentrations and motility were quantified via computer-aided sperm analysis. Cellular apoptosis was assessed using a TUNEL staining assay. The Fhad1-/-mice did not exhibit any abnormal changes in fertility or testicular morphology compared to wild-type littermates. Histological analyses confirmed that the testicular morphology of both Fhad1-/-and Fhad1+/+ mice was normal, with both exhibiting intact seminiferous tubules. Relative to Fhad1+/+ mice, however, Fhad1-/-did exhibit reductions in the total and progressive motility of epididymal sperm. Analyses of meiotic division in Fhad1-/-mice also revealed higher levels of apoptotic death during the first wave of spermatogenesis. The findings suggest that FHAD1 is involved in both meiosis and the modulation of sperm motility.

1-DNJ Alleviates Obesity-Induced Testicular Inflammation in Mice Model by Inhibiting IKKβ/ NF-kB Pathway

Obesity is associated with chronic inflammation that affects various organs in the body, including the reproductive system, which is a key factor in male infertility. 1-Deoxynojirimycin (1-DNJ) is a natural alkaloid in mulberry leaves, which has anti-inflammatory capabilities, yet, it’s effects on obesity-induced inflammation-related male infertility remain unclear. Therefore, this research investigates the underlying mechanism by which 1-DNJ may mitigate fertility impairment in male mice caused by obesity-related inflammation. Male mice with high-fat diet (HFD)-induced obesity were treated with 1-DNJ or metformin for 8 weeks. Metabolic profiles were evaluated by enzyme method. Reproductive capacity was assessed by sperm viability, motility and counts, immunohistochemistry was performed to evaluate the testicular damage caused by obesity and inflammation. The inflammation was assessed by measuring the levels of tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and interleukin 6 (IL-6). The activation of IκB kinase β (IKKβ) and nuclear factor κB (NF-κB) was examined using western blot and immunohistochemistry. HFD induced obesity in mice with obvious lipid metabolism disorder. The obese male mice had a decreased testosterone level, impaired sperm motility, and increased inflammatory factors. 1-DNJ treatment improved the testosterone level in the obese mice, ameliorated the testicular structure damage and improve sperm viability. In addition, 1-DNJ treatment inhibited IKKβ/NF-kB signaling pathway and reduced inflammation in obese mice. 1-DNJ can improve the fertility of obese men by reducing obesity as well as obesity-induced inflammation. These findings provide new insights for 1-DNJ to alleviate inflammation caused by obesity and provide future possibilities for treating male infertility.

Urine microbes and predictive metagenomic profiles associate with abnormalities in sperm parameters: implications for male subfertility

To explore the taxonomic and predicted functional relationship between the urine microbiome and alterations of semen analysis (SA) parameters. Cross-sectional study. Academic medical center. Men presenting for fertility evaluation or men presenting for vasectomy consultation with proven biological paternity were recruited and stratified on the basis of alterations, or lack thereof, in SA parameters. Changes in the functional and taxonomic urine microbiome profiles of participants with or without alterations in SA parameters. Seventy-three participants were included in our study. Men with abnormal sperm motility (N = 27) showed a nearly 50-fold higher abundance of Dialister micraerophilus compared with those with normal sperm motility (N = 46). This relationship persisted on canonical correlational analysis (r = 0.439). Men with abnormal sperm concentration (N = 20) showed a lower abundance of Enterococcus faecalis and Staphylococcus aureus, compared with those with normal sperm concentration (N = 53). The urine of participants with impaired sperm motility demonstrated dramatic differences in predictive functional profiles in pathways involved in oxidation-reduction balance and cell longevity. Our findings underscore differences in the urinary microbiome and abnormalities in semen parameters, especially sperm motility. By incorporating predictive functional profiling, we also highlight possible mechanisms that may drive the observed differences in sperm parameters.

LRRC52 is likely a functional component of human KSper†.

Completion of fertilization is orchestrated by various ion channels in sperm membrane. Hyperpolarization of membrane potential, an indispensable event during the capacitation process, is dominated by sperm potassium channel (KSper). In addition to sperm-specific SLO3, which forms the channel pore, the auxiliary subunit leucine-rich-repeat-containing protein 52 (LRRC52) is required to form mKSper to function under physiological conditions. However, in human sperm, although most evidence supports that hSLO3 is the pore-forming subunit, whether hLRRC52 contributes to hKSper conductance and modulates sperm function remains to be understood. Here, using an extracellular segment that is homologous between mice and humans as an antigen, we developed a polyclonal antibody designed as LID1 that specifically detected mLRRC52 and performed co-immunoprecipitation with mSLO3. Additionally, patch-clamp recordings of mouse sperm showed that, physiological activation of mKSper and sperm functions were dramatically attenuated after treatment with LID1, indicating that LID1 functionally disrupted the regulation of mLRRC52 on mKSper. Next, LID1 was used to investigate the significance of hLRRC52 for hKSper activation. As a result, hLRRC52 was expressed in human sperm and might be assembled with hSLO3. More importantly, LID1 inhibited hKSper currents and depolarized sperm membrane potential, supporting essential modulation of hLRRC52 in hKSper. Ca2+ signaling of human sperm was also compromised in the presence of LID1, which impaired sperm motility and acrosome reaction. Because LID1 specifically inhibited both mKSper and hKSper but not mCatSper or hCatSper, our results suggest that hLRRC52 functions as an important component of hKSper and regulates sperm physiological functions.

A Mini Review on Reproductive Toxicity of Cyclosporine in Male Animals

Cyclosporine is an immunosuppressive drug that is widely used in organ transplantation and autoimmune diseases. However, its potential reproductive toxicity in male animals is not fully understood. This mini-review aims to provide an overview of the current knowledge on the reproductive toxicity of cyclosporine in male animals, focusing on its effects on spermatogenesis, sperm quality, and fertility. A literature search was conducted using PubMed, Google Scholar, and other databases to identify relevant studies. Studies have shown that cyclosporine can have various adverse effects on spermatogenesis in male animals, including decreased sperm production, impaired sperm motility, and increased sperm abnormalities. Cyclosporine can also affect sperm quality by reducing sperm concentration, viability, and DNA integrity. These effects may result in decreased fertility in male animals. The available evidence suggests that cyclosporine has reproductive toxic effects in male animals. Further research is needed to fully elucidate the mechanisms of action and to develop strategies to mitigate these effects.

Elusive physiological role of prostatic acid phosphatase (PAP): generation of choline for sperm motility via auto-and paracrine cholinergic signaling.

Prostatic acid phosphatase (PAP) exists as two splice variants, secreted PAP and transmembrane PAP, the latter of which is implicated in antinociceptive signaling in dorsal root ganglia. However, PAP is predominantly expressed in the prostate gland and the physiological role of seminal PAP, first identified in 1938, is largely unknown. Here, the author proposes that PAP, following ejaculation, functions to hydrolyze phosphocholine (PC) in seminal fluid and generate choline, which is imported by sperm via a choline transporter and converted to acetylcholine (ACh) by choline acetyltransferase. Auto- and paracrine cholinergic signaling, or choline directly, may subsequently stimulate sperm motility via α7 nicotinic ACh receptors (nAChRs) and contractility of the female reproductive tract through muscarinic ACh receptors (mAChRs). Consistent with a role of PAP in cholinergic signaling, 1) seminal vesicles secrete PC, 2) the prostate gland secretes PAP, 3) PAP specifically catalyzes the hydrolysis of PC into inorganic phosphate and choline, 4) seminal choline levels increase post-ejaculation, 5) pharmacological inhibition of choline acetyltransferase inhibits sperm motility, 6) inhibition or genetic deletion of α7 nAChRs impairs sperm motility, and 7) mAChRs are expressed in the uterus and oviduct (fallopian tube). Notably, PAP does not degrade glycerophosphocholine (GPC), the predominant choline source in the semen of rats and other mammals. Instead, uterine GPC phosphodiesterases may liberate choline from seminal GPC. In summary, the author deduces that PAP in humans, and uterine GPC phosphodiesterases in other mammals, function to generate choline for sperm cholinergic signaling, which promotes sperm motility and possibly contractility of the female reproductive tract.