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AbstractGFH009 is a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor currently under phase II clinical trials. In this study, we investigated the metabolism and disposition of GFH009 in Sprague-Dawley (SD) rats, as well as in vitro metabolism of CD-1 mouse, SD rat, beagle dog, cynomolgus monkey, and human.A radiolabelled study indicated that [14C]GFH009 was quickly and widely distributed throughout the body, but presented low levels in brain, testis, and epididymis after a single intravenous dose of 6 mg (100 µCi)/kg to SD rats.GFH009 undergoes systemic metabolic changes, primarily through O-demethylation, oxidation to carboxylic acid and N-dealkylation, cleavage off the methoxyisopropyl moiety being a minor pathway. These metabolic pathways were found to be mainly consistent both in vitro and in vivo.In SD rats, GFH009 was rapidly and completely eliminated, with faeces serving as the major excretion pathway and urine serving as the minor one. Besides, the major clearance pathway for GFH009 was excretion and the minor one was metabolism.GFH009 exhibits favourable drug metabolism and pharmacokinetics (DMPK) properties, which provides valuable insights into the disposition of GFH009 and can be used to guide future clinical studies.GFH009 is a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor currently under phase II clinical trials. In this study, we investigated the metabolism and disposition of GFH009 in Sprague-Dawley (SD) rats, as well as in vitro metabolism of CD-1 mouse, SD rat, beagle dog, cynomolgus monkey, and human.A radiolabelled study indicated that [14C]GFH009 was quickly and widely distributed throughout the body, but presented low levels in brain, testis, and epididymis after a single intravenous dose of 6 mg (100 µCi)/kg to SD rats.GFH009 undergoes systemic metabolic changes, primarily through O-demethylation, oxidation to carboxylic acid and N-dealkylation, cleavage off the methoxyisopropyl moiety being a minor pathway. These metabolic pathways were found to be mainly consistent both in vitro and in vivo.In SD rats, GFH009 was rapidly and completely eliminated, with faeces serving as the major excretion pathway and urine serving as the minor one. Besides, the major clearance pathway for GFH009 was excretion and the minor one was metabolism.GFH009 exhibits favourable drug metabolism and pharmacokinetics (DMPK) properties, which provides valuable insights into the disposition of GFH009 and can be used to guide future clinical studies. [ABSTRACT FROM AUTHOR]

Background: Chickens play a crucial role as the primary global source of eggs and poultry, and the quality of rooster semen significantly impacts poultry reproductive efficiency. Therefore, it is imperative to comprehend the regulatory mechanisms underlying sperm development. Results: In this study, we established transcriptome profiles of lncRNAs, miRNAs, and mRNAs in 3 testis tissues and 3 epididymis tissues from "Jing Hong No.1" roosters at 24, 35, and 64 weeks of age. Using the data, we conducted whole transcriptome analysis and constructed a ceRNA network. We detected 10 differentially expressed mRNAs (DEmRNAs), 33 differentially expressed lncRNAs (DElncRNAs), and 10 differentially expressed miRNAs (DEmiRNAs) in the testis, as well as 149 DEmRNAs, 12 DElncRNAs, and 10 DEmiRNAs in the epididymis. These genes were found to be involved in cell differentiation and development, as well as various signaling pathways such as GnRH, MAPK, TGF-β, mTOR, VEGF, and calcium ion pathways. Subsequently, we constructed two competing endogenous RNA (ceRNA) networks comprising DEmRNAs, DElncRNAs, and DEmiRNAs. Furthermore, we identified four crucial lncRNA-mRNA-miRNA interactions that govern specific biological processes in the chicken reproductive system: MSTRG.2423.1-gga-miR-1563-PPP3CA and MSTRG.10064.2-gga-miR-32-5p-GPR12 regulating sperm motility in the testis; MSTRG.152556.1-gga-miR-9-3p-GREM1/THYN1 governing immunomodulation in the epididymis; and MSTRG.124708.1-gga-miR-375-NDUFB9/YBX1 controlling epididymal sperm maturation and motility. Conclusions: Whole transcriptome sequencing of chicken testis and epididymis screened several key genes and ceRNA regulatory networks, which may be involved in the regulation of epididymal immunity, spermatogenesis and sperm viability through the pathways of MAPK, TGF-β, mTOR, and calcium ion. These findings contribute to our comprehensive understanding of the intricate molecular processes underlying rooster spermatogenesis, maturation and motility. [ABSTRACT FROM AUTHOR]

Background: As a component of the nucleosome remodeling and deacetylating (NuRD) complex, metastasis‐associated protein 1 (MTA1) has been reported to be abundant in male reproductive system and might participate in spermatogenesis and sperm maturation, whereas the precise functional role of MTA1 in these processes is still undetermined. Objective: To investigate the effect and potential function of MTA1 in male fertility. Materials and methods: Mta1 knockout mice (Mta1−/−) were employed to detect their reproductive phenotype. The pH value of Mta1−/− epididymal luminal fluid was measured, and the potential mechanism of MTA1 involved in regulating luminal acidification was detected in vivo and in vitro. A vasectomy model with abnormal pH of epididymal lumen was established to further detect the effect of MTA1 on epididymal luminal microenvironment. Results: Mta1−/− mice were fertile without any detectable defects in spermatogenesis or sperm motility while the deficiency of MTA1 could acidify the initial segment of epididymis to a certain extent. MTA1 could interact with estrogen receptor alpha (ERα) and inhibit the transcription of ERα target gene, hydrogen exchanger 3 (NHE3), and ultimately affect the epididymal luminal milieu. After vasectomy, the Mta1−/− mice presented a more acidic epididymal lumen which was closer to the normal state compared to the wild‐type model. Discussion and conclusion: MTA1 is dispensable for male fertility in mice, but plays a potentially important function in regulating luminal acidification of the epididymis. [ABSTRACT FROM AUTHOR]

Background: Severe acute syndrome coronavirus 2 can invade a variety of tissues, including the testis. Even though this virus is scarcely found in human semen polymerase chain reaction tests, autopsy studies confirm the viral presence in all testicular cell types, including spermatozoa and spermatids. Objective: To investigate whether the severe acute syndrome coronavirus 2 is present inside the spermatozoa of negative polymerase chain reaction‐infected men up to 3 months after hospital discharge. Materials and methods: This cross‐sectional study included 13 confirmed moderate‐to‐severe COVID‐19 patients enrolled 30–90 days after the diagnosis. Semen samples were obtained and examined with real‐time polymerase chain reaction for RNA detection and by transmission electron microscopy. Results: In moderate‐to‐severe clinical scenarios, we identified the severe acute syndrome coronavirus 2 inside spermatozoa in nine of 13 patients up to 90 days after discharge from the hospital. Moreover, some DNA‐based extracellular traps were reported in all studied specimens. Discussion and conclusion: Although severe acute syndrome coronavirus 2 was not present in the infected men's semen, it was intracellularly present in the spermatozoa till 3 months after hospital discharge. The Electron microscopy (EM) findings also suggest that spermatozoa produce nuclear DNA‐based extracellular traps, probably in a cell‐free DNA‐dependent manner, similar to those previously described in the systemic inflammatory response to COVID‐19. In moderate‐to‐severe cases, the blood–testes barrier grants little defence against different pathogenic viruses, including the severe acute syndrome coronavirus 2. The virus could also use the epididymis as a post‐testicular route to bind and fuse to the mature spermatozoon and possibly accomplish the reverse transcription of the single‐stranded viral RNA into proviral DNA. These mechanisms can elicit extracellular cell‐free DNA formation. The potential implications of our findings for assisted conception must be addressed, and the evolutionary history of DNA‐based extracellular traps as preserved ammunition in animals' innate defence might improve our understanding of the severe acute syndrome coronavirus 2 pathophysiology in the testis and spermatozoa. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are highly heterogeneous, and different EV subpopulations from various origins mediate different biological effects. The separation of different subpopulations of EVs from mixtures is critical but challenging. Epididymosomes are secreted by the epididymal epithelium and play a key role in sperm maturation and function. However, limited access to human epididymal tissue and epididymal fluid has hampered further study of epididymosomes and their potential clinical applications. Here, we established a novel strategy based on flow cytometry sorting to isolate human CD63‐positive epididymosomes from ejaculate. We identified CD52, a membrane‐located protein expressed exclusively in the epididymis, as the sorting marker for human epididymosomes. Then, CD63‐positive epididymosomes were isolated from human semen using a flow cytometry sorting instrument and concentrated. Additionally, we observed that isolated CD63‐positive epididymosomes improved sperm function more than other CD63‐positive seminal EV subpopulations did, demonstrating the successful isolation of a subpopulation of epididymosomes from human semen and their potential application in the clinic. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Discussion and conclusion The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus caused the coronavirus disease 2019 pandemic, and the prevalence of deaths among men is higher than among women. The epididymis, divided into caput, corpus, and cauda, shows a region‐specific immunity. The K18‐hACE2 mouse expresses human angiotensin‐converting enzyme 2 (hACE2), the receptor that allows SARS‐CoV‐2 infection. However, studies using this transgenic mouse to evaluate the impact of this viral infection in epididymis have not yet been performed.We evaluated the expression of hACE2 in the epididymis of SARS‐CoV‐2‐infected K18‐hACE2 mice, and assessed the epididymal immune response, focusing on F4/80+ mononuclear phagocytes and tumor necrosis factor‐alpha expression.The following analyses were performed in the epididymal sections of infected mice: epithelial height and duct diameter, birefringent collagen, Terminal deoxynucleotidyl Transferase‐mediated dUTP Nick End Labelling, immunoreactions for detection of hACE2, spike, FGF, V‐ATPase, F4/80, tumor necrosis factor‐alpha, and iNOS. Viral particles were identified under electron microscopy. hACE2, Rigi, Tgfb1 and Tnfa expression were also evaluated by real‐time quantitative polymerase chain reaction.All epididymal regions expressed hACE2, which increased in all epididymal regions in the infected mice. However, the caput appeared to be the most infected region. Despite this, the caput region showed minimal changes while the cauda showed significant epithelial changes associated with increased iNOS immunoexpression. The F4/80+ mononuclear phagocyte area increased significantly in both stroma and epithelium. In addition to the epithelial and stromal mononuclear phagocytes, tumor necrosis factor‐alpha was also detected in clear cells, whose cytoplasm showed a significant increase of this cytokine in the infected animals.The K18‐hACE2 mouse is a useful model for evaluating the impact of SARS‐CoV‐2 infection in the epididymis. The infection induced hACE2 upregulation, favoring the virulence in the epididymis. The epididymal regions responded differentially to infection, and the activation of F4/80+ mononuclear phagocytes associated with the increased tumor necrosis factor‐alpha immunolabeling in clear cells indicates a role of clear cells/mononuclear phagocytes immunoregulatory mechanisms in the epididymal immune response to SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

The epididymis is a crucial component of the goat's reproductive structure. The epididymis is responsible for the transportation, concentration, and maturation of sperm. This study aimed to examine the differences in the structure of macro and microanatomy, tissue composition, and the existence of androgen receptors in the epididymis of Kacang goats aged 4, 8, and 12 months. The assessment of macroscopic organ growth was done immediately after sampling, whereas microscopic measurements were carried out following histological preparations using hematoxylin-eosin (HE) and immunohistochemical (IHC) procedures. The results on the macroscopic anatomy of the epididymis indicated a significant association between age with the width of the caput dexter and sinister and the circumference of the right cauda. However, no significant relationship was found between age with the corpus length and the left cauda's circumference. Significant variations were observed in the diameter and concentration of the agglutinated spermatozoa in the lumen during histomorphometry of the epididymis in three age groups of Kacang goats. There were no statistically significant variations in the expression of androgen receptors among the three age groups. This study showed that the correlation coefficient test reveals a positive relationship between age and the caput width and corpus length dimensions, indicating that these measurements tend to grow as age increases. On the other hand, the diameter of the agglutinated spermatozoa in the epididymal lumen exhibits significant variations between the ages of 4 months, with the ages of 8 months and 12 months, suggesting that the sperm becomes fully matured by the age of 8 months. [ABSTRACT FROM AUTHOR]

Melatonin plays a major role in regulating the sleep-wake cycle and enhancing testosterone production. We investigated the short-term effects of melatonin treatment for 14 consecutive days in the cryptorchidism model. We categorized experimental mice into Sham (S), Orchiopexy (O), Melatonin (Mel), and Orchiopexy + Melatonin (OMel) groups. Surgery involved inducing cryptorchidism in the left testis for seven days, followed by orchiopexy. The Mel group's testes did not descend, but they received melatonin injections after seven days of cryptorchidism. The OMel group underwent both orchiopexy and melatonin treatment. Both O and Mel groups exhibited decreased sperm and round-headed sperm in the epididymis. Significant increases were observed in the numbers of giant cells and negative Nectin-3 cells at p -value<0.05. The pattern of Cadm1 expression changed, and Nectin-2 and Nectin-3 co-expression was lacking in abnormal spermatids. Sertoli cell cytoplasm in both O and Mel groups exhibited autophagosomes and multivesicular bodies, which correlated with increased cyclooxygenase-2 expression. However, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell numbers increased significantly in all treatment groups compared to the S group. Our study found that the combination of orchiopexy and melatonin positively influenced the expression of cell adhesion molecules (Cadm1, Nectin-2, and Nectin-3) involved in spermatogenesis, while reducing giant cells, autophagosomes, and apoptosis. [ABSTRACT FROM AUTHOR]

The molecular mechanism of sterility in cattleyak is still unresolved. The related factors of infertility in cattleyak were studied by tissue section, SERPINA5 gene cloning and bioinformatics technology. Tissue sections of the epididymis showed poorly structured and disorganized epithelial cells in the corpus of the epididymis compared to the caput of the epididymis, while in the cauda part of the epididymis, the extra basal smooth muscle was thinner, the surface of the epithelial lumen was discontinuous and the epithelium was markedly degenerated. The results of gene cloning showed that the coding sequence (CDS) region of the SERPINA5 gene in cattleyak was 1215 bp in length, encoding a total of 404 amino acids, of which the isoleucine content was the highest, accounting for a total of 49 amino acids (12.1%). The results of real-time fluorescence quantitative PCR (qPCR) showed that the expression of the SERPINA5 gene in the epididymis caput in cattleyak was significantly higher than that in the corpus and cauda (P < 0.05), but there were no significant differences between the corpus and cauda. In the current study, histological and bioinformatics analysis, physicochemical properties, and the expression analysis of the SERPINA5 gene in different regions of the epididymis in cattleyak were carried out to explore the biological complications of cattleyak infertility. [ABSTRACT FROM AUTHOR]

Simple Summary: Sugar gliders are exotic animals that have become pets in recent years. As a result, these small marsupials are increasingly coming to the veterinary practices. Marsupials are a group of mammals characterized by their peculiar way of reproduction. This translates into the distinct anatomy of their genital apparatus, both male and female. There are not many references concerning the anatomy of this particular species. The male reproductive system of the Petaurus breviceps follows the general pattern in marsupials, but each species has its own peculiarities that the veterinary clinician should know. It includes two testes, epididymis, and deferent ducts, as well as two types of accessory glands: the prostate and the bulbourethral glands, in addition to the male urethra and the penis, which is bifid at its end. The purpose of this study was to describe the male genital gross anatomy of the sugar gliders (supplemented with some microscopic observations), to provide detailed information to veterinary clinicians to facilitate accurate diagnosis and surgery. The present study provides a detailed macroscopic examination (with some microscopic insights) of the genital apparatus of seven adult and intact male sugar gliders, as well as one castrated individual. The scrotum is pendulous and attached to the ventral abdominal wall, situated in the caudal part of the abdomen and cranial to the cloacal opening. The testes are oval shaped with their long axes oriented vertically. The epididymides are attached along the caudomedial border of their respective testes. The head and tail of the epididymides are in close proximity to the poles of the testes but are not directly attached. The deferent ducts are positioned laterally to their ipsilateral ureter as they run near the dorsal surface of the urinary bladder. The ampulla of the deferent duct is absent. The penis is located post-scrotally, lacks insertion into the bony pelvis, and has a bifid distal end. The crura of the penis originate within the ischiocavernosus muscles, and there are two bulbs of the penis. When flaccid, the entire penis is concealed in the perineal region and externalizes through an orifice situated in the ventral part of the cloaca, traversing its floor towards the cloacal opening. The urethral external orifice is positioned at the point where the bifurcation of the free part of the penis begins. The prostate gland resides in the pelvic cavity and consists of two parts: a macroscopically visible body surrounding the urethra and a microscopically identifiable portion embedded within the walls of the duct. Sugar gliders possess two pairs of bulbous bulbourethral glands, located dorsally and laterally to the rectum, but lack vesicular glands. [ABSTRACT FROM AUTHOR]

Introduction: Recently, acrylamide (Acr), which is a chemical compound utilised in industry, was detected in food rich in carbohydrates that had been subjected to a high temperature. It exerts its toxic effect through generation of oxidative species. Luteolin (Lut) is a potent antioxidant flavonoid that may mitigate this toxic effect. Aim to the Work: To evaluate the histochemical changes induced by Acr on adult rat epididymal caput and the probable role of Lut in ameliorating these changes. Materials and Methods: 30 adult rats were allocated into: group I (Control) received either distilled water (subgroup IA) or corn oil (subgroup IB), group II received 100 mg/kg/day of Lut orally, group III received 6.25 mg/kg/day of Acr orally, and group IV co-administrated Lut and Acr at doses as those of groups II and III. After 21 days, the rats were sacrificed after being weighed at the start and the end of the experiment. Sera were obtained for detection of testosterone level. Caudal fluid was collected for sperm count and motility analysis. Tissue homogenates were used to measure the level of malondialdehyde (MDA), superoxide dismutase (SOD), and the gene expression of Bcl2-Associated X Protein (BAX) and B-cell lymphoma 2 (Bcl2). Caputs were processed and examined by light and electron microscopies. All data were subjected to statistical analyses. Results: Acr induced disruption of the caput epithelium with widening of the intercellular spaces, vacuolations, nuclear changes, reduction in sperm count and motility, a significant decline in animal weights, serum testosterone, increase in MDA and reduction in SOD. Moreover, gene expression of BAX showed a significant up-regulation with down-regulation of Bcl2. Co-administration of Lut with Acr led to improvement in structure of epididymal caput, the animal weights, the testosterone level, SOD, Bcl2, sperm count and motility. Conclusion: Acr induced histochemical toxicity in epididymal caput, meanwhile Lut attenuated this effect. [ABSTRACT FROM AUTHOR]

The purpose of this study is to examine the effect of baicalin on cyclophosphamide (CP)-induced testicular damage in rats. Twenty-eight Wistar albino rats were assigned to the control, baicalin, CP, and CP+Baicalin groups. A single dose of CP (200 mg/kg) was induced intraperitoneally (i.p.) in the CP and CP+Baicalin groups. Baicalin (100 mg/kg/day, i.p.) was administered in the baicalin and CP+ Baicalin groups for 6 days. After sacrification, the testes, epididymis and blood samples were taken. Testis tissues were investigated for general morphology, proliferating, and apoptotic cells. Oxidative stress parameters in testis tissue and hormone levels in serum were examined by biochemical analysis. Sperm analysis was performed on smear samples obtained from the epididymis. In CP + Baicalin group, decreases in both the number of abnormal spermatozoa and degeneration of seminiferous tubules were observed compared to the CP group. Also, decreased apoptotic cells and increased proliferative cells were detected in these seminiferous tubules. Furthermore, the treatment with Baicalin reversed the changes observed in the markers of oxidative damage including malondialdehyde, total oxidant status, and oxidative stress index, and markers of the antioxidant defense system including glutathione, total antioxidant capacity, superoxide dismutase, and catalase except for glutathione s-transferase (GST) in testicular tissue. Decreased serum levels of follicle-stimulating hormone, luteinizing hormone, and testosterone related to CP significantly improved in CP + Baicalin group. Conclusion: Baicalin attenuates CP-induced testicular damage by inhibiting oxidative stress possibly due to its antioxidant properties. Considering on the proposed beneficial effects of Baicalin against testicular damage induced by CP, it might have the potential to be a promising agent for male infertility related to chemotherapy. [ABSTRACT FROM AUTHOR]

Context: Integrated omics studies hold a crucial role in improving our understanding of reproductive biology. However, the complex datasets so generated are often only accessible via supplementary data files, which lack the capacity for interactive features to allow users to readily interrogate and visualise data of interest. Aims: The intent of this technical note was to develop an interactive web-based application that enables detailed interrogation of a representative sperm proteome, facilitating a deeper understanding of the proteins identified, their relative abundance, classifications, functions, and associated phenotypes. Methods: We developed a Shiny web application, ShinySperm (), utilising R and several complementary libraries for data manipulation (dplyr), interactive tables (DT), and visualisation (ggplot2, plotly). ShinySperm features a responsive user interface, dynamic filtering options, interactive charts, and data export capabilities. Key results: ShinySperm allows users to interactively search, filter, and visualise sperm proteomics data based on key features (e.g. protein classification, sperm cell domain, presence, or absence at different maturation stages). This application responds live to filtering options and enables the generation of interactive plots and tables, thus enhancing user engagement and understanding of the data. Conclusions: ShinySperm provides a robust platform for the dynamic exploration of epididymal sperm proteome data. It significantly improves accessibility and interpretability of complex datasets, allowing for effective data-driven insights. Implications: This technical note highlights the potential of interactive web applications in reproductive biology and provides a plug and play script for the field to produce applications for meaningful researcher interaction with complex omic datasets. Understanding complex biological data is crucial for advancements in reproductive biology. Our study developed ShinySperm, a web application that allows researchers to easily explore, interrogate, and visualise intricate sperm proteomic data. This tool sets out a blueprint for future research, enabling researchers to bring their intricate datasets to life, allowing others to interact with and interpret more effectively, ultimately driving innovation in reproductive biology. Image by David Skerrett-Byrne. This article belongs to the Collection Frontiers in Reproduction Science – Rising Stars at the Society for Reproductive Biology 2023. [ABSTRACT FROM AUTHOR]

The purpose of this research was to characterise the echogenicity of the different structures within the scrotal bag in rams. Three studies that included 43 rams were conducted. Ultrasound sections (US) were made with the Mindray® equipment. It was found that pubertal males showed greater echogenicity (P<0.05) in testes and the pampiniform plexus, whereas prepubertal males (P<0.05) - in the epididymis and in the right pampiniform plexus. Rams in mating showed the highest echogenicity values (P<0.05). In non-mating animals, the highest values were found in the epididymis (P<0.05). Rams with injuries presented higher echogenicity in testes (P<0.05). In pampiniform plexuses, males without injuries demonstrated the highest values (P<0.05). A high and positive correlation (P<0.0001) was found between the evaluated variables, specifically the right cranial longitudinal (RCL), right proximal transverse (RPT), right medial transverse (RMT), right distal transverse (RDT) measures. Echotexture in rams was affected by age, presence of injuries and sexual activity. In addition, the high correlation suggests that the evaluation of testicular health in rams could be carried out only with several US. [ABSTRACT FROM AUTHOR]

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Abstract Background Chickens play a crucial role as the primary global source of eggs and poultry, and the quality of rooster semen significantly impacts poultry reproductive efficiency. Therefore, it is imperative to comprehend the regulatory mechanisms underlying sperm development. Results In this study, we established transcriptome profiles of lncRNAs, miRNAs, and mRNAs in 3 testis tissues and 3 epididymis tissues from “Jing Hong No.1” roosters at 24, 35, and 64 weeks of age. Using the data, we conducted whole transcriptome analysis and constructed a ceRNA network. We detected 10 differentially expressed mRNAs (DEmRNAs), 33 differentially expressed lncRNAs (DElncRNAs), and 10 differentially expressed miRNAs (DEmiRNAs) in the testis, as well as 149 DEmRNAs, 12 DElncRNAs, and 10 DEmiRNAs in the epididymis. These genes were found to be involved in cell differentiation and development, as well as various signaling pathways such as GnRH, MAPK, TGF-β, mTOR, VEGF, and calcium ion pathways. Subsequently, we constructed two competing endogenous RNA (ceRNA) networks comprising DEmRNAs, DElncRNAs, and DEmiRNAs. Furthermore, we identified four crucial lncRNA-mRNA-miRNA interactions that govern specific biological processes in the chicken reproductive system: MSTRG.2423.1-gga-miR-1563-PPP3CA and MSTRG.10064.2-gga-miR-32-5p-GPR12 regulating sperm motility in the testis; MSTRG.152556.1-gga-miR-9-3p-GREM1/THYN1 governing immunomodulation in the epididymis; and MSTRG.124708.1-gga-miR-375-NDUFB9/YBX1 controlling epididymal sperm maturation and motility. Conclusions Whole transcriptome sequencing of chicken testis and epididymis screened several key genes and ceRNA regulatory networks, which may be involved in the regulation of epididymal immunity, spermatogenesis and sperm viability through the pathways of MAPK, TGF-β, mTOR, and calcium ion. These findings contribute to our comprehensive understanding of the intricate molecular processes underlying rooster spermatogenesis, maturation and motility.

Although microsurgical vasoepididymostomy (MVE) is an effective treatment for epididymal obstructive azoospermia, some patients may experience delayed patency or suboptimal semen parameters after patency. However, research into patency time, semen quality postpatency, and associated influencing factors remains limited. This study aimed to address these issues by evaluating 181 patients who underwent at least one-sided MVE employing asingle-armed longitudinal intussusception vasoepididymostomy technique, with a follow-up period of over 12 months for 150 patients. The overall patency rate was 75.3%, with 86.0% of patients achieving patency within 6 months following MVE. Unexpectedly, factors such as age, history of epididymitis, duration of surgery, side of anastomosis, sperm motility in epididymal fluid, and the site of anastomosis showed no correlation with patency time. Nonetheless, our univariate and multivariate linear regression analysis indicated that only the site of anastomosis was positively correlated with and could independently predict postoperative total motile sperm count. Therefore, the site of anastomosis might serve as a predictor for optimal postoperative semen quality following the MVE procedure.

The epididymis is a crucial component of the goat's reproductive structure. The epididymis is responsible for the transportation, concentration, and maturation of sperm. This study aimed to examine the differences in the structure of macro and microanatomy, tissue composition, and the existence of androgen receptors in the epididymis of Kacang goats aged 4, 8, and 12 months. The assessment of macroscopic organ growth was done immediately after sampling, whereas microscopic measurements were carried out following histological preparations using hematoxylin-eosin (HE) and immunohistochemical (IHC) procedures. The results on the macroscopic anatomy of the epididymis indicated a significant association between age with the width of the caput dexter and sinister and the circumference of the right cauda. However, no significant relationship was found between age with the corpus length and the left cauda's circumference. Significant variations were observed in the diameter and concentration of the agglutinated spermatozoa in the lumen during histomorphometry of the epididymis in three age groups of Kacang goats. There were no statistically significant variations in the expression of androgen receptors among the three age groups. This study showed that the correlation coefficient test reveals a positive relationship between age and the caput width and corpus length dimensions, indicating that these measurements tend to grow as age increases. On the other hand, the diameter of the agglutinated spermatozoa in the epididymal lumen exhibits significant variations between the ages of 4 months, with the ages of 8 months and 12 months, suggesting that the sperm becomes fully matured by the age of 8 months.

The present research investigation intends at investigating the effect of on Sialic acid components in male albino rats of an aqueous extract of seeded papaya fruit pulp and seed extract specified as a combined dose and seedless variety papaya fruit pulp extract. The primary objective of the current research investigation was to evaluate the effects that occurred on male albino Wistar rats of semi-ripe fruit pulp extract from Carica papaya (fruits with and without seeds). The development of spermatozoa's ability to fertilise, the coating of spermatozoa with specific antigens, and changes in their membrane surface are all related to Sialic acid. Less spermatozoa cells in the testicular compartments and fewer of these cells are indicated by the decrease in Sialic acid contents in the testis and epididymis of both experimental groups.

Background Objective Materials and Methods Results Discussion and Conclusions Previous research has illustrated the role of cilia as mechanical and sensory antennae in various organs within the mammalian male reproductive system across different developmental stages. Despite their significance in both organ development and homeostasis, primary cilia in the human male reproductive excurrent duct have been overlooked due to limited access to human specimens.This study aimed to characterize the unique cellular composition of human efferent and epididymal ducts, with a focus on their association with primary cilia.Human efferent ductules/epididymides from five donors aged 32–47 years, were obtained through our local organ transplant program. Cell lineage specificity and primary cilia features were examined by immunofluorescent staining and confocal microscopy in the efferent ductules and the distinct segments of the epididymis.The epithelium of the human efferent duct exhibited estrogen receptor‐positive cells with primary cilia, FoxJ1‐positive multiciliated cells with numerous motile cilia, and non‐ciliated intraepithelial immune cells. Notably, intraluminal macrophages, identified by CD163/CD68 positivity, were observed to engage in sperm phagocytosis. In all three segments of the human epididymis, primary cilia were found on the surface of principal and basal cells.Our research indicates that the human efferent ductules create a distinct environment, characterized by the presence of two types of ciliated cells that are in contact with immune cells. The discovery of sensory primary cilia exposed on the surface of reabsorptive cells in the efferent ductules, as well as on basal and principal cells in the epididymis, lays the foundation for complementary functional studies. This research uncovers novel characteristics exclusive to human efferent ductules and epididymides, providing a basis for exploring innovative approaches to male contraception and infertility treatment. [ABSTRACT FROM AUTHOR]

Zinc (Zn) is an essential trace element; it exhibits a plethora of physiological properties and biochemical functions. It plays a pivotal role in regulating the cell cycle, apoptosis, and DNA organization, as well as in protein, lipid, and carbohydrate metabolism. Among other important processes, Zn plays an essential role in reproductive health. The ZIP and ZnT proteins are responsible for the mobilization of Zn within the cell. Zn is an inert antioxidant through its interaction with a variety of proteins and enzymes to regulate the redox system, including metallothioneins (MTs), metalloenzymes, and gene regulatory proteins. The role of Zn in the reproductive system is of great importance; processes, such as spermatogenesis and sperm maturation that occur in the testicle and epididymis, respectively, depend on this element for their development and function. Zn modulates the synthesis of androgens, such as testosterone, for these reproductive processes, so Zn deficiency is related to alterations in sperm parameters that lead to male infertility. [ABSTRACT FROM AUTHOR]

Introduction: The epididymis is important for sperm transport, maturation, and storage. Methods: The head and tail of the epididymis of 5-week-old and 10-week-old C57 BL/6J male mice were used for single-cell sequencing. Results: 10 cell types including main, basal, and narrow/clear cells are identified. Next, we performed cell subgroup analysis, functional enrichment analysis, and differentiation potential prediction on principal cells, clear cells, and basal cells. Our study indicates that the principal cells are significantly involved in sperm maturation, as well as in antiviral and anti-tumor immune responses. Clear cells are likely to play a crucial role in safeguarding sperm and maintaining epididymal pH levels. Basal cells are implicated in the regulation of inflammatory and stress responses. The composition and functions of the various cell types within the epididymis undergo significant changes before and after sexual maturity. Furthermore, pseudo-temporal analysis elucidates the protective and supportive roles of epididymal cells in sperm maturation during sexual maturation. Discussion: This study offers a theoretical framework and forecasts for the investigation of epididymal sperm maturation and epididymal immunity. [ABSTRACT FROM AUTHOR]

The ubiquitous existence of microplastics and nanoplastics raises concerns about their potential impact on the human reproductive system. Limited data exists on microplastics within the human reproductive system and their potential consequences on sperm quality. Our objectives were to quantify and characterize the prevalence and composition of microplastics within both canine and human testes and investigate potential associations with the sperm count, and weights of testis and epididymis. Using advanced sensitive pyrolysis-gas chromatography/mass spectrometry, we quantified 12 types of microplastics within 47 canine and 23 human testes. Data on reproductive organ weights, and sperm count in dogs were collected. Statistical analyses, including descriptive analysis, correlational analysis, and multivariate linear regression analyses were applied to investigate the association of microplastics with reproductive functions. Our study revealed the presence of microplastics in all canine and human testes, with significant inter-individual variability. Mean total microplastic levels were 122.63 µg/g in dogs and 328.44 µg/g in humans. Both humans and canines exhibit relatively similar proportions of the major polymer types, with PE being dominant. Furthermore, a negative correlation between specific polymers such as PVC and PET and the normalized weight of the testis was observed. These findings highlight the pervasive presence of microplastics in the male reproductive system in both canine and human testes, with potential consequences on male fertility. [ABSTRACT FROM AUTHOR]

The epididymis, a key reproductive organ, is crucial for sperm concentration, maturation, and storage. Despite a comprehensive understanding of many of its functions, several aspects of the complex processes within the epididymis remain obscure. Dysfunction in this organ is intricately connected to the formation of the microenvironment, disruptions in sperm maturation, and the progression of male infertility. Thus, elucidating the functional mechanisms of the epididymal epithelium is imperative. Given the variety of cell types present within the epididymal epithelium, utilizing a three-dimensional (3D) in vitro model provides a holistic and practical framework for exploring the multifaceted roles of the epididymis. Organoid cell culture, involving the co-cultivation of pluripotent or adult stem cells with growth factors on artificial matrix scaffolds, effectively recreates the in vivo cell growth microenvironment, thereby offering a promising avenue for studying the epididymis. The field of epididymal organoids is relatively new, with few studies focusing on their formation and even fewer detailing the generation of organoids that exhibit epididymis-specific structures and functions. Ongoing challenges in both clinical applications and mechanistic studies underscore the importance of this research. This review summarizes the established methodologies for inducing the in vitro cultivation of epididymal cells, outlines the various approaches for the development of epididymal organoids, and explores their potential applications in the field of male reproductive biology. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Sleep deprivation (SD) can cause damage to the male reproductive system. However, the duration required for such damage and the specific sequence and severity of damage to the testis and epididymis remain unclear.To investigate the effects of different durations of SD on different parts of the testis and epididymis caput, corpus, and cauda.Adult ICR mice were randomly assigned to five groups: the SD group (SD for 18 h/day for 1, 2, 3, or 4 weeks), the SD + Vit E group (supplemented with Vit E 50 mg/kg/d during 4 weeks of SD, the SD+NS group (saline supplementation during 4 weeks of SD), the SD + RS group (5 weeks of recovery sleep after 4 weeks of SD), and a normal sleep control (Ctrl) group. Following the interventions, sperm parameters, testicular and epididymal histopathology, inflammatory response, and oxidative stress markers were compared between the groups.Compared to the Ctrl group, the SD group showed a decrease in sperm motility and concentration from SD 2 W and SD 3 W, respectively. Decreases in sperm concentration and motility were more pronounced in the cauda compared to the caput and corpus. Pathological damage was less severe in the epididymis caput than in the corpus and cauda. After 4 weeks of SD, inflammation and oxidative stress increased in both testes and epididymis. Both sleep recovery and vitamin E supplementation showed significant improvements, though they did not fully reach the level of the Ctrl group.Chronic SD for more than 2 weeks causes varying degrees of damage to the testis, epididymis caput, corpus, and cauda in male mice. This damage is not fully reversible after 5 weeks of sleep recovery and antioxidant stress treatment. These findings help us to identify and prevent SD damage to the male reproduction at an early stage. [ABSTRACT FROM AUTHOR]

Background Objectives Material and methods Results Discussion and conclusion The endoplasmic reticulum (ER) is the central hub for protein quality control, where the protein disulfide isomerases (PDIs), encoded by at least 21 genes, play a pivotal role. These multifunctional proteins contribute to disulfide bond formation, proper folding, and protein modifications, and may act as hormone‐binding proteins (e.g., steroids), influencing hormone biology. The interplay between ER proteostasis, PDIs, and epididymis—a crucial site for sperm maturation—remains largely understudied.This study characterizes transcriptional signatures of Pdi genes in the epididymis.Transcriptional profiles of selected Pdi genes were assessed in adult Wistar rat tissues, and epididymis under different experimental conditions (developmental stages, surgical castration, and efferent ductules ligation [EDL]). In silico bioinformatic analyses identified expression trends of this gene family in human epididymal segments.P4hb, Pdia3, Pdia5, Pdia6, Erp44, Erp29, and Casq1 transcripts were detected in both reproductive and non‐reproductive tissues, while Casq2 exhibited higher abundance in vas deferens, prostate, and heart. Pdilt, highly expressed in testis, and Pdia2, highly expressed in heart, showed minimal mRNA levels in the epididymis. In the mesonephric duct, epididymal embryonic precursor, P4hb, Pdia3, Pdia5, Pdia6, and Erp29 mRNAs were found at gestational day (GD) 17.5. Except for Erp29, which remained stable, these Pdi transcript levels increased from GD17.5 to GD20.5, when epididymal morphogenesis occurs, and were maintained to varying degrees in the epididymis during postnatal development. Surgical castration downregulated P4hb, Pdia3, Pdia5, Pdia6, Pdilt and Erp29 transcripts, an effect reversed by testosterone replacement. Conversely, transcript levels remained unaffected by EDL, except P4hb, which was reduced in caput epididymis. All 21 PDI genes exhibited diverse transcriptional profiles across the human epididymis.The findings lay the foundations to explore Pdi genes in epididymal biology. As a considerable proportion of male infertility cases are idiopathic, targeting hormonal regulation of protein quality control in epididymis represents a route to address male infertility and advance therapeutic interventions in this domain. [ABSTRACT FROM AUTHOR]

To date, only 1 example of cystadenofibroma of the epididymis has been reported in the English literature. Here, we present a second cystadenofibroma originating from the epididymis of a 54-year-old man who presented with painful swelling in the scrotum. The scrotal mass measured 6.3 cm and contained a clear yellow, serous to gelatinous fluid-filled cyst with internal papillae. Microscopically, the mass contained both stromal and epithelial components. The stromal component consisted of spindle cells arranged in small intervening fascicles, forming simple cyst and papillae. The cyst and papillae were lined by cuboidal to columnar and ciliated epithelium. Immunohistochemistry staining showed that the stromal component was positive for estrogen receptor, progesterone receptor, and CD10, which are characteristic of ovarian-type stroma. However, the epithelium lining was positive for keratin cocktail AE1/3&CAM5.2, CD10, PAX8, androgen receptor, and alpha-1 antitrypsin, suggesting a possible Wolffian duct origin. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility of diffusion tensor imaging (DTI) and fiber tractography (FT) of the normal epididymis and to determine normative apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values. Methods: Twenty-eight healthy volunteers underwent MRI of the scrotum, including DTI on a 3.0 T system. For each anatomic part of the epididymis (head, body and tail) free-hand regions of interest were drawn and the mean ADC and FA were measured by two radiologists in consensus. Parametric statistical tests were used to determine intersubject differences in ADC and FA between the anatomic parts of each normal epididymis and between bilateral epididymides. Fiber tracts of the epididymis were reconstructed using the MR Diffusion tool. Results: The mean ADC and FA of the normal epididymis was 1.31 × 10–3 mm2/s and 0.20, respectively. No differences in ADC (p = 0.736) and FA (p = 0.628) between the anatomic parts of each normal epididymis were found. Differences (p = 0.020) were observed in FA of the body between the right and the left epididymis. FT showed the fiber tracts of the normal epididymis. Main study's limitations include the following: small number of participants with narrow age range, absence of histologic confirmation and lack of quantitative assessment of the FT reconstructions. Conclusion: DTI and FT of the normal epididymis is feasible and allow the noninvasive assessment of the structural and geometric organization of the organ. [ABSTRACT FROM AUTHOR]

Background: Leiomyosarcoma is a tumor that can develop in any organ that contains smooth muscles. Although leiomyosarcoma is common, its epididymal localization is quite rare. Case presentation: A 79-year-old male Chinese Han patient presented with mild pain in the right groin and scrotum for 3 years concomitant with right scrotal swelling. Ultrasonography and magnetic resonance imaging of the scrotum showed a irregular and heterogeneous mass that was extratesticular. Right high orchiectomy was performed, and pathological examination of the resected specimen confirmed the diagnosis of leiomyosarcoma of the epididymis with surgical margins clear of tumor. Conclusion: Epididymal leiomyosarcoma is rare and difficult to diagnose preoperatively. The final diagnosis of epididymal leiomyosarcoma requires histologic examination. Resection must be extensive and complete. The effect of chemotherapy and radiation on the epididymal leiomyosarcoma remains unclear. Recurrence is common, so follow-up is necessary. [ABSTRACT FROM AUTHOR]

Aquaporins (AQPs), also known as water channels, appear to be particularly promising in maintaining male reproductive potential. Therefore, this study aimed to determine the presence of classical AQPs in the bovine (Bos taurus) reproductive system and analyze changes in their expression with age using immunohistochemistry and Western blotting. Of the six classical AQPs, AQP0, AQP1, AQP4, AQP5 and AQP6 were detected, while AQP2 was absent. In the testis, AQP0 was visible in Leydig cells in selected animals, while AQP1 was found in myoid cells surrounding the seminiferous tubules of mature individuals. This characteristic expression patterns of AQP0, limited only to certain bulls, is difficult to explain unequivocally. It is possible that AQP0 expression in cattle is subject to individual variability or changes in response to specific physiological conditions. In the caput and corpus epididymis, AQP0 showed weak expression in epithelial cells of immature animals and stronger expression in basal and principal cells of reproductive bulls. In all animals, AQP1 was present on the apical surface of epithelial cells in the initial segment of the caput epididymis. AQP4, AQP5 and AQP6 were identified in principal and basal cells along the entire epididymis of reproductive bulls. The abundance of AQP4 and AQP6 increased from the caput to the cauda epididymis with the growth and development of the animals. In all males, AQP4, AQP5 and AQP6 were observed in epithelial cells of the vas deferens, and their expression in this section increased with age. In conclusion, the abundance and distribution of the classical AQPs in various cell types and parts of the male reproductive system indicate their crucial role in maintaining water homeostasis, which is essential for normal reproductive function in cattle. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results and discussion Conclusion The epididymis is important for sperm maturation and without its proper development, male infertility will result. Biomechanical properties of tissues/organs play key roles during their morphogenesis, including the Wolffian duct. It is hypothesized that structural/bulk stiffness of the capsule and mesenchyme/extracellular matrix that surround the duct is a major biomechanical property that regulates Wolffian duct morphogenesis. These data will provide key information as to the mechanisms that regulate the development of this important organ.To measure the structural/bulk stiffness in Pascals (force/area) of the capsule and the capsule and mesenchyme together that surrounds the Wolffian duct during the development. To examine the relative membrane tension of mesenchymal cells during the Wolffian duct development. Since Ptk7 was previously shown to regulate ECM integrity and Wolffian duct elongation and coiling, the hypothesis that Ptk7 regulates structural/bulk stiffness and mesenchymal cell membrane tension was tested.Atomic force microscopy and a microsquisher compression apparatus were used to measure the structural stiffness. Biomechanical properties within the membranes of cells within the capsule and mesenchyme were examined using a membrane‐tension fluorescent probe.The structural stiffness (Pascals) of the capsule and underlying mesenchyme was relatively constant during development, with a significant increase in the capsule at the later stages. However, this increase may reflect the ECM and associated mesenchyme being close to the capsule because the coiling of the duct pushed or compressed them into that space. Keeping the capsule and mesenchyme/ECM at constant stiffness would ensure that the duct will continue to coil under similar biomechanical forces throughout the development. Cells within the capsule and mesenchyme at different Wolffian duct regions during the development had varying degrees of membrane lipid tension. It is hypothesized that the dynamic changes ensure the duct is kept at a constant stiffness regardless of any external forces. Loss of Ptk7 resulted in an increase in stiffness at E18.5, which was presumable due to the loss of integrity of the ECM within the mesenchyme.Biomechanical properties of the capsule and the mesenchyme/extracellular matrix that surround the Wolffian duct play an important role toward Wolffian duct morphogenesis, thereby allowing for the proper development of the epididymis and subsequent male fertility. [ABSTRACT FROM AUTHOR]

Sperm complete their maturation in the epididymis. Mature sperm are highly sensitive to oxidative damage. Peroxiredoxin-6 (PRDX6) is an important antioxidant enzyme. In this study, we investigated PRDX6 expression in the epididymal microenvironment and its distribution in the sperm of sheep. We found that PRDX6 mRNA and protein had the highest expression in the caput epididymis, followed by the corpus epididymis and cauda epididymis (p<0.01). PRDX6 protein expression in epididymal fluid was higher in the caput epididymis than in the corpus epididymis and cauda epididymis (p<0.01). Similarly, PRDX6 protein expression was higher in sperm derived from the caput epididymis and corpus epididymis than in sperm derived from the cauda epididymis (p<0.01). Immunofluorescence revealed that PRDX6 was present only in the head of sperm derived from the caput epididymis and corpus epididymis but was distributed within the principal and middle regions of sperm derived from the cauda epididymis. Furthermore, PRDX6 was present in all parts of ejaculated sperm. In conclusion, PRDX6 showed a wider distribution in sperm cells during transport through the epididymis, and PRDX6 expression levels in epididymal tissue, epididymal fluid, and epididymal sperm decreased from the caput epididymis to the cauda epididymis. These results suggest that PRDX6 has an important role during sperm maturation in the epididymis. [ABSTRACT FROM AUTHOR]

We report a histiocytic sarcoma originating from the epididymis observed in a 110-week-old male CD-1 mouse in a carcinogenicity study. At necropsy, no lesions were observed in the epididymis. Histologically, a neoplastic lesion was observed in the cauda of the epididymis that was well demarcated from the surrounding tissues. The lesion mainly consisted of spindle-shaped tumor cells with oval to elongated nuclei and abundant eosinophilic or foamy cytoplasm. The tumor cells were arranged in a fascicular pattern, interlacing bundles, or a whorl pattern. The nuclei showed mild atypia with irregular shapes and varied sizes, whereas few mitotic figures and no typical multinucleated cells were observed. The epididymal ducts remained within the neoplastic lesion, and the tumor cells invaded between the epithelium and the smooth muscle layer of the epididymal duct. Immunohistochemically, the tumor cells were positive for vimentin and macrophage markers (Iba1, CD204, F4/80, and Mac-2) but negative for cytokeratin and other mesenchymal cell (a-smooth muscle actin, desmin, CD31, and platelet-derived growth factor receptor-ß), neural cell (S-100 and nestin), or Leydig cell markers (calretinin). Proliferating cell nuclear antigen-positive tumor cells were sporadically observed in the lesion. Based on these results, the tumor was diagnosed as a histiocytic sarcoma originating from the epididymis. This report provides additional histopathological evidence of spontaneous histiocytic sarcomas originating from the epididymis of aged mice. [ABSTRACT FROM AUTHOR]

Duplicate testes lined in series were observed in the right scrotum of a 6-week-old Sprague-Dawley rat in a single-dose toxicity study. Of the two right testicles, one was spherical and less than half the size of a normal testis. The other was oval-shaped, slightly smaller than a normal testis, and possessed clear, tortuous blood vessels similar to those of a normal testis. Each right testis was grossly separated but faced the intertesticular adipose tissue and was sparsely joined by thin cord-like structures. Only one epididymis covered or encompassed the two right testes. The caput epididymis was attached to the smaller spherical testis, whereas the cauda epididymis was attached to the oval testis. Histopathological examination revealed that the smaller spherical testis on the right side and the testis on the left side were normal. The oval-shaped testis on the right exhibited markedly dilated degenerative seminiferous tubules with one to two layers of Sertoli or germ cells, and almost no spermatogenesis was observed. Multinucleated germ cells were observed in the lumen of the degenerated seminiferous tubules. The right epididymis was morphologically normal and contained few sperm in the epididymal duct of the tail. The cord-like structures between duplicate testes comprised fibrous and adipose tissues. Single efferent ductules, ectopic cartilage, and skeletal muscle tissues were buried in the adipose tissue. To our knowledge, this is the first report of spontaneous polyorchidism in a rodent. [ABSTRACT FROM AUTHOR]

Only a few cases of inflammatory myofibroblastic tumor (IMT) occurring in epididymis were reported, and all of them were single tumors. We reported a case of multiple IMT of epididymis. The patient found a mass in the right scrotum for a year, and the mass increased progressively. Ultrasonography showed multiple solid nodules in the right scrotum. Right scrotal exploration and resection of mass were performed. Multiple round pleniform masses were found in the right epididymis during the operation. The pathology of the masses was IMT. No recurrence of the masses was found after 6 months of postoperative follow-up. By reviewing the literature, we supposed that IMT of the epididymis had similar clinical symptoms to other masses occurring in the epididymis. It was generally difficult to clarify the IMT before surgery. The tumor would grow progressively and had low malignant potential, so it was recommended to remove the tumor surgically. The patients did not need other special treatment after surgery, because the IMT would not recur generally. However, the regular review was required. [ABSTRACT FROM AUTHOR]

The sperm‐associated antigen 11a (Spag11a) gene is exclusively expressed in the caput epididymis. Our previous studies demonstrated that small interfering RNA (siRNA)‐mediated ablation of this gene resulted in increased proliferation of epididymal epithelial cells. Further, active immunization‐mediated ablation of SPAG11A protein increased the susceptibility of male reproductive tract tissues to diethylnitrosamine (DEN)‐induced tumorigenesis. In this study, we report that the caput epididymis of Spag11a knockout mice displayed hyperplasia and inflammation, while the caput epididymis of wild‐type mice exhibited normal anatomical structure. Global transcriptome analyses in the caput epididymis of knockout mice indicated differential expression of genes involved in a variety of cellular processes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses suggested that the absence of Spag11a may activate microRNAs associated with cancer, chemical carcinogenesis‐receptor activation, and chemical carcinogenesis‐DNA adducts pathways; which may contribute to the promotion of tumorigenesis in the epididymis. The susceptibility of caput epididymis to chemically induced carcinogenesis in Spag11a knockout mice was analyzed. Histological analyses indicated that while the epididymis of wild‐type mice did not show any signs of tumorigenesis, knockout mice displayed hyperplasia, anaplasia, dysplasia, neoplasia, and inflammation in the caput epididymis. Our results provide concrete evidence that deletion of Spag11a induces histopathological and molecular changes that contribute to tumorigenesis. It is possible that the expression of Spag11a gene could be one of the reasons for the rarity of epididymal cancers. The involvement of an epididymal gene in tumorigenesis is being demonstrated for the first time. Significance statement: Epididymal cancers are rare, and it was proposed that a large number of factors that are specifically expressed in the epididymis contribute to this unique property. The Spag11a gene is specifically expressed in the epididymis. We demonstrated that ablation of Spag11a gene in epididymal primary cells induced proliferation, while overexpression in an immortalized caput‐derived cell line inhibited proliferation. We also demonstrated that ablation of SPAG11A protein by active immunization rendered the microenvironment of the epididymis favorable for tumorigenesis. We propose that Spag11a gene could be one of the factors that renders the epididymis resistant to tumorigenesis. In‐depth analysis on the role of this gene could provide strategies to address tumorigenesis in other organ systems as well. [ABSTRACT FROM AUTHOR]

The epididymal duct exhibits spontaneous phasic contractions (SPCs) to store and transport sperm. Here, we explored molecular identification of pacemaker cells driving SPCs in the caudal epididymal duct and also investigated properties of pacemaker currents underlying SPCs focusing on ANO1 Ca2+-activated Cl− channels (CaCCs). Immunohistochemistry was performed to visualise the distribution of platelet-derived growth factor receptor α (PDGFRα)- or ANO1-positive cells in the rat caudal epididymal duct. Perforated whole-cell patch clamp technique was applied to enzymatically isolated epididymal cells, while SPCs were recorded with video edge-tracking technique. Immunohistochemistry revealed the distribution of α-smooth muscle actin (α-SMA)-positive cells co-expressing both PDGFRα and ANO1 in the innermost smooth muscle layer. Approximately one-third of isolated epididymis cells exhibited spontaneous transient inward currents (STICs) at the holding potential −60 mV. The reversal potential for STICs was close to the calculated chloride equivalent potential depending on intracellular Cl− concentrations. Ani9 (3 µM), the ANO1 specific inhibitor, decreased both amplitude and frequency of STICs, while cyclopiazonic acid (CPA, 30 µM), a sarco-/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, abolished STICs. Ani9 (3 or 10 µM) reduced the frequency of SPCs without changing their amplitude. Thus, PDGFRα+, ANO1+ specialised smooth muscle cells (SMCs) appear to function as pacemaker cells to electrically drive epididymal SPCs by generating ANO1-dependnet STICs. STICs arising from spontaneous Ca2+ release from intracellular Ca2+ store and subsequent opening of ANO1 result in depolarisations that spread into adjacent SMCs where L-type voltage-dependent Ca2+ channels are activated to develop SPCs. [ABSTRACT FROM AUTHOR]

Background: The epididymis has long been of interest owing to its role in promoting the functional maturation of the male germline. More recent evidence has also implicated the epididymis as an important sensory tissue responsible for remodeling of the sperm epigenome, both under physiological conditions and in response to diverse forms of environmental stress. Despite this knowledge, the intricacies of the molecular pathways involved in regulating the adaptation of epididymal tissue to paternal stressors remains to be fully resolved. Objective: The overall objective of this study was to investigate the direct impact of corticosterone challenge on a tractable epididymal epithelial cell line (i.e., mECap18 cells), in terms of driving adaptation of the cellular proteome and phosphoproteome signaling networks. Materials and methods: The newly developed phosphoproteomic platform EasyPhos coupled with sequencing via an Orbitrap Exploris 480 mass spectrometer, was applied to survey global changes in the mECap18 cell (phospho)proteome resulting from sub‐chronic (10‐day) corticosterone challenge. Results: The imposed corticosterone exposure regimen elicited relatively subtle modifications of the global mECap18 proteome (i.e., only 73 out of 4171 [∼1.8%] proteins displayed altered abundance). By contrast, ∼15% of the mECap18 phosphoproteome was substantially altered following corticosterone challenge. In silico analysis of the corresponding parent proteins revealed an activation of pathways linked to DNA damage repair and oxidative stress responses as well as a reciprocal inhibition of pathways associated with organismal death. Corticosterone challenge also induced the phosphorylation of several proteins linked to the biogenesis of microRNAs. Accordingly, orthogonal validation strategies confirmed an increase in DNA damage, which was ameliorated upon selective kinase inhibition, and an altered abundance profile of a subset of microRNAs in corticosterone‐treated cells. Conclusions: Together, these data confirm that epididymal epithelial cells are reactive to corticosterone challenge, and that their response is tightly coupled to the opposing action of cellular kinases and phosphatases. [ABSTRACT FROM AUTHOR]

Background: Region‐specific immune environments in the epididymis influence the immune responses to uropathogenic Escherichia coli (UPEC) infection, a relevant cause of epididymitis in men. Toll‐like receptors (TLRs) are essential to orchestrate immune responses against bacterial infections. The epididymis displays region‐specific inflammatory responses to bacterial‐derived TLR agonists, such as lipopolysaccharide (LPS; TLR4 agonist) and lipoteichoic acid (LTA; TLR2/TLR6 agonist), suggesting that TLR‐associated signaling pathways could influence the magnitude of inflammatory responses in epididymitis. Objectives: To investigate the expression and regulation of key genes associated with TLR4 and TLR2/TLR6 signaling pathways during epididymitis induced by UPEC, LPS, and LTA in mice. Material and methods: Epididymitis was induced in mice using UPEC, ultrapure LPS, or LTA, injected into the interstitial space of the initial segment or the lumen of the vas deferens close to the cauda epididymidis. Samples were harvested after 1, 5, and 10 days for UPEC‐treated animals and 6 and 24 h for LPS‐/LTA‐treated animals. Ex vivo epididymitis was induced by incubating epididymal regions from naive mice with LPS or LTA. RT‐qPCR and Western blot assays were conducted. Results: UPEC infection up‐regulated Tlr2, Tlr4, and Tlr6 transcripts and their associated signaling molecules Cd14, Ticam1, and Traf6 in the cauda epididymidis but not in the initial segment. In these epididymal regions, LPS and LTA differentially modulated Tlr2, Tlr4, Tlr6, Cd14, Myd88, Ticam1, Traf3, and Traf6 expression levels. NFKB and AP1 activation was required for LPS‐ and LTA‐induced up‐regulation of TLR‐associated signaling transcripts in the cauda epididymidis and initial segment, respectively. Conclusion: The dynamic modulation of TLR4 and TLR2/TLR6 signaling pathways gene expression during epididymitis indicates bacterial‐derived antigens elicit an increased tissue sensitivity to combat microbial infection in a spatial manner in the epididymis. Differential activation of TLR‐associated signaling pathways may contribute to fine‐tuning inflammatory responses along the epididymis. [ABSTRACT FROM AUTHOR]

Background: Chronic preconception paternal alcohol use adversely modifies the sperm epigenome, inducing fetoplacental and craniofacial growth defects in the offspring of exposed males. A crucial outstanding question in the field of paternal epigenetic inheritance concerns the resilience of the male germline and its capacity to recover and correct sperm‐inherited epigenetic errors after stressor withdrawal. Objectives: We set out to determine if measures of the sperm‐inherited epigenetic program revert to match the control treatment 1 month after withdrawing the daily alcohol treatments. Materials and methods: Using a voluntary access model, we exposed C57BL/6J males to 6% or 10% alcohol for 10 weeks, withdrew the alcohol treatments for 4 weeks, and used RNA sequencing to examine gene expression patterns in the caput section of the epididymis. We then compared the abundance of sperm small RNA species between treatments. Results: In the caput section of the epididymis, chronic alcohol exposure induced changes in the transcriptional control of genetic pathways related to the mitochondrial function, oxidative phosphorylation, and the generalized stress response (EIF2 signaling). Subsequent analysis identified region‐specific, alcohol‐induced changes in mitochondrial DNA copy number across the epididymis, which correlated with increases in the mitochondrial DNA content of alcohol‐exposed sperm. Notably, in the corpus section of the epididymis, increases in mitochondrial DNA copy number persisted 1 month after alcohol cessation. Analysis of sperm noncoding RNAs between control and alcohol‐exposed males 1 month after alcohol withdrawal revealed a ∼100‐fold increase in mir‐196a, a microRNA induced as part of the nuclear factor erythroid 2‐related factor 2 (Nrf2)‐driven cellular antioxidant response. Discussion and conclusion: Our data reveal that alcohol‐induced epididymal mitochondrial dysfunction and differences in sperm noncoding RNA content persist after alcohol withdrawal. Further, differences in mir‐196a and sperm mitochondrial DNA copy number may serve as viable biomarkers of adverse alterations in the sperm‐inherited epigenetic program. [ABSTRACT FROM AUTHOR]

The activins (A and B) and their binding protein, follistatin, play crucial roles in development, immunoregulation and inflammation throughout the body. In the male reproductive tract of the mouse, activin A and B production is largely confined to the initial segment and proximal caput of the epididymis and the efferent ducts, under normal conditions, with very low expression in the corpus, cauda and vas deferens. However, activin A protein is present throughout the epididymis and vas deferens and is largely associated with the epithelium and interstitial macrophages. Conversely, the activin‐binding protein follistatin is produced in the distal epididymis, with very high expression in the vas deferens. Activin activity in the distal tract is inhibited by follistatin, and the activin–follistatin balance is important for regulating coiling of the duct during epididymal development. In further experiments, as described in this report, in situ hybridisation was used to localise activin A mRNA principally to cells in the periductal zone and interstitium in the efferent ducts and proximal caput. Activin B mRNA, on the other hand, was localised to periductal cells in the efferent ducts and proximal epididymis and, most notably, to epithelial cells in the initial segment. Activin A is implicated in the regulation of mononuclear phagocyte function and immune responses in the caput and stimulates the expression of the key immunoregulatory protein, indoleamine 2,3‐dioxygenase in this region. Activin A production in the corpus and cauda increases dramatically during bacterial epididymitis in mice, promoting inflammation and fibrosis and causing damage to the epithelium and obstruction of the epididymal duct. Consequently, it appears that the activin–follistatin axis is crucial for maintaining normal epididymal structure and function, but disruption of this balance during inflammation has deleterious effects on male fertility. Follistatin has therapeutic potential in ameliorating the proinflammatory and profibrotic effects of activins. [ABSTRACT FROM AUTHOR]

Introduction: One of the most intriguing aspects of male reproductive physiology is the ability of the epididymis to prevent the mounting of immune responses against the onslaught of foreign antigens carried by spermatozoa while initiating very efficient immune responses versus stressors. Epithelial clear cells are strategically positioned to work in a concerted manner with region‐specific heterogeneous subsets of mononuclear phagocytes to survey the epididymal barrier and regulate the balance between inflammation and immune tolerance in the post‐testicular environment. Objective: This review aims to describe how clear cells communicate with mononuclear phagocytes to contribute to the unique immune environment in which sperm mature and are stored in the epididymis. Materials/methods: A comprehensive systematic review was performed. PubMed was searched for articles specific to clear cells, mononuclear phagocytes, and epididymis. Articles that did not specifically address the target material were excluded. Results: In this review, we discuss the unexpected roles of clear cells, including the transfer of new proteins to spermatozoa via extracellular vesicles and nanotubes as they transit along the epididymal tubule; and we summarize the immune phenotype, morphology, and antigen capturing, processing, and presenting abilities of mononuclear phagocytes. Moreover, we present the current knowledge of immunoregulatory mechanisms by which clear cells and mononuclear phagocytes may contribute to the immune‐privileged environment optimal for sperm maturation and storage. Discussion and conclusion: Notably, we provide an in‐depth characterization of clear cell‐mononuclear phagocyte communication networks in the steady‐state epididymis and in the presence of injury. This review highlights crucial concepts of mucosal immunology and cellcell interactions, all of which are critical but understudied facets of human male reproductive health. [ABSTRACT FROM AUTHOR]

There is considerable evidence showing that highly ordered aggregate structures known as amyloids carry out essential biological roles in species ranging from bacteria to humans. Indeed, many antimicrobial peptides/proteins form amyloids to carry out their host defense functions and many amyloids are antimicrobial. The similarity of host defense amyloids from bacterial biofilms to the mammalian epididymal amyloid matrix implies highly conserved host defense structures/functions. With an emphasis on the epididymal amyloid matrix, here we review the common properties of host defense amyloids including unique traits that would allow them to function as powerful biosensors of the immune system. [ABSTRACT FROM AUTHOR]

Background: Spermatozoa become mature and competent for fertilization during transit from the caput epididymis to the cauda epididymis. However, detailed molecular mechanisms of epididymal sperm maturation are still unclear. Here, we focused on multiple epididymis‐enriched genes: lipocalin family genes (Lcn5, Lcn6, Lcn8, Lcn9, and Lcn10) and Ly6 family genes (Ly6g5b and Ly6g5c). These genes are evolutionarily conserved in mammals and form clusters on chromosomes 2 and 17 in the mouse, respectively. Objective: To clarify whether these genes are required for epididymal sperm maturation and acquisition of fertilizing ability, we generated knockout (KO) mice using the CRISPR/Cas9 system and analyzed their phenotype. Materials and methods: We generated four lines of KO mice: Lcn9 single KO, the lipocalin family quadruple KO (Lcn5, Lcn6, Lcn8, and Lcn10), quintuple KO (Lcn5, Lcn6, Lcn8, Lcn10, and Lcn9), and double KO of Ly6 family genes (Ly6g5b and Ly6g5c). Results: Although the Lcn9 single KO did not affect male fertility, the quadruple KO and quintuple KO male mice were subfertile and mostly infertile, respectively, with a reduced amount of ADAM3, an essential protein for sperm binding to the zona pellucida. Further analysis revealed that the quintuple KO spermatozoa lack the CMTM2A/B that are required for ADAM3 maturation. Intriguingly, Ly6g5b and Ly6g5c double KO male mice also showed subfertility with reduced sperm ADAM3. Conclusion: These results suggest epididymal secretory proteins are involved in ADAM3 maturation and acquisition of sperm fertilizing ability. [ABSTRACT FROM AUTHOR]

Background: The mammalian epididymis is a specialized duct system that serves a critical role in sperm maturation and storage. Its distinctive, highly coiled tissue morphology provides a unique opportunity to investigate the link between form and function in reproductive biology. Although recent genetic studies have identified key genes and signaling pathways involved in the development and physiological functions of the epididymis, there has been limited discussion about the underlying dynamic and mechanical processes that govern these phenomena. Aims: In this review, we aim to address this gap by examining two key aspects of the epididymis across its developmental and physiological phases. Results and Discussion: First, we discuss how the complex morphology of the Wolffian/epididymal duct emerges through collective cell dynamics, including duct elongation, cell proliferation, and arrangement during embryonic development. Second, we highlight dynamic aspects of luminal fluid flow in the epididymis, essential for regulating the microenvironment for sperm maturation and motility, and discuss how this phenomenon emerges and interplays with epididymal epithelial cells. Conclusion: This review not only aims to summarize current knowledge but also to provide a starting point for further exploration of mechanobiological aspects related to the cellular and extracellular fluid dynamics in the epididymis. [ABSTRACT FROM AUTHOR]

Background: The human epididymis is poorly studied due to the lack of availability of tissue samples. Our understanding of its structure and function depends upon anatomical and histological observations of archived material. Objectives: Here we used single‐cell RNA sequencing (scRNA‐seq) technologies to elucidate the identity of cells within the human efferent ducts (EDs) and compared them to caput epididymis cells. We also compared the cellularity of primary tissues with those of 2D and 3D (organoid) culture models used for functional studies. Materials and methods: Human epididymis tissue was dissected to separate different anatomical regions and digested to release single cells for processing on the 10X Genomics Chromium platform. Primary human epididymis epithelial (HEE) cells and HEE organoids were grown as described previously and subjected to scRNA‐seq. scRNA‐seq data were processed by standard bioinformatics pipelines and used for comparative analysis. Results: We define the cell types in the EDs which include specialized epithelial cells, connective tissue stromal cells, vascular endothelial cells, smooth muscle cells, and immune cells, but lack basal cells that are seen in the caput epididymis. Furthermore, we identify a sub‐population of epithelial cells which have marker genes found in the bladder and urothelium. Comparative genomics analysis of the 2D and 3D culture models shows cellular identities adapted to the culture environment while still maintaining similarity to the primary tissue. Discussion: Our data suggest that EDs are lined with a transitional epithelium, which like the urothelium is able to stretch and contract depending on luminal volume. This is consistent with its primary role in seminal fluid resorption and sperm concentration. Moreover, we describe the cellularity of models to study the human epididymis epithelium in vitro. Conclusion: Single‐cell RNA‐seq data from the human epididymis make a valuable contribution to our understanding of this highly specialized organ. [ABSTRACT FROM AUTHOR]

The scenario of the fertile spermatozoa with high fertilizing capability is basically dependent on gene expression‐based epididymal function. The current investigation aimed to declare the varied expression of different candidate genes (PLA2G4D, LCN15, CLUAP1, SPP1, AQP12B, DEFB110 and ESR1) relevant to spermatozoa features between the different epididymal segments in the mature dromedary camels (n = 30). Scrotal contents were collected post‐slaughtering, during the breeding season and the epididymis was separated from the testicles and divided into three segments (caput, corpus and cauda) based on its morphology and anatomical characteristics. Epididymal spermatozoa were harvested from each epididymal portion and evaluated for motility, count, viability and morphology. Samples were grouped depending on their epididymal sperm cells features into high‐fertile (n = 15) and low‐fertile (n = 15) groups. The gene expression of the candidate genes was defined in the isolated RNA from each epididymal portion tissue. The segmental sperm motion and count were significantly (p <.05 and p <.01) higher in the three epididymal parts of high‐fertile camels than the lower ones. There were some candidate genes markedly up‐regulated in its expression in epididymal head of high‐fertile camels (PLA2G4D and LCN15) and low fertile (CLUAP1), while others in the body region of the high‐fertile group (SPP1, AQP12B and DEFB110). Nevertheless, ER1 did not differ in the expression among the epididymal segments. In conclusion, the variant expression patterns of these epididymal genes in relation to the regional spermatozoa features might suggest important roles of these genes in sperm maturation process in the epididymis and focusing more interest on their potential utility as markers for male camel fertility prediction. [ABSTRACT FROM AUTHOR]

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Stanozolol and nandrolone decanoate hormones are mainly used in dogs and horses to strengthen muscle growth, increase of body weight, treatment of anemia and stimulation of appetite; nevertheless, some side effects have been reported, including testicular atrophy, and decrease of spermatozoid count in dogs. The aim of the present study is to evaluate the histopathological changes of testicular and epididymal tissues in dogs treated with stanozolol and nandrolone decanoate. The present survey was performed on sixtheen male dogs. The studied animals were divided into two equal groups of eight. Stanozolol was administered to dogs in group A with dosage of 50 mg per dog intramuscularly for 6 continuous weeks. Group B was similar to group A, but instead of stanozolol, nandrolone decanoate was injected with dosage of 1 mg/kg. To evaluate the possible side effects on the testicles, one of them was surgically removed before the investigation and the second testicle was removed on days 28 (four dogs in each group) and 42 (the remaining four of each group). Before the testes were placed in 10% formalin buffer, sperm quality in the epididymis was evaluated for indicators such as motility, morphology and number in times zero, 28 and 42 days. The results showed that destructive effects were obtained such as hyperplasia of interstitial Leydig cells, vacuolation, the presence of multinucleated cells and different stages of spermatogonia in testicular tissue; also, the destruction of duct covering cells and the detachment of cilia in the epididymal epithelium was observed. These changes were significantly greater in the stanozolol group than nandrolone decanoate. The quantitative changes were more pronounced in the stanozolol group and the qualitative changes in the nanderlone decanoate group. Although both drugs had side effects on testicular and epididymal tissues; the side effects of stanozolol were greater than nandrolone decanoate; therefore, it is recommended minimum dose of nandrolone decanate for therapeutic purposes. [ABSTRACT FROM AUTHOR]