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Background Recommendations for cardiovascular disease prevention advocate lowering both cholesterol and low-density lipoprotein cholesterol systemic levels, notably by statin intake. However, statins are the subject of questions concerning their impact on male fertility. This study aimed to evaluate, by a prospective pilot assay, the efficacy and the toxicity of a decrease of cholesterol blood levels, induced by atorvastatin on semen quality and sexual hormone levels of healthy, normocholesterolaemic and normozoospermic men. Methods Atorvastatin (10 mg daily) was administrated orally during 5 months to 17 men with normal plasma lipid and standard semen parameters. Spermatozoa parameters, accessory gland markers, semen lipid levels and blood levels of gonadal hormones were assayed before statin intake, during the treatment, and 3 months after its withdrawal. Results Atorvastatin treatment significantly decreased circulating low-density lipoprotein cholesterol (LDL-C) and total cholesterol concentrations by 42% and 24% (p < 0.0001) respectively, and reached the efficacy objective of the protocol. During atorvastatin therapy and/or 3 months after its withdrawal numerous semen parameters were significantly modified, such as total number of spermatozoa (-31%, p < 0.05), vitality (-9.5%, p < 0.05), total motility (+7.5%, p < 0.05), morphology (head, neck and midpiece abnormalities, p < 0.05), and the kinetics of acrosome reaction (p < 0.05). Seminal concentrations of acid phosphatases (p < 0.01), α-glucosidase (p < 0.05) and L-carnitine (p < 0.05) were also decreased during the therapy, indicating an alteration of prostatic and epididymal functions. Moreover, we measured at least one altered semen parameter in 35% of the subjects during atorvastatin treatment, and in 65% of the subjects after withdrawal, which led us to consider that atorvastatin is unsafe in the context of our study. Conclusions Our results show for the first time that atorvastatin significantly affects the sperm parameters and the seminal fluid composition of healthy men. Trial registration ClinicalTrials.gov: NCT02094313 .

ObjectiveHigh-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility.DesignFaecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin.ResultsTransplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus Bacteroides and Prevotella, both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of Bacteroides-Prevotella and sperm motility, and a positive correlation between blood endotoxin and Bacteroides abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice.ConclusionWe revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes.Trial registration number NCT03634644.

Androgen receptor (AR) is regulated by SUMOylation at its transactivation domain. In vitro, the SUMOylation is linked to transcriptional repression and/or target gene-selective regulation. Here, we generated a mouse model (ArKI) in which the conserved SUMO acceptor lysines of AR are permanently abolished ( Ar K381R , K500R ). ArKI males develop normally, without apparent defects in their systemic androgen action in reproductive tissues. However, the ArKI males are infertile. Their spermatogenesis appears unaffected, but their epididymal sperm maturation is defective, shown by severely compromised motility and fertilization capacity of the sperm. Fittingly, their epididymal AR chromatin-binding and gene expression associated with sperm maturation and function are misregulated. AR is SUMOylated in the wild-type epididymis but not in the testis, which could explain the tissue-specific response to the lack of AR SUMOylation. Our studies thus indicate that epididymal AR SUMOylation is essential for the post-testicular sperm maturation and normal reproductive capability of male mice. SUMOylation is known to regulate androgen receptor (AR) activity in cultured cells. Here, using SUMOylation-deficient AR knock-in mice, the authors demonstrate that SUMOylation is required for AR-related gene expression specifically in the epididymal tissues, but not the testis.

It is well-established that testicular spermatozoa are immature and acquire motility and fertilization capabilities during transit throughout the epididymis. The epididymis is a duct-like organ that connects the testis to the vas deferens and is comprised of four anatomical regions: the initial segment, caput, corpus, and cauda. Sperm maturation occurs during epididymal transit by the interaction of sperm cells with the unique luminal environment of each epididymal region. In this review we discuss the epididymis as an essential reproductive organ responsible for sperm concentration, maturation (including sperm motility acquisition and fertilizing ability), protection and storage. Importantly, we also discuss specific characteristics and roles of epididymal-derived exosomes (epididymosomes) in establishing sperm competency within the intricate process of reproduction. This review suggests that an increasing body of evidence is working to develop a complete picture of the role of the epididymis in male reproduction, offspring health, and disease susceptibility.

Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64hiMHCIIlo and CD64loMHCIIhi macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs.

Heparan sulfate (HS), an abundant component of the apical cell surface and basement membrane, belongs to the glycosaminoglycan family of carbohydrates covalently linked to proteins called heparan sulfate proteoglycans. After endocytosis, HS is degraded in the lysosome by several enzymes, including heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT), and in its absence causes Mucopolysaccharidosis III type C (Sanfilippo type C). Since endocytosis occurs in epithelial cells of the testis and epididymis, we examined the morphological effects of Hgsnat inactivation in these organs. In the testis, Hgsnat knockout ( Hgsnat-Geo ) mice revealed statistically significant decrease in tubule and epithelial profile area of seminiferous tubules. Electron microscopy (EM) analysis revealed cross-sectional tubule profiles with normal and moderately to severely altered appearances. Abnormalities in Sertoli cells and blood-testis barrier and the absence of germ cells in some tubules were noted along with altered morphology of sperm, sperm motility parameters and a reduction in fertilization rates in vitro . Along with quantitatively increased epithelial and tubular profile areas in the epididymis, EM demonstrated significant accumulations of electrolucent lysosomes in the caput-cauda regions that were reactive for cathepsin D and prosaposin antibodies. Lysosomes with similar storage materials were also found in basal, clear and myoid cells. In the mid/basal region of the epithelium of caput-cauda regions of KO mice, large vacuolated cells, unreactive for cytokeratin 5, a basal cell marker, were identified morphologically as epididymal mononuclear phagocytes (eMPs). The cytoplasm of the eMPs was occupied by a gigantic lysosome suggesting an active role of these cells in removing debris from the epithelium. Some eMPs were found in proximity to T-lymphocytes, a feature of dendritic cells. Taken together, our results reveal that upon Hgsnat inactivation, morphological alterations occur to the testis affecting sperm morphology and motility parameters and abnormal lysosomes in epididymal epithelial cells, indicative of a lysosomal storage disease.

Using ultrasound findings and clinical characteristics, we constructed and validated a new nomogram for distinguishing epididymal tuberculosis from nontuberculous epididymitis, both of which share similar symptoms. We retrospectively examined data of patients with epididymal tuberculosis and nontuberculous epididymitis hospitalized between January 1, 2013, and March 31, 2023. Eligible patients were randomly assigned to derivation and validation cohorts (ratio, 7:3). We drew a nomogram to construct a diagnostic model through multivariate logistic regression and visualize the model. We used concordance index, calibration plots, and decision curve analysis to assess the discrimination, calibration, and clinical usefulness of the nomogram, respectively. In this study, 136 participants had epididymal tuberculosis and 79 had nontuberculous epididymitis. Five variables—C-reactive protein level, elevated scrotal skin temperature, nodular lesion, chronic infection, and scrotal skin ulceration—were significant and used to construct the nomogram. Concordance indices of the derivation and validation cohorts were 0.95 and 0.96, respectively (95% confidence intervals, 0.91–0.98 and 0.92–1.00, respectively). Decision curve analysis of this nomogram revealed that it helped differentiate epididymal tuberculosis from nontuberculous epididymitis. This nomogram may help clinicians distinguish between epididymal tuberculosis and nontuberculous epididymitis, thereby increasing diagnosis accuracy.

Mammalian epididymal epithelial cells are crucial for sperm maturation. Historically, vacuole-like ultrastructures in epididymal epithelial cells were observed via transmission electron microscopy but were undefined. Here, we utilize volume electron microscopy (vEM) to generate 3D reconstructions of epididymal epithelial cells and identify these vacuoles as intercellular organelle reservoirs (IORs) in the lateral intercellular space (LIS), which contains protein aggregates, autophagosomes, lysosome-related organelles and mitochondrial residues. Immunolabelling of organelle markers such as P62, LC3, LAMP1 and TOMM20 confirm these findings. The IOR size or number varies across four epididymal regions and decreases with age. Rab27a mutant mice exhibit reduced IORs in the caput epididymis and a subfertility phenotype, suggesting the involvement of Rab27a in the formation of IORs. Furthermore, we observe the presence of IORs between intestinal epithelial cells besides epididymis. Amino acid transporters at IOR edges suggest dynamic protein recycling. Our findings reveal that the IOR is an important structure critical for organelle turnover and recycling outside epithelial cells with limited self-degradation capabilities. Undefined vacuole-like ultrastructures between epididymal cells have been observed. Here, the authors reveal that these structures contain organelle residues and protein aggregates that suggest a reservoir for protein recycling.

Melatonin (Mel), an important mediator of photoperiodic annual rhythm regulation and seasonal reproduction in animals, directly modulates the expression of specific genes in the epididymis and protects sperm from oxidative damage. Bactrian camel is a dominant species in desert and semi-desert areas, exhibiting the unique reproductive regulation patterns. However, the underlying regulation mechanism of Mel on Bactrian camel is still unclear. This study isolated the epididymal caput epithelial cells of Bactrian camels and investigated the expression of specific genes involving sperm protection after Mel treatment and overexpression/knockdown of Mel receptor MT1/MT2 using real-time quantitative PCR assay (qPCR), ELISA, and western blotting assay. The results showed that MT1, MT2, clock genes cryptochrome 1/2 (Cry1/Cry2) were all positively expressed in the epididymal lumen epithelial cells, peritubular myoid cells, and luminal spermatozoa. Intriguingly, Mel treatment activated receptor MT1 in epididymal caput epithelial cells, indicating that Mel treatment regulated genes expression mainly via MT1-dependent manner. Mel treatment or overexpression of MT1 both increased secretion of glutathione peroxidase 5 (GPX5) and prostaglandin D2 synthase (PTGDS), and MT1 silencing induced downregulation of GPX5 and PTGDS expression, indicating that the expression of GPX5 and PTGDS were regulated by Mel-MT1. Overexpression of MT1 or MT2 promoted Cry2 expression, and overexpression of Cry2 also activated the MT1/MT2 expression by feedback regulation. Finally, the double luciferase reports assay showed that the activation of MT1 by Cry2 occurred during transcription. These results help to understand the regulatory effect of Mel on the epididymis in Bactrian camels. Graphical Abstract

Bisphenol A (BPA) is a commonly used environmental toxicant, is easily exposed to the human body and causes testicular damage, sperm abnormalities, DNA damage and apoptosis, and interferes in the process spermatogenesis and steroidal hormone production along with obstruction in testes and epididymis development. Zinc (Zn), a potent regulator of antioxidant balance, is responsible for cellular homeostasis, enzymes and proteins activities during spermatogenesis for cell defence mechanisms in the testes. Selenium (Se) is required for spermatogenesis, antioxidant action and in the activities of different selenoproteins. Both Zn and Se are essential simultaneously for the proper regulation of spermatogenesis and sperm maturation as well as protection against chemical and disease-associated germ cell toxicity. Thus, the study aimed to understand the importance and beneficial effect of Zn and Se co-treatment against BPA-exposed testicular damage in rats. BPA 100 and 200 mg/kg/day was exposed through an oral gavage. Zn (3 mg/kg/day) i.p. and Se (0.5 mg/kg/day) i.p. were injected for 8 weeks. The testicular toxicity was evaluated by measuring body and organs weight, biochemical investigations, sperm parameters, testicular and epididymal histopathology, quantification DNA damage by halo assay, DNA breaks (TUNEL assay), immunohistochemistry and western blot. Results revealed that Zn and Se co-treatment ameliorated BPA-associated male gonadal toxicity in rat as revealed by decreased SGPT, SGOT and BUN levels in serum, reduced testes and epididymis tissue injury, DNA breaks, apoptosis, expressions of 8-OHdG, γ-H2AX and NFκB with an increased serum testosterone and catalase levels. These findings suggest that Zn and Se co-treatment could be a beneficial and protective option against BPA-exposed testicular and epididymal toxicity.