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This evidence suggests that vesicles secreted from epididymal epithelial cells, such as epididymosomes, are capable of mediating epigenetic inheritance of neuro- and behavioral disorders from fathers. Epididymosomes are still a relatively new discovery within the epididymis, an essential reproductive organ with well characterized functions.

Incredible progress has been made, especially in the last decade, at determining what role these epididymosomes and their cargo may play in reproduction. However, evidence for these roles at this stage still tends to be inconsistent, with many groups reporting slightly, to completely different results despite apparently strong study design and techniques.

Additionally, a massive gap in knowledge exists both up- and downstream of the altered preimplantation gene expression observed in association with epididymal sRNAs. It has been suggested that they post-transcriptionally regulate gene expression, however, the mechanism of action and specificity of targets is largely unknown.

Downstream, it is unknown how altered preimplantation gene expression translates into the developmental, metabolic, or behavioral alterations observed in embryos and offspring.

In many respects, these knowledge gaps are unsurprising considering there is generally limited understanding of the molecular events that govern genome activation and other critical pathways in early development.

Deliberate interrogation of intricacies in genome activation and transcription factor signaling cascades might provide much needed clarity as to how epididymosomal sRNA cargo could direct larger changes in embryos and offspring. In the study of the epididymis, historical research provides interesting perspectives and insights into current literature. Advances in assisted reproductive techniques ART have allowed clinicians and researchers to bypass some limitations native to male reproduction that exist within the epididymis such as a necessity for motile and mature spermatozoa.

Some evidence does suggest, however, that ART may come with a health cost to offspring [ 88 ]. Increased knowledge into potentially novel functions of a historically well described organ such as the epididymis may allow for new treatment options, not only for natural conception but also to increase positive health outcomes in children conceived with ART.

Epididymal and specifically epididymosomal function is clearly an increasingly popular area of research and many high-quality studies have been and continue to be published on the subject.

Intriguingly, research in this area spans a broad spectrum, including basic science principals yet having direct translational research implications as well. Current research, as detailed in this review, suggests that clinical consequences of epididymosomes and their cargo are far-reaching.

Epididymosome-mediated effects span many fields, including those that are directly related to public health such as metabolic disease, behavioral disorders and infertility.

Taken together, 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 and beyond to offspring health and disease susceptibility.

All authors made substantial contributions in writing and editing the manuscript before submission. Conceptualization, E. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Int J Mol Sci. Published online Jul Emma R. James , 1, 2 Douglas T. Carrell , 1, 2 Kenneth I. Aston , 1 Timothy G. Douglas T. Kenneth I. Find articles by Kenneth I.

Timothy G. Find articles by Albert Salas-Huetos. Author information Article notes Copyright and License information Disclaimer. Received Jul 7; Accepted Jul This article has been cited by other articles in PMC. Abstract It is well-established that testicular spermatozoa are immature and acquire motility and fertilization capabilities during transit throughout the epididymis.

Keywords: exosomes, epididymis, epididymosomes, reproduction, spermatozoa, sperm transport, sperm maturation. Spermatogenesis: From PGC to Spermatozoa The creation of a male gamete also known as spermatozoa or sperm begins with the differentiation of primordial germ cells PGC into spermatogonial stem cells. Transit of Gametes and the Fertilization Process The path of an oocyte from the location of ovulation at the ovary to the location of fertilization in the fallopian tube, while highly regulated, is relatively short in distance [ 16 ].

The Epididymis: An Essential Reproductive Organ The epididymis is one of the male sex accessory ducts that also include: the seminiferous tubules, rete testis, efferent ducts, vas deferens, ejaculatory duct, and urethra. Open in a separate window. Figure 1. Epididymal Structure To appreciate all of the functions of the epididymis, it is important to understand the structure of the tubules that make up this organ. Epididymal Functions 3.

Sperm Transport The most obvious function of the epididymis is to transport sperm from the rete testes to the vas deferens. Sperm Concentration The main process that occurs in the initial segment of the epididymis is the absorption of fluid by epithelial cells. Sperm Protection An additional function of the epididymis is to protect sperm cells during epididymal transit from damage caused by the external environment [ 26 ]. Sperm Storage The cauda epididymis functions as a storage location for functionally mature sperm cells prior to ejaculation [ 22 ].

Sperm Maturation An essential process required for normal male fertility that occurs during epididymal transit is sperm maturation. Acquisition of Motility Testicular sperm are considered immotile. Fertilization Capabilities In addition to the development of motility, sperm also gain factors necessary for fertilization of an oocyte during maturation in the epididymis.

Sperm Maturation and Reproduction New and historical data point to the importance of proper sperm maturation in successful reproduction. Epididymosomes Epididymosomes are exosomes that are found within the epididymal lumen and are released by the epididymal epithelium [ 5 ]. Figure 2. Epididymosomal Proteins Epididymosomes have been shown to contain hundreds of different proteins from various functional classes. Functions of Epididymosomal Proteins Many of the proteins previously discussed which are gained during epididymal transit and required for sperm fertilization capabilities have been identified in epididymosomes.

Epididymosomal ncRNAs A relatively recent addition to the knowledge base surrounding epididymosomes is the profiling of non-coding RNA species in epididymosome cargo. Functions of Epididymosomal sRNAs Considering the significant contribution that epididymosomal protein cargo has to sperm competency it is possible that epididymosomal sRNA content has equally important roles. Epithelial Cell Communication A primary, known function of exosomes is mediating cell-to-cell communication.

Support of Embryogenesis Increasing evidence suggests that the contribution that sperm makes to the developing embryo is greater than just providing genomic DNA. Epigenetic Inheritance Another major focus of studies on epididymosomal sRNAs is their potential ability to serve as a mechanism of epigenetic inheritance from fathers to offspring.

Inheritance of a Metabolic Phenotype Zygotic microinjection of sRNAs isolated from the sperm of altered diet fed mice has been the preferred method for studying the transmission of metabolic phenotypes to offspring. Inheritance of Behavioral Phenotypes From epidemiologic evidence to studies in animal models, there is a large basis of support for observations that pre-conception paternal stress can impact offspring neuro- and behavioral development.

Conclusions and Future Directions Epididymosomes are still a relatively new discovery within the epididymis, an essential reproductive organ with well characterized functions.

Author Contributions All authors made substantial contributions in writing and editing the manuscript before submission. Funding This research received no external funding. Conflicts of Interest The authors declare no conflict of interest. References 1. Jones R. Human Reproductive Biology. Robaire B. In: Neill K. Nixon B. Profiling of epididymal small non-protein-coding RNAs. Sullivan R. Epididymosomes: A heterogeneous population of microvesicles with multiple functions in sperm maturation and storage.

Asian J. Epididymosomes, prostasomes, and liposomes: Their roles in mammalian male reproductive physiology. Trigg N. The contribution of epididymosomes to the sperm small RNA profile. Abbot P. What is a placental mammal anyway? Wildman D. Evolution of the mammalian placenta revealed by phylogenetic analysis. Saitou M. Gametogenesis from Pluripotent Stem Cells. Cell Stem Cell. Griswold M. Spermatogenesis: The Commitment to Meiosis. Jauregui E. Retinoic acid receptor signaling is necessary in steroidogenic cells for normal spermatogenesis and epididymal function.

Gilbert S. Developmental Biology. Virant-Klun I. Postnatal oogenesis in humans: A review of recent findings. Stem Cells Cloning. McGee E. Regulators of ovarian preantral follicle development. Zhai F.

Human Reproductive and Prenatal Genetics. The Molecular Genetics of Oogenesis. Robker R. Yeung C. In: Robaire B. Yeste M. Results Probl. Cell Differ. Topfer-Petersen E. Oocyte-sperm interactions. Gervasi M. Molecular changes and signaling events occurring in spermatozoa during epididymal maturation. Brooks D. Epididymal functions and their hormonal regulation. Cornwall G. New insights into epididymal biology and function. Leung G. Regulation of epididymal principal cell functions by basal cells: Role of transient receptor potential Trp proteins and cyclooxygenase-1 COX-1 Mol.

Cell Endocrinol. Elfgen V. Contractility of the epididymal duct: Function, regulation and potential drug effects. Turner T. Resorption versus secretion in the rat epididymis.

Hinton B. The role of the epididymis in the protection of spermatozoa. Orchestrating the antioxidant defenses in the epididymis. To store or mature spermatozoa? The primary role of the epididymis. The human epididymis: Its function in sperm maturation. Maldera J. Thaler C. The initial molecular interaction between mouse sperm and the zona pellucida is a complex binding event.

Cohen D. Plante G. Epididymal Binder of SPerm genes and proteins: What do we know a decade later? ADAM7 is associated with epididymosomes and integrated into sperm plasma membrane. Skerget S. Sperm Proteome Maturation in the Mouse Epididymis. Wong G. Analysis of fertilin alpha ADAM1 -mediated sperm-egg cell adhesion during fertilization and identification of an adhesion-mediating sequence in the disintegrin-like domain. Caballero J.

CD9-positive microvesicles mediate the transfer of molecules to Bovine Spermatozoa during epididymal maturation. Epididymosomes are involved in the acquisition of new sperm proteins during epididymal transit. Orgebin-Crist M. Sperm maturation in rabbit epididymis. Studies on the function of the epididymis. Delayed cleavage of rabbit ova after fertilization by young epididymal spermatozoa. Wazzan W. Zona drilling enhances fertilization by mouse caput epididymal sperm.

Conine C. Sharma U. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Suganuma R. Decline in fertility of mouse sperm with abnormal chromatin during epididymal passage as revealed by ICSI.

Zhou D. Battistelli M. Doyle L. Zhou W. Mechanisms of tethering and cargo transfer during epididymosome-sperm interactions.

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Spermatic cord Medically reviewed by the Healthline Medical Network. The body of the epididymis is a highly convoluted duct which connects the head to the tail of the epididymis.

Sperm mature in this section of the epididymis. The tail of the epididymis is continuous with the deferent duct. The deferent duct is the excretory duct of the testis which joins the excretory duct of the seminal vesicle to form the ejaculatory duct. Epididymis Head of epididymis Lobules of epididymis Body of epididymis Tail of epididymis Duct of epididymis Deferent duct ductus deferens or vas deferens.



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