Role of Na+/H+ exchanger 3 in the acidification of the male reproductive tract and male fertility

Mitochondria are structurally and functionally distinct organelles that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), to provide energy to spermatozoa. They can also produce reactive oxidation species (ROS). While a moderate concentration of ROS is critical for tyrosine phosphorylation in cholesterol efflux, sperm–egg interaction, and fertilization, excessive ROS generation is associated with male infertility. Moreover, mitochondria participate in diverse processes ranging from spermatogenesis to fertilization to regulate male fertility. This review aimed to summarize the roles of mitochondria in male fertility depending on the sperm developmental stage (from male reproductive tract to female reproductive tract). Moreover, mitochondria are also involved in testosterone production, regulation of proton secretion into the lumen to maintain an acidic condition in the epididymis, and sperm DNA condensation during epididymal maturation. We also established the new signaling pathway using previous proteomic data associated with male fertility, to understand the overall role of mitochondria in male fertility. The pathway revealed that male infertility is associated with a loss of mitochondrial proteins in spermatozoa, which induces low sperm motility, reduces OXPHOS activity, and results in male infertility.

Download Full-text

Estrogen-Dependent and -Independent Estrogen Receptor-α Signaling Separately Regulate Male Fertility

Endocrinology ◽

10.1210/en.2008-1016 ◽

2009 ◽

Vol 150 (6) ◽

pp. 2898-2905 ◽

Cited By ~ 46

Author(s):

Kerstin W. Sinkevicius ◽

Muriel Laine ◽

Tamara L. Lotan ◽

Karolina Woloszyn ◽

John H. Richburg ◽

...

Keyword(s):

Estrogen Receptor ◽

Male Fertility ◽

Reproductive Tract ◽

Cell Function ◽

Critical Role ◽

Estrogen Receptor Α ◽

Male Reproductive Tract ◽

Efferent Ductule

Estrogen receptor-α (ERα) plays a critical role in male reproductive tract development and fertility. To determine whether estrogen-dependent and -independent ERα mechanisms are involved in male fertility, we examined male estrogen nonresponsive ERα knock-in mice. These animals have a point mutation (G525L) in the ligand-binding domain of ERα that significantly reduces interaction with, and response to, endogenous estrogens but does not affect growth factor activation of ligand-independent ERα pathways. Surprisingly, we found that ligand-independent ERα signaling is essential for concentrating epididymal sperm via regulation of efferent ductule fluid reabsorption. In contrast, estrogen-dependent ERα signaling is required for germ cell viability, most likely through support of Sertoli cell function. By treating estrogen nonresponsive ERα knock-in (ENERKI) mice with the ERα selective synthetic agonist propyl pyrazole triol, which is able to bind and activate G525L ERα in vivo, we discovered male fertility required neonatal estrogen-mediated ERα signaling. Thus, our work indicates both estrogen-dependent and -independent pathways play separable roles in male murine reproductive tract development and that the role of ERα in human infertility should be examined more closely.

Download Full-text

Role of Acid/Base Transporters in the Male Reproductive Tract and Potential Consequences of Their Malfunction

Physiology ◽

10.1152/physiol.00036.2005 ◽

2005 ◽

Vol 20 (6) ◽

pp. 417-428 ◽

Cited By ~ 72

Author(s):

Nuria Pastor-Soler ◽

Christine Piétrement ◽

Sylvie Breton

Keyword(s):

Environmental Factors ◽

Male Fertility ◽

Reproductive Tract ◽

Sperm Maturation ◽

Genetic Mutations ◽

Acid Base ◽

Male Reproductive Tract ◽

Acidification Capacity ◽

And Storage

Acid/base transporters play a key role in establishing an acidic luminal environment for sperm maturation and storage in the male reproductive tract. Impairment of the acidification capacity of the epididymis, via either genetic mutations or exposure to environmental factors, may have profound consequences on male fertility.

Download Full-text

Role of V-ATPase-rich cells in acidification of the male reproductive tract.

Journal of Experimental Biology ◽

10.1242/jeb.200.2.257 ◽

1997 ◽

Vol 200 (2) ◽

pp. 257-262 ◽

Cited By ~ 5

Author(s):

D Brown ◽

P J Smith ◽

S Breton

Keyword(s):

Male Fertility ◽

Reproductive Tract ◽

Vas Deferens ◽

Apical Membrane ◽

Major Contributor ◽

Physiological Control ◽

Male Reproductive Tract ◽

Secretory Pathways ◽

Immunocytochemical Detection

Specialized proton-secreting cells play important physiological roles in a variety of tissues. On the basis of the immunocytochemical detection of carbonic anhydrase and V-ATPase in distinct epithelial cells of the epididymis and vas deferens, we predicted that the vacuolar V-ATPase that is located on the apical membrane of these cells should be a major contributor to luminal acidification in parts of the male reproductive tract. Physiological studies using the proton-selective vibrating probe in the vas deferens confirmed this hypothesis. As discussed recently, maintenance of the pH of the reproductive tract is probably under tight physiological control, by analogy with the situation in the kidney. Manipulation of luminal pH might, therefore, provide a point of intervention for the regulation of male fertility. In addition, it is possible that some cases of unexplained male infertility might result from defective acidification, resulting either from pathological states or potentially from environmental factors that may inhibit proton secretory pathways.

Download Full-text

The Effect of PDE5 Inhibitors on the Male Reproductive Tract

Current Pharmaceutical Design ◽

10.2174/1381612826666200226121510 ◽

2020 ◽

Vol 26 ◽

Cited By ~ 2

Author(s):

Nikolaos Sofikitis ◽

Aris Kaltsas ◽

Fotios Dimitriadis ◽

Jens Rassweiler ◽

Nikolaos Grivas ◽

...

Keyword(s):

Male Infertility ◽

Reproductive Tract ◽

Tunica Albuginea ◽

Scientific Data ◽

Secretory Function ◽

Pde5 Inhibitors ◽

Male Reproductive Tract ◽

Review Study ◽

Phosphodiesterase 5

The therapeutic range of cyclic nucleotide phosphodiesterase 5 inhibitors (PDE5) inhibitors is getting wider in the last years. This review study focuses on the potential employment of PDE5 inhibitors as an adjunct tool for the therapeutic management of male infertility. The literature tends to suggest a beneficial effect of PDE5 inhibitors on Leydig and Sertoli cells secretory function. It also appears that PDE5 inhibitors play a role in the regulation of the contractility of the testicular tunica albuginea and the epididymis. Moreover scientific data suggest that PDE5 inhibitors enhance the prostatic secretory function leading to an improvement in sperm motility. Other studies additionally demonstrate a role of PDE5 inhibitors in the regulation of sperm capacitation process. Placebo-controlled, randomized, blind studies are necessary to unambiguously incorporate PDE5 inhibitors as an adjunct tool for the pharmaceutical treatment of semen disorders and male infertility.

Download Full-text

Identification of multiple male reproductive tract-specific proteins that regulate sperm migration through the oviduct in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1908736116 ◽

2019 ◽

Vol 116 (37) ◽

pp. 18498-18506 ◽

Cited By ~ 13

Author(s):

Yoshitaka Fujihara ◽

Taichi Noda ◽

Kiyonori Kobayashi ◽

Asami Oji ◽

Sumire Kobayashi ◽

...

Keyword(s):

Membrane Protein ◽

Male Fertility ◽

Reproductive Tract ◽

Gene Families ◽

Gene Clusters ◽

Mutant Mice ◽

Male Reproductive Tract ◽

Sperm Migration ◽

Specific Proteins ◽

Multiple Male

CRISPR/Cas9-mediated genome editing technology enables researchers to efficiently generate and analyze genetically modified animals. We have taken advantage of this game-changing technology to uncover essential factors for fertility. In this study, we generated knockouts (KOs) of multiple male reproductive organ-specific genes and performed phenotypic screening of these null mutant mice to attempt to identify proteins essential for male fertility. We focused on making large deletions (dels) within 2 gene clusters encoding cystatin (CST) and prostate and testis expressed (PATE) proteins and individual gene mutations in 2 other gene families encoding glycerophosphodiester phosphodiesterase domain (GDPD) containing and lymphocyte antigen 6 (Ly6)/Plaur domain (LYPD) containing proteins. These gene families were chosen because many of the genes demonstrate male reproductive tract-specific expression. AlthoughGdpd1andGdpd4mutant mice were fertile, disruptions ofCstandPategene clusters andLypd4resulted in male sterility or severe fertility defects secondary to impaired sperm migration through the oviduct. While absence of the epididymal protein families CST and PATE affect the localization of the sperm membrane protein A disintegrin and metallopeptidase domain 3 (ADAM3), the sperm acrosomal membrane protein LYPD4 regulates sperm fertilizing ability via an ADAM3-independent pathway. Thus, use of CRISPR/Cas9 technologies has allowed us to quickly rule in and rule out proteins required for male fertility and expand our list of male-specific proteins that function in sperm migration through the oviduct.

Download Full-text

Carboxylesterase overexpression in the male reproductive tract: a universal safeguarding mechanism?

Reproduction Fertility and Development ◽

10.1071/rd99011 ◽

1999 ◽

Vol 11 (3) ◽

pp. 133 ◽

Cited By ~ 16

Author(s):

A. T. Mikhailov ◽

M. Torrado

Keyword(s):

Reproductive Tract ◽

Expression Patterns ◽

Cell Lineage ◽

Environmental Chemicals ◽

Male Reproductive Tract ◽

Morphological Organization ◽

Associated Functions ◽

And Function ◽

Hypothetical Explanation

Data on expression patterns of carboxylesterases in the male reproductive tract of different animal groups (i.e. bivalve mollusks, fruitflies and rodents) are summarized to highlight some particularly interesting questions in the context of sperm differentiation, maturation and function. The male reproduc-tive system, in spite of extreme variation in the anatomical/morphological organization in different species, is characterized by similar patterns of male-dependent carboxylesterase overexpression. The phenomenon of conserved carboxylesterase overexpression indicates similar male sex-associated functions of the enzymes. There is possible evidence of carboxylesterase recruitment by male reproductive-tract tissues indi-cating that it could be adaptive for spermatogenesis, sperm maturation and sperm use. Moreover, this idea can be extended to include a sperm cell lineage protection. This issue is discussed in the light of recent data on environmental reproductive xenobiotics that can provide a basis for a hypothetical explanation of car-boxylesterase overexpression in the male reproductive tract. Based on a well-known role of car-boxylesterases in detoxification of environmental chemicals such as organophosphate pesticides, it is proposed that various male genital tract carboxylesterases may be characterized by a similar physiological function to protect the male reproductive system against xenobiotic influences that could provoke its dys-function, thus altering sperm differentiation and maturation.

Download Full-text

ATP secretion in the male reproductive tract: essential role of CFTR

The Journal of Physiology ◽

10.1113/jphysiol.2012.230581 ◽

2012 ◽

Vol 590 (17) ◽

pp. 4209-4222 ◽

Cited By ~ 29

Author(s):

Ye Chun Ruan ◽

Winnie W. C. Shum ◽

Clémence Belleannée ◽

Nicolas Da Silva ◽

Sylvie Breton

Keyword(s):

Essential Role ◽

Reproductive Tract ◽

Male Reproductive Tract ◽

Atp Secretion

Download Full-text

Estrogen Modulates Glycerol Permeability in Sertoli Cells through Downregulation of Aquaporin-9

Cells ◽

10.3390/cells7100153 ◽

2018 ◽

Vol 7 (10) ◽

pp. 153 ◽

Cited By ~ 9

Author(s):

Raquel Bernardino ◽

David Carrageta ◽

Ana Silva ◽

Giuseppe Calamita ◽

Marco Alves ◽

...

Keyword(s):

Sertoli Cells ◽

Reproductive Tract ◽

Fluid Secretion ◽

Male Reproductive Tract ◽

Aquaporin 9 ◽

Important Regulator ◽

17Β Estradiol ◽

And Function ◽

Glycerol Permeability

High 17β-Estradiol (E2) levels are known to cause alterations of spermatogenesis and environments throughout the male reproductive tract. Sertoli cells (SCs) ensure an adequate environment inside the seminiferous tubule. Glycerol stands as essential for the maintenance of blood–testis barrier created by SCs, however, the role of E2 in this process is not known. Herein, we hypothesized that the effect of E2 on glycerol permeability in mouse SCs (mSCs) could be mediated by aquaglyceroporins. The expression of aquaglyceroporins was assessed by RT-PCR and qRT-PCR. Glycerol permeability was evaluated by stopped-flow light scattering. We were able to identify the expression of AQP3 and AQP9 in mSCs where AQP9 is more abundant than AQP3. Our results show that high E2 levels decrease AQP9 mRNA abundance with no influence on AQP3 in mSCs. Interestingly, high E2 levels decreased mSCs’ permeability to glycerol, while downregulating AQP9 expression, thus suggesting a novel mechanism by which E2 modulates fluid secretion in the testis. In conclusion, E2 is an important regulator of mSCs physiology and secretion through changes in AQP9 expression and function. Thus, alterations in glycerol permeability induced by E2 may be the cause for male infertility in cases associated with the presence of high E2 levels.

Download Full-text

Changes in distribution of labile zinc in mouse spermatozoa during maturation in the epididymis assessed by the fluorophore Zinquin

Reproduction Fertility and Development ◽

10.1071/rd9961097 ◽

1996 ◽

Vol 8 (7) ◽

pp. 1097 ◽

Cited By ~ 41

Author(s):

PD Zalewski ◽

X Jian ◽

LL Soon ◽

WG Breed ◽

RF Seamark ◽

...

Keyword(s):

Sodium Dodecyl Sulfate ◽

Reproductive Tract ◽

Regional Distribution ◽

Sodium Dodecyl ◽

Sperm Head ◽

Male Reproductive Tract ◽

Intracellular Location ◽

And Function ◽

Triton X

The Zn(II)-specific fluorophore Zinquin was used to determine the regional distribution of free or loosely-bound Zn(II) in mouse spermatozoa. Spermatozoa from the testes exhibited bright fluorescence over the entire head; those from the caput epididymides generally fluoresced more brightly in the post-acrosomal region; and spermatozoa from the caudae epididymides fluoresced less brightly, with foci of fluorescence over the sperm head which were lost after extraction with Triton X-100 and hence appeared to be membrane-associated. Treatment of cauda sperm with sodium dodecyl sulfate resulted in a bright uniform Zinquin fluorescence in the heads, similar to that observed in caput sperm, indicating that the two types of sperm have similar amounts of head Zn(II) but that the availability of Zn(II) for binding Zinquin is different. By contrast, the intensity of tail fluorescence was similar in spermatozoa from different regions of the male reproductive tract and was largely unaffected by Triton X-100 extraction, consistent with an intracellular location. Similar differences were observed between caput sperm and cauda sperm in the rat. It is concluded that visualization and measurement of free or loosely-bound Zn(II) in subcellular compartments of spermatozoa should facilitate investigation of the role of this metal in the development and function of spermatozoa and abnormalities that might accompany infertility and Zn(II) deficiency.

Download Full-text