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Schematic illustration of the seminiferous epithelium and spermatogenesis. The seminiferous epithelium is composed by Sertoli cells (SCs) and different subtypes of developing germ cells. Male gametes (spermatozoa) are formed in the seminiferous tubules of the testis in a complex process, known as spermatogenesis, the cellular division and transformation that produce male haploid germ cells from diploid spermatogonial stem cells. The supporting SCs adhere to the basement membrane where spermatogonia are also adherent. Then, spermatogonia type A divide and develop into spermatogonia type B, which enter meiotic prophase and differentiate into primary spermatocytes that separate the homologous pairs of chromosomes in meiosis I (reduction division) to form the haploid secondary spermatocytes. The meiosis II yields four equalized spermatids that migrate toward the lumen where fully formed spermatozoa are finally released.
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Sertoli cells (SCs) are essential for the testis functional development and hence for the expression of male phenotype. They provide a unique and protected environment in testis, within the seminiferous tubules, necessary for the successful progression of germ cells into fully competent spermatozoa. SC has the ability to metabolize various substrat...
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... Sertoli cells support the advancement of germ cells in spermatozoa by direct interaction and by controlling the environmental microenvironment inside the seminiferous tubules. Sertoli cells have been shown to consume glucose aerobically at a high rate and release lactate and pyruvate; lactate and pyruvate are needed for germ cell maintenance [17,18]. In non-obstructive azoospermia, we show that the genes pyruvate dehydrogenase phosphatase regulatory (PDPR) and sorbitol dehydrogenase regulatory (SORD) were decreased (downregulated). ...
... According to our previous research, human Sertoli cells were isolated and identified [17]. In brief, testicular tissues were washed three times before being cut into 0.2 cm pieces and treated with Enzyme I (10 mL of DMEM containing 2 mg/mL type IV collagenase and 10 mg/mL DNase I) for 15 min at 34 • C. ...
Non-obstructive azoospermia (NOA) is a serious cause of male infertility. The Sertoli cell responds to androgens and takes on roles supporting spermatogenesis, which may cause infertility. This work aims to enhance the genetic diagnosis of NOA via the discovery of new and hub genes implicated in human NOA and to better assess the odds of successful sperm extraction according to the individual’s genotype. Whole exome sequencing (WES) was done on three NOA patients to find key genes involved in NOA. We evaluated genome-wide transcripts (about 50,000 transcripts) by microarray between the Sertoli of non-obstructive azoospermia and normal cells. The microarray analysis of three human cases with different non-obstructive azoospermia revealed that 32 genes were upregulated, and the expressions of 113 genes were downregulated versus the normal case. For this purpose, Enrich Shiny GO, STRING, and Cytoscape online evaluations were applied to predict the functional and molecular interactions of proteins and then recognize the master pathways. The functional enrichment analysis demonstrated that the biological process (BP) terms “inositol lipid-mediated signaling”, “positive regulation of transcription by RNA polymerase II”, and “positive regulation of DNA-templated transcription” significantly changed in upregulated differentially expressed genes (DEGs). The BP investigation of downregulated DEGs highlighted “mitotic cytokinesis”, “regulation of protein-containing complex assembly”, “cytoskeleton-dependent cytokinesis”, and the “peptide metabolic process”. Overrepresented molecular function (MF) terms in upregulated DEGs included “ubiquitin-specific protease binding”, “protease binding”, “phosphatidylinositol trisphosphate phosphatase activity”, and “clathrin light chain binding”. Interestingly, the MF analysis of the downregulated DEGs revealed overexpression in “ATPase inhibitor activity”, “glutathione transferase activity”, and “ATPase regulator activity”. Our findings suggest that these genes and their interacting hub proteins could help determine the pathophysiologies of germ cell abnormalities and infertility.
... The reproductive fertility of males is highly dependent of glucose uptake and metabolism by testicular tissue. Glucose metabolism is critical for normal functions of the testicular cells and more specifically, spermatogenesis (8). In addition, the thyroid hormones (THs) play an important role in the utilization of energy, oxygen consumption, and overall metabolism (9). ...
... Interestingly, our study found significant increase in the glucose levels after 1 month of L-arginine oral administration. As known, glucose uptake and metabolism by testicular tissue have an essential role in the male reproductive performance, moreover, normal glucose metabolism is critical for spermatogenesis since the developing germ cells in the Sertoli cells consume lactate, a waste product of glucose, as their main energy source (8). ...
This study aimed to investigate the effect of oral supplementation of rumen-protected L-arginine on semen quality, testes, and accessory genital glands biometry in rams. Ten apparently healthy and fertile rams were randomly divided into two equal groups; control, and rumen-protected L-arginine (20 mg/Kg body weight for 30 days) treated group. In all rams, ultrasonographic measurements of the testes and the accessory genital glands and blood sampling were performed at day (D)10, D20, and D30 (D0 is the start of supplementation). Semen ejaculates were collected twice/week and semen quantity, and quality was examined. Our results showed that, in the L-arginine treated group, there were significant increase in the ultrasound biometric measurement of right seminal vesicle (RSV) and right Cowper's gland (RCG) at D10, both testes, tail of the epididymis (TE), SV, and CG of both sides at D20, and of both testes, RTE, RSV, RCG, and LSV at D30. Semen quality and quantity parameters were significantly improved in L-arginine treated group. Moreover, testosterone level in the L-arginine treated group was significantly higher than that in the Control group. Serum thyroxine and glutathione peroxidase concentrations were significantly higher in the L-arginine treated group. The present study concluded that oral supplementation with rumen-protected L-arginine is beneficial in improvement of rams' fertility.
... The BTB is composed of specialized junctions between adjacent Sertoli cells, which is located near the basement membrane, is responsible for maintaining the different levels of substances between rete testis fluid and the lymph or plasma (16). Sertoli cells provide structural and functional support for the development of the germ cells due to their role in maintaining the suitable ionic and metabolic microenvironment in testes (17,18). They use different metabolic substrates, including glucose and fatty acids, and growth factors to meet their metabolic demands and nurture germ cells (19)(20)(21)(22). ...
The physiological process of male reproduction relies on the orchestration of neuroendocrine, immune, and energy metabolism. Spermatogenesis is controlled by the hypothalamic-pituitary-testicular (HPT) axis, which modulates the production of gonadal steroid hormones in the testes. The immune cells and cytokines in testes provide a protective microenvironment for the development and maturation of germ cells. The metabolic cellular responses and processes in testes provide energy production and biosynthetic precursors to regulate germ cell development and control testicular immunity and inflammation. The metabolism of immune cells is crucial for both inflammatory and anti-inflammatory responses, which supposes to affect the spermatogenesis in testes. In this review, the role of immunometabolism in male reproduction will be highlighted. Obesity, metabolic dysfunction, such as type 2 diabetes mellitus, are well documented to impact male fertility; thus, their impacts on the immune cells distributed in testes will also be discussed. Finally, the potential significance of the medicine targeting the specific metabolic intermediates or immune metabolism checkpoints to improve male reproduction will also be reassessed.
... The role of adenosine triphosphate (ATP) as the energy metabolism of the mitochondria is a major factor supporting multiple functions of the sperm. They harbour significant metabolic pathways during germ cell development and fertilization, energy maintenance and fertility (17). Testicular energy metabolism is desired to maintain spermatogenesis and research reveals that the germ cells depend on lactate for energy. ...
This study assessed the influence of direct exposure of rodents to Awotan Solid Waste Dumpsite (ASWD) in Ibadan, Nigeria. Reproductive energy content was evaluated by assessing testicular ATP activity, testicular polychlorinated biphenyls (PCBs), testicular heavy metal and fructose levels in seminal vesicle and coagulating glands. The exposure of the male rats was from postnatal day 22 and for a period of 10 weeks. The direct municipal dumpsite exposure resulted in testicular heavy metal accumulation viz: mercury > iron > zinc > nickel > cadmium > arsenic. There was a decrease in serum lactate dehydrogenase (LDH) concentration, an increase in testicular LDH concentration (markers of cellular ATP) and a decrease in the fructose level in the seminal vesicle of the dumpsite exposed (DSE) animals compared with the control. The PCBs were not detected in the testis of DSE animals but there was significant correlation between testicular LDH and some metals. It is concluded that some possible mechanisms by which direct exposure to a dumpsite elicits energy depletion in the male rat testes could be through the inhibition of fructose level and LDH activity.
... Tight hormonal control of these metabolic processes involves a variety of complex signaling cascades that are yet to be fully elucidated [61]. Moreover, the precise molecular mechanisms coordinated by the respective hormone during Sertoli cell glucose uptake and metabolism are not fully known [62], although studies have begun to shed some light on the matter. ...
... Glucose metabolism in Sertoli cells is a well-controlled process essential for normal spermatogenesis. As such, any compromise in the Sertoli cells' ability to metabolize glucose could jeopardize the energy supply to the germ cells, which would then disrupt spermatogenesis and subsequently impact male fertility [62]. ...
Spermatozoa consume energy in the form of intracellular adenosine triphosphate (ATP) generated by its fuel machinery. Energy is required to facilitate sperm functions, from sperm motility and hyperactivation to capacitation and acrosome reaction, all of which are crucial for the success of fertilization. Glycolysis and oxidative phosphorylation are the two metabolic pathways known to generate energy in spermatozoa. However, the cellular mechanism and signaling pathways that spermatozoa predominantly utilize to generate the energy it requires to achieve successful fertilization are not fully elucidated. Oxidative phosphorylation occurs in the mitochondria and is a more efficient pathway for ATP production compared to glycolysis. Mitochondrial respiration is reported to be the primary source of energy for sperm motility, yet the diffusion potential of ATP from the mitochondria downwards of the entire flagellar length is inadequate to support sperm motility. On the other hand, glycolysis, which takes place in the sperm head and tail, is the main source of ATP along the flagellum. Although inhibition of the glycolysis process does not appear to disrupt sperm function and motility, it is uncertain whether such motility is sustainable over an extended time period or if it is vigorous enough for fertilization to occur effectively. This chapter provides an overview of sperm energy metabolism, which is supported by the unique anatomical and physiological characteristics in spermatozoa as well as the coordination between the Sertoli cells and spermatogonial cells during energy production in spermatozoa. Energy utilization during each sperm process and the consequence of fuel depletion on sperm function are also described. Understanding the intricacies of sperm energy metabolism would help improve the in vitro sperm storage media and contribute toward the development of non-hormonal contraceptives.
... Quando incubadas com concentrações farmacológicas de metformina (50 µM), as células de Sertoli produziram e secretaram maior quantidade de lactato 10 . Estes resultados foram vistos como um bom indicador de proteção do evento espermatogénico, visto que o lactato, além de ser o subs-trato preferencial para produção de ener-gia, possui propriedades antiapoptóticas para as células germinativas 44,45 . Tendo isto em conta, estes mecanismos podem ser os responsáveis pelo aumento do potencial fértil associado ao tratamento com metformina de pacientes com doenças metabólicas. ...
Diabetes and obesity are two closely linked metabolic diseases which treatment is essential due to their implication on metabolic homeodynamics. Metformin is a drug that can stimulate insulin synthesis and reduce insulin resistance, the prescription of which is the first line of treatment against diabetes. This has spurred several studies on the effect of this drug on multiple organs and tissues. However, published studies on the effect of metformin on the male reproductive system are much smaller than those of the opposite sex. In this paper, a critical analysis of available studies describing the negative effects that metabolic diseases such as diabetes (type 1 and type 2) and obesity have on male fertility and the possible mechanisms by which metformin treatment can regulate these effects have been described. The known effects that this pharmacological agent has on male fertility are further presented and discussed. Indeed, it can be concluded that there is solid evidence that in metabolically ill individuals, metformin has a protective effect on reproductive function however, in healthy individuals, the effect may be deleterious, highlighting the importance of further studies in this area.
... As remarked above, lactate synthesis by SCs is a crucial step in testicular metabolic cycle, which produces more desirable energy substrate for springing up germ cells and has a prominent anti-apoptotic effect [47]. Also, some studies showed that metformin plays a role as a suppressor of complex I of the mitochondrial electron transport chain that directly decreases oxidative metabolism and accordingly increases anaerobic respiration and lactate secretion [48]. ...
... The metabolic cooperation established between Sertoli and germ cells is pivotal for spermatogenesis, as the former provide the nutritional support required by the latter during their development. That process is mainly mediated through glucose metabolism that is essential for the normal development of spermatogenesis ( Dias et al. 2013). Sertoli cells, the somatic cells of seminiferous tubules, take up glucose from the extracellular compartment by the glucose transporters (GLUTs), Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00441-019-03028-4) ...
Lactate is a key metabolite for the normal occurrence of spermatogenesis. In the testis, lactate is produced by the Sertoli cells and transported to germline cells. Monocarboxylate transporters (MCTs) are key players in that process. Among the family of MCTs, MCT1 is at least partly responsible for lactate uptake by the germ cells. We aimed to perform a first assessment of the role of MCT1 in male reproductive potential. Mct1 conditional knockout (cKO) mice were used for morphometric evaluation, testicular morphology, and sperm parameter assessment. Serum steroid hormones levels were also measured. cKO animals showed a decrease in gonadosomatic index, testis weight, and seminiferous tubular diameters. Deletion of MCT1 also causes morphological changes in the organization of the seminiferous tubules and on Sertoli cell morphology. These changes resulted in failure of spermatogenesis with depletion of germ cells and total absence of spermatozoa. MCT1 cKO animals presented also hormonal dysregulation, with a decrease in serum 17β-estradiol levels. In conclusion, MCT1 is pivotal for male reproductive potential. Absence of MCT1 results in maintenance of undifferentiated spermatogonia pool and compromised sperm production.
... These cells constitute the blood-testis-barrier (BTB), which is crucial for the physical support and protection of developing germ cells. They are also responsible for the production of several growth factors and nutrients, essential for germ cell survival and differentiation into spermatozoa [1]. The normal function of SCs metabolic processes is crucial for the preservation of male reproductive potential. ...
... We could not detect pyruvate in the extracellular media, as analyzed by the 1 H-NMR, which indicates that it is being used by the cells. Pyruvate is an important regulatory point of cell metabolism as it can follow three different pathways: (1) it can be converted to lactate by LDH; (2) it can produce alanine; or (3) it can enter the mitochondria to form acetyl-CoA and fuel the Krebs cycle [1]. Both LDH protein expression levels and activity were similar between the experimental groups, resulting in a normal production of lactate in hSCs exposed to l-theanine. ...
Purpose: L-Theanine is the major free amino acid present in tea (Camellia sinensis L.). The effects of several tea constituents on male reproduction have been investigated, but L-theanine has been overlooked. Sertoli cells (SCs) are essential for the physical and nutritional support of germ cells. In this study, we aimed to investigate the ability of L-theanine to modulate important mechanisms of human SCs (hSCs) metabolism, mitochondrial function and oxidative profile, which are essential to prevent or counteract spermatogenesis disruption in several health conditions.
Methods: We evaluated the effect of a dose of l-theanine attained by tea intake (5 μM) or a pharmacological dose (50 μM) on the metabolism (proton nuclear magnetic resonance and Western blot), mitochondrial functionality (protein expression of mitochondrial complexes and JC1 ratio) and oxidative profile (carbonyl levels, nitration and lipid peroxidation) of cultured hSCs.
Results: Exposure of hSCs to 50 μM of l-theanine increased cell proliferation and glucose consumption. In response to this metabolic adaptation, there was an increase in mitochondrial membrane potential, which may compromise the prooxidant–antioxidant balance. Still, no alterations were observed regarding the oxidative damages.
Conclusions: A pharmacological dose of l-theanine (50 μM) prompts an increase in hSCs proliferation and a higher glucose metabolization to sustain the pool of Krebs cycle intermediates, which are crucial for cellular bioenergetics and biosynthesis. This study suggests an interplay between glycolysis and glutaminolysis in the regulation of hSCs metabolism.
... Lactate is essential for the development of germ cells. Developing germ cells are unable to metabolize glucose and use the lactate produced by SCs as an energy substrate [32,33]. In addition, it has been suggested that lactate production can also be obtained by other pathways, although these processes are not well understood. ...
The process that allows cells to control their pH and bicarbonate levels is essential for ionic and metabolic equilibrium. Carbonic anhydrases (CAs) catalyse the conversion of CO2 to HCO3− and H⁺ and are thus essential for this process. Herein, we inhibited CAs with acetazolamide – ACT and SLC‐0111 – to study their involvement in the metabolism, mitochondrial potential, mitochondrial biogenesis and lipid metabolism of human Sertoli cells (hSCs), obtained from biopsies from men with conserved spermatogenesis. We were able to identify three isoforms of CAs, one mitochondrial isoform (CA VB) and two cell membrane‐bound isoforms (CA IX and CA XII) in hSCs. When assessing the expression of markers for mitochondrial biogenesis, we observed a decrease in HIF‐1α, SIRT1, PGC1α and NRF‐1 mRNAs after all CAs were inhibited, resulting in decreased mitochondrial DNA copy numbers. This was followed by an increased production of lactate and alanine in the same conditions. In addition, consumption of glucose was maintained after inhibition of all CAs in hSCs. These results indicate a reduced conversion of pyruvate to acetyl‐coA, possibly due to decreased mitochondrial function, caused by CA inhibition in hSCs. Inhibition of CAs also caused alterations in lipid metabolism, since we detected an increased expression of hormone‐sensitive lipase (HSL) in hSCs. Our results suggest that CAs are essential for mitochondrial biogenesis, glucose and lipid metabolism in hSCs. This is the first report showing that CAs play an essential role in hSC metabolic dynamics, being involved in mitochondrial biogenesis and controlling lactate production.
