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Abstract

Male factor infertility is increasing in developed countries, and several factors linked to lifestyle have been shown to negatively affect spermatogenesis. Sertoli cells are pivotal to spermatogenesis, providing nutritional support to germ cells throughout their development. Sertoli cells display atypical features in their cellular metabolism; they can metabolize various substrates, preferentially glucose, the majority of which is converted to lactate and not oxidized via the tricarboxylic acid cycle. Why Sertoli cells preferentially export lactate for germ cells is not entirely understood. However, lactate is utilized as the main energy substrate by developing germ cells and has an antiapoptotic effect on these cells. Several biochemical mechanisms contribute to the modulation of lactate secretion by Sertoli cells. These include the transport of glucose through the plasma membrane, mediated by glucose transporters; the interconversion of pyruvate to lactate by lactate dehydrogenase; and the release of lactate mediated by monocarboxylate transporters. Several factors that modulate Sertoli cell metabolism have been identified, including sex steroid hormones, which are crucial for maintenance of energy homeostasis, influencing the metabolic balance of the whole body. In fact, energy status is essential for normal reproductive function, since the reproductive axis has the capacity to respond to metabolic cues.
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... During differentiation, germ cells have specific metabolic requirements, switching their metabolic profile throughout development. They are supported with lactate [157], which is produced by Sertoli cells via the metabolism of various substrates, preferentially glucose [158]. ...
... During differentiation, germ cells have specific metabolic requirements, switching their metabolic profile throughout development. They are supported with lactate [157], which is produced by Sertoli cells via the metabolism of various substrates, preferentially glucose [158]. Thus, both aerobic and anaerobic pathways of carbohydrate metabolism are vital for germ cells [159,160]. ...
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Telomeres—special DNA–protein structures at the ends of linear eukaryotic chromosomes—define the proliferation potential of cells. Extremely short telomeres promote a DNA damage response and cell death to eliminate cells that may have accumulated mutations after multiple divisions. However, telomere elongation is associated with the increased proliferative potential of specific cell types, such as stem and germ cells. This elongation can be permanent in these cells and is activated temporally during immune response activation and regeneration processes. The activation of telomere lengthening mechanisms is coupled with increased proliferation and the cells’ need for energy and building resources. To obtain the necessary nutrients, cells are capable of finely regulating energy production and consumption, switching between catabolic and anabolic processes. In this review, we focused on the interconnection between metabolism programs and telomere lengthening mechanisms during programmed activation of proliferation, such as in germ cell maturation, early embryonic development, neoplastic lesion growth, and immune response activation. It is generally accepted that telomere disturbance influences biological processes and promotes dysfunctionality. Here, we propose that metabolic conditions within proliferating cells should be involved in regulating telomere lengthening mechanisms, and telomere length may serve as a marker of defects in cellular functionality. We propose that it is possible to reprogram metabolism in order to regulate the telomere length and proliferative activity of cells, which may be important for the development of approaches to regeneration, immune response modulation, and cancer therapy. However, further investigations in this area are necessary to improve the understanding and manipulation of the molecular mechanisms involved in the regulation of proliferation, metabolism, and aging.
... Subsequently, lactate dehydrogenase (LDH) rapidly reduces pyruvate to lactate, which is exported to testicular spermatogenic cells through monocarboxylic acid transporters (MCTs) to support spermatogenesis with energy. 21,22 . Studies have demonstrated that DM significantly alters the expressions of various enzymes involved in glucose metabolism. ...
... Testis is a naturally oxygen-deprived organ, and spermatogenesis relies heavily on glycolysis to provide energy. 22 Sertoli cells (SCs) in the testis play a crucial role in quickly providing lactate to meet the energy demands of spermatogenesis. The efficiency of glucose absorption by SCs, lactate production through glycolysis, and the transport of lactate to spermatogenic cells are essential for successful spermatogenesis. ...
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Objective This study aims to investigate potential beneficial actions of icariin (ICA) on testicular spermatogenic function in male rats with streptozotocin (STZ)-induced diabetes and to explore the underlying mechanisms. Background: ICA was found to reduce blood glucose, regulate the endocrine function of the reproductive system, and improve testicular spermatogenic function. Methods Adult rats were intraperitoneally injected with STZ (65 mg/kg) to induce type 1 diabetes mellitus (T1DM). Diabetic rats were randomly classified intoT1DM (n = 6) and T1DM + ICA (n = 6) groups. Rats without STZ and ICA treatment were assigned as control group (n = 6). The morphology of testicular tissues was examined by histological staining. The mRNA and protein expression levels were determined by quantitative real-time PCR, Western blot and immunostaining, respectively. Results Rats from T1DM group showed a reduction in epididymis and testis weight, and a decrease in sperm count when compared to control group (p < 0.01), which was attenuated by ICA treatment (p < 0.05) Diabetic rats from T1DM group also exhibited reduced diameter and area of seminiferous tubules, along with decreased spermatogonia and primary spermatocytes number when compared to control group (p < 0.01), which was partially reversed by ICA treatment (p < 0.05) Rats from T1DM group exhibited down-regulation of PCNA mRNA and protein in the testis when compared to control group (p < 0.01); while ICA treatment up-regulated PCNA expression in the testis of diabetic rats compared to T1DM group (p < 0.05). Rats from T1DM group showed up-regulation of Bax and capase-3 and down-regulation of Bcl-2, PKM2, HK2 and lactate dehydrogenase A in the testes when compared to control group (p < 0.05), which was reversed by ICA treatment (p < 0.05). Conclusion These findings suggest that ICA may exert its protective effects on testicular damage in diabetic rats through modulation of glycolysis pathway and suppression of apoptosis.
... Monocarboxylic acid transport, through several members of the solute carrier 16 (SLC16) family, is important for the metabolic regulation of spermatogenesis. SLC16 proteins are involved in the transport of lactate (among other molecules), the main energy substrate of developing germ cells, and has an antiapoptotic effect on these cells (reviewed in Rato et al., 2012). Two genes (slc16a9a and slc16a1a) were specifically upregulated in males after heat wave exposure and might be related to a compensatory mechanism to counteract the apoptosis process in sperm cells as a consequence of redox imbalance. ...
... There was a decrease in protein, sialic acid, glycogen, and seminal vesicular fructose indicating alteration in the testicular and sperm metabolic processes required for the production of sperm cells. Spermatogenesis is a biological process that involves the production of mature sperm cells from primitive germ cells [107] in the presence of adequate levels of energy substrates, otherwise, they degenerate and apoptosis or necrosis ensue [108]. This may explain the increase in apoptotic marginal nuclei or necrotic spermatocytes explained by Tripathy et al. [109]. ...
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Adaptogens, comprising plants and mushrooms, modulate the immune system, energy balance, and various physiological processes, including reproduction. Despite their potential benefits, the impact of adaptogens on reproductive function remains understudied. This review examines the effects of common adaptogens on male and female reproductive functions, highlighting their regulation of neuro-endocrine-immune interactions crucial for reproduction. While existing literature reveals varying impacts on reproductive function, most adaptogens exhibit beneficial effects, modulating neuroimmunology and promoting gonadal steroidogenesis, spermatogenesis, and folliculogenesis through direct mechanisms or suppression of oxidative stress and inflammation. Further experimental research is necessary to elucidate the mechanisms of action of adaptogens, which would significantly advance the management of reproductive disorders and other diseases. Validating these findings in clinical trials is also essential.
... During the male germ cell maturation process, the mitochondria remain relatively inactive during the early stages of germ cell development and then become progressively more active as maturation progresses [63,64]. According to this model, the spermatogonia exhibit increased glycolytic activity, while the spermatocytes and the spermatids synthesize ATP, mainly through the oxidative phosphorylation complex (OXPHOS) pathway [65][66][67]. Therefore, the metabolic changes that occur during meiosis require increased mitochondrial content (biogenesis and fission), mitochondrial elongation (fusion), and increased levels of OXPHOS [68,69]. ...
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D-aspartate (D-Asp) is an amino acid found in high concentrations in the testis and pituitary gland. Increasing evidence suggests that D-Asp promotes spermatogenesis by activating testosterone production in the Leydig cells via LH release from the pituitary gland. In vitro studies indicate that D-Asp may also influence steroidogenesis and spermatogenesis through autocrine and paracrine signals. D-Asp enhances StAR and steroidogenic enzyme expressions, facilitating testicular cell proliferation via the GluR/ERK1/2 pathway. Moreover, it supports spermatogenesis by enhancing the mitochondrial function in spermatocytes, aiding in the metabolic shift during meiosis. Enhanced mitochondrial function, along with improved MAM stability and reduced ER stress, has been observed in Leydig and Sertoli cells treated with D-Asp, indicating potential benefits in steroidogenesis and spermatogenesis efficiency. Conversely, D-Asp exerts a notable anti-apoptotic effect in the testis via the AMPAR/AKT pathway, potentially mediated by antioxidant enzyme modulation to mitigate testicular oxidative stress. This review lays the groundwork for future investigations into the molecules promoting spermatogenesis by stimulating endogenous testosterone biosynthesis, with D-amino acids emerging as promising candidates.
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Exposure to pesticides, poses a significant threat to male fertility by compromising crucial cells involved in spermatogenesis. Aminocarb, is a widely used carbamate insecticide, although its detrimental effects on the male reproductive system, especially on sustentacular Sertoli cells, pivotal for spermatogenesis, remains poorly understood. In this study, we investigated the effects of escalating concentrations of aminocarb on a mouse Sertoli cell line, TM4. Assessments included cytotoxic analysis, mitochondrial biogenesis and membrane potential, expression of apoptotic proteins, caspase-3 activity, and oxidative stress evaluation. Our findings revealed a dose-dependent reduction in the proliferation and viability of TM4 cells following exposure to increasing concentrations of aminocarb. Notably, exposure to 5 μM of aminocarb induced depolarization of mitochondria membrane potential, and a significant decrease in the ratio of phosphorylated eIF2α to total eIF2α, suggesting heightened endoplasmic reticulum stress via the activation of the eIF2α pathway. Moreover, the same aminocarb concentration was demonstrated to increase both caspase-3 protein levels and activity, indicating an apoptotic induction. Collectively, our results demonstrate that aminocarb serves as an apoptotic inducer for mouse sustentacular Sertoli cells in vitro, suggesting its potential to modulate independent pathways of the apoptotic cascade. These findings underscore the deleterious impact of aminocarb on spermatogenic performance and male fertility, highlighting the urgent need for further investigation into its mechanisms of action and mitigation strategies to safeguard male fertility.
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Infertility has become a significant health burden around the globe as it is believed that 15% of married couples struggle with infertility, with half of the problem accrued to the male. The issue of male infertility could be traced to insufficient or absence of spermatozoa. Glucose metabolism is essential for continued spermatogenesis and for the reproductive potential of sperm cells. Appropriate nutrition is critical in maintaining reproductive function as caloric restriction along with weight reduction, excessive food consumption and obesity are harmful to reproductive function. The link between metabolism and reproduction is tied to metabolic hormones like insulin, leptin and thyroid, extracellular environment, mitochondria function, nutrient substrate, availability, and environmental stressors. Although matured spermatozoa utilize glucose directly, it is not the preferred energy substrate for germ cells as they rely on Sertoli cells to supply lactate. The reproductive potential of sperm cells depends on certain modifications like hyperactivated motility, which is mainly dependent on glucose metabolism. Without other energy sources, spermatozoa utilize their internal lipid stores. The uptake and metabolism of glucose by sperm are essential endpoints for determining the potential fertility of male individuals. The biological energy in sperm cells fuels all the physiological processes they engage in, from their deposition in the female reproductive tract to the point where they fertilize an egg. This article thus reviews facts pertinent to the energy metabolism of male germ cells and Sertoli cells.
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Background Previous studies have shown that the activation of p38MAPK signaling plays a crucial role in regulating gonadal cell fate decisions in both mouse and human. Excessive activation of p38MAPK by radiation significantly causes testicular damage and negatively affects the male reproductive function. Therefore, fine‐tuned regulation of p38MAPK signaling is critical in both physiological and pathological conditions. Result This review summarizes the impact of p38MAPK signaling on testicular germ cells and microenvironment under normal condition. The relationship between radiation, reactive oxygen species (ROS), and p38MAPK is summarized. In conclusion, radiation exposure triggers the overactivation of p38MAPK, which is regulated by ROS, resulting in testicular damage. Various p38MAPK‐targeting agents are discussed, providing guidance for developing new strategies.
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Background Increased oxidative stress (OS), resulting from the delicate balance between reactive oxygen species (ROS) production and antioxidant defense, is closely linked to sperm abnormalities and male subfertility. Elevated ROS levels particularly affect sperm quality. The vulnerability of spermatozoa to ROS is due to the absence of DNA repair mechanisms and the high presence of polyunsaturated fatty acids in their membranes. Methods This article updates and advances our understanding of the molecular damage caused by OS in spermatozoa, including lipid peroxidation, DNA damage, motility, and functionality. Additionally, the review discusses the challenges in diagnosing OS in semen and recommends accurate and sensitive testing methods. Case studies are utilized to demonstrate the effective management of male infertility caused by OS. Main findings Highlighting the need to bridge the gap between research and clinical practice, this review suggests strategies for clinicians, such as lifestyle and dietary changes and antioxidant therapies. The review emphasizes lifestyle modifications and personalized care as effective strategies in managing male infertility caused by OS. Conclusion This review calls for early detection and intervention and interdisciplinary collaboration to improve patient care in male infertility cases related to increased OS.
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Spermatogenesis is a crucial indicator of geese reproduction performance and production. The testis is the main organ responsible for sperm production, and the egg-laying cycle in geese is a complex physiological process that demands precise orchestration of hormonal cues and cellular events within the testes, however, the seasonal changes in the transcriptomic and proteomic profiles of goose testicles remain unclear. To explore various aspects of the mechanisms of the seasonal cyclicity of testicles in different goose breeds, in this study, we used an integrative transcriptomic and proteomic approach to screen the key genes and proteins in the testes of two goose males, the Hungarian white goose and the Wanxi white goose, at three different periods of the laying cycle: beginning of laying cycle (BLC), peak of laying cycle (PLC), and end of laying cycle (ELC). The results showed that a total of 9273 differentially expressed genes and 4543 differentially expressed proteins were identified in the geese testicles among the comparison groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that the DEGs, in the comparison groups, were mainly enrichment in metabolic pathways, neuroactive ligand-receptor interaction, cyctokine-cyctokine receptor interaction, calcium signaling pathway, apelin signaling pathway, ether lipid metabolism, cysteine, and methionine metabolism. While the DEPs, in the three comparison groups, were mainly involved in the ribosome, metabolic pathways, carbon metabolism, proteasome, endocytosis, lysosome, regulation of actin cytoskeleton, oxidative phosphorylation, nucleocytoplasmic transport, and tight junction. The protein-protein interaction network analysis (PPI) indicated that selected DEPs, such as CHD1L, RAB18, FANCM, TAF5, TSC1/2, PHLDB2, DNAJA2, NCOA5, DEPTOR, TJP1, and RAPGEF2, were highly associated with male reproductive regulation. Further, the expression trends of four identified DEGs were validated by qRT-PCR. In conclusion, this work offers a new perspective on comprehending the molecular mechanisms and pathways involved in the seasonal cyclicity of testicles in the Hungarian white goose and the Wanxi white goose, as well as contributing to improving goose reproductive performance.
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By using cultured rat Sertoli cells as a model, both the action of basic fibroblast growth factor (bFGF) on lactate production and the site of this action were studied. bFGF stimulated Sertoli cell lactate production in a dose-dependent manner (basal: 7·30·5; 0·1 ng/ml bFGF: 7·50·5; 1 ng/ml bFGF: 7·50·6; 10 ng/ml bFGF: 10·31·0; 30 ng/ml bFGF: 15·21·5; 50 ng/ml bFGF: 15·41·6 µg/µg DNA). Two major sites for the action of this growth factor were identified. First, bFGF was shown to exert short-and long-term stimulatory effects on glucose transport (basal: 1170102; 30 ng/ml bFGF for 120 min: 1718152 and basal: 71864; 30 ng/ml bFGF for 48 h: 106969 d.p.m./µg DNA respectively). Short-term bFGF stimulation of glucose transport was not inhibited by the protein synthesis inhibi-tor cycloheximide. These results indicate that short-term bFGF stimulation of glucose uptake does not involve an increase in the number of glucose transporters. On the other hand, stimulation with bFGF for periods of time longer than 12 h increased glucose transporter 1 (GLUT1) mRNA levels. These increased mRNA levels were probably ultimately responsible for the increments in glucose uptake that are observed in long-term treated cultures. Secondly, bFGF increased lactate dehydrogenase (LDH) activity (basal: 31·01·4; 30 ng/ml bFGF: 45·7 2·4 mIU/µg DNA). The principal subunit component of those LDH isozymes that favors the transformation of pyruvate to lactate is subunit A. bFGF increased LDH A mRNA levels in a dose-and time-dependent manner. In summary, the results presented herein show that glucose transport, LDH activity and GLUT1 and LDH A mRNA levels are regulated by bFGF to achieve an increase in lactate production. These observed regulatory actions provide unequivocal evidence of the participation of bFGF in Sertoli cell lactate production which may be related to normal germ cell development.
Article
Various barriers in the testis may prevent hormones from readily reaching the cells they are supposed to stimulate, especially the hydrophilic hormones from the pituitary. For example, LH must pass through or between the endothelial cells lining the blood vessels to reach the surface of the Leydig cells, and FSH has the additional barrier of the peritubular myoid cells before it reaches the Sertoli cells. The specialised junctions between pairs of Sertoli cells would severely restrict the passage of peptides from blood to the luminal fluid and therefore to the cells inside this barrier, such as the later spermatocytes and spermatids. There is evidence in the literature that radioactively labelled LH does not pass readily into the testis from the blood, and the concentration of native LH in the interstitial extracellular fluid surrounding the Leydig cells in rats is only about one-fifth of that in blood plasma. Furthermore, after injection with LHRH, there are large rises in LH in the blood within 15 min, at which time the Leydig cells have already responded by increasing their content of testosterone, but with no significant change in the concentration of LH in the interstitial extracellular fluid. Either the Leydig cells respond to very small changes in LH, or the testicular endothelial cells in some way mediate the response of the Leydig cells to LH, for which there is now some evidence from co-cultures of endothelial and Leydig cells. The lipophilic steroid hormones, such as testosterone, which are produced by the Leydig cells, have actions within the seminiferous tubules in the testis but also in other parts of the body. They should pass more readily through cells than the hydrophilic peptides; however, the concentration of testosterone in the fluid inside the seminiferous tubules is less than in the interstitial extracellular fluid in the testis, especially after stimulation by LH released after injection of LHRH and despite the presence inside the tubules of high concentrations of an androgen-binding protein. The concentration of testosterone in testicular venous blood does not rise to the same extent as that in the interstitial extracellular fluid, suggesting that there may also be some restriction to movement of the steroid across the endothelium. There is a very poor correlation between the concentrations of testosterone in fluids from the various compartments of the testis and in peripheral blood plasma. Determination of the testosterone concentration in the whole testis is also probably of little predictive value, because the high concentrations of lipid in the Leydig cells would tend to concentrate testosterone there, and hormones inside these cells are unlikely to have any direct effect on other cells in the testis. The best predictor of testosterone concentrations around cells in the testis is the level of testosterone in testicular venous blood, the collection of which for testosterone analysis is a reasonably simple procedure in experimental animals and should be substituted for tissue sampling. There seems to be no simple way of determining the concentrations of peptide hormones in the vicinity of the testicular cells.
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We analyzed the expression of hexose transporters in human testis and in human, rat, and bull spermatozoa and studied the uptake of hexoses and vitamin C in bull spermatozoa. Immunocytochemical and reverse transcription-polymerase chain reaction analyses demonstrated that adult human testis expressed the hexose transporters GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5. Immunoblotting experiments demonstrated the presence of proteins of about 50–70 kD reactive with anti-GLUT1, GLUT2, GLUT3, and GLUT5 in membranes prepared from human spermatozoa, but no proteins reactive with GLUT4 antibodies were detected. Immunolocalization experiments confirmed the presence of GLUT1, GLUT2, GLUT3, GLUT5, and low levels of GLUT4 in human, rat, and bull spermatozoa. Each transporter isoform showed a typical subcellular localization in the head and the sperm tail. In the tail, GLUT3 and GLUT5 were present at the level of the middle piece in the three species examined, GLUT1 was present in the principal piece, and the localization of GLUT2 differed according of the species examined. Bull spermatozoa transported deoxyglucose, fructose, and the oxidized form of vitamin C, dehydroascorbic acid. Transport of deoxyglucose and dehydroascorbic acid was inhibited by cytochalasin B, indicating the direct participation of facilitative hexose transporters in the transport of both substrates by bull spermatozoa. Transport of fructose was not affected by cytochalasin B, which is consistent for an important role for GLUT5 in the transport of fructose in these cells. The data show that human, rat, and bull spermatozoa express several hexose transporter isoforms that allow for the efficient uptake of glucose, fructose, and dehydroascorbic acid by these cells. J. Cell. Biochem. 71:189–203, 1998. © 1998 Wiley-Liss, Inc.
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"Every university, medical school and research institute should have these volumes in their libraries." - V. Daniel Castracane, Foundation for Blood Research, Scarborough, ME for TRENDS IN ENDOCRINOLOGY & METABOLISM (2006).
Chapter
Sertoli cells play an important role in the formation and development of the testis and suppression of the female reproductive tract. Sertoli cells are the first cells to differentiate in the indifferent fetal gonad and this differentiation results in seminiferous cord formation, prevention of germ-cell entry into meiosis, and differentiation and function of the other somatic cells of the testis. In some species, the presumptive Sertoli cells are actively involved in the "production of spermatozoa" while in others their role has not been investigated. In mammals, Sertoli cells have dual roles in the embryology and development of the testis. The appearance of Sertoli cells is the focal point for the formation of the testis and ultimately for the continuance of the male germ line. The maturation of a number of Sertoli cells ultimately determines the sperm output of an adult mammalian testis. The development of germ cells from stem cells to spermatozoa appears to be possible at some level in the absence of Sertoli cells. At least in mammals, it appears that Sertoli cells enhance the efficiency of this process dramatically. In mammals, the actions of hormones such as follicle-stimulating hormone (FSH) and testosterone on spermatogenesis occur via actions on Sertoli cells. Also, in mammals, one of the ways that Sertoli cells enhance the efficiency of spermatogenesis is by the creation of a unique environment for meiotic and postmeiotic germ cells.
Article
Dysregulation of male germ cell apoptosis has been associated with the pathogenesis of male infertility. Therefore, factors involved in the regulation of germ cell death are being actively investigated. Here, we studied the effects of lactate on human male germ cell death, using as a model a testis tissue culture in which physiological contacts are maintained between the germ cells and the supportive somatic Sertoli cells. Apoptosis of spermatocytes, spermatids and a few spermatogonia was induced by culturing segments of seminiferous tubules under serum-free conditions. This germ cell death was inhibited effectively and dose-dependently by lactate, indicating that it plays a crucial role in controlling cell death cascades of male germ cells. Interestingly, the anti-apoptotic role of lactate was not associated with changes in testicular adenine nucleotide (ATP, ADP and AMP) levels. In the seminiferous tubules, the final site of the death-suppressing action of lactate appeared to be downstream along the cell death pathway activated by the Fas receptor of the germ cells. In conclusion, testicular cell death was effectively regulated by lactate, which may be regarded as a potential compound for optimizing in-vitro methods involving male germ cells for assisted reproduction.