Male Reproductive Dysfunction Research Articles

Hyperglycemia induces spermatogenic disruption via major pathways of diabetes pathogenesis

Diabetes-induced hyperglycemia has previously been shown to impact on male sub-/infertility, however, still little is known about the underlying mechanisms. In the present study we have addressed three major biochemical pathways implicated in the pathogenesis of hyperglycemia induced organ damage (the advanced glycation end product (AGE) formation pathway, the diacylglycerol-protein kinase C pathway (PKC), and the polyol pathway) in both testis and epididymis of the Ins2Akita mouse model of Type 1 diabetes (T1DM). Hyperglycemia activated both the PKC and the polyol pathway in a significant and progressive manner within the testis, but not within the epididymis. While the AGE receptor was ubiquitiously expressed in the testis, concentrations of precursor methylglyoxal and AGE carboxymethyllysine were increased in both epididymis and testis in diabetic mice. However, AGEs did not activate intracellular pathways of ERK1, ERK2, Rela, Nrf-2, IkBkB, NFkB except CDC42, Akt1. In conclusion, two of the major pathways of hyperglycemia-induced organ damage were clearly activated within the testis of T1DM mice. This provides therapeutical opportunities in the treatment of diabetic male reproductive dysfunction.

Obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system.

Obesity and metabolic syndrome (MetS) are global epidemics, driven by an obesogenic environment. This is mediated by complex underlying pathophysiology, in which chronic inflammation is an important aetiological and mechanistic phenomenon. A shift towards a subclinical TH 1-lymphocyte mediated innate and chronic inflammatory response is well defined in obesity and MetS, demonstrated in multiple systems including visceral adiposity, brain (hypothalamus), muscles, vasculature, liver, pancreas, testes, epididymis, prostate and seminal fluid. Inflammatory cytokines disrupt the hypothalamic-pituitary-testes axis and steroidogenesis cascades (hypogonadotropic hypogonadism), spermatogenesis (poor semen parameters, including DNA fragmentation and detrimental epigenetic modification) and results in subclinical prostatitis and prostate hyperplasia. This review aims to highlight the role of chronic inflammation in obesity and MetS, cytokines in male reproductive physiology and pathophysiology, the impact on steroidogenesis and spermatogenesis, prostate pathology and erectile dysfunction. Currently, it is recommended that clinical assessment of male infertility and reproductive dysfunction in obese and MetS patients includes inflammation assessment (highly sensitive C-reactive protein), and appropriate advice and therapeutic options are incorporated in the management options. However, the mechanisms and therapeutic options remain poorly understood and require significant interdisciplinary research to identify potential novel therapeutic strategies.

Differentiation of human adipose derived stem cells into Leydig-like cells with molecular compounds.

Leydig cells (LCs) are the primary source of testosterone in the testis, and testosterone deficiency caused by LC functional degeneration can lead to male reproductive dysfunction. LC replacement transplantation is a very promising approach for this disease therapy. Here, we report that human adipose derived stem cells (ADSCs) can be differentiated into Leydig‐like cells using a novel differentiation method based on molecular compounds. The isolated human ADSCs expressed positive CD29, CD44, CD59 and CD105, negative CD34, CD45 and HLA‐DR using flow cytometry, and had the capacity of adipogenic and osteogenic differentiation. ADSCs derived Leydig‐like cells (ADSC‐LCs) acquired testosterone synthesis capabilities, and positively expressed LC lineage‐specific markers LHCGR, STAR, SCARB1, SF‐1, CYP11A1, CYP17A1, HSD3B1 and HSD17B3 as well as negatively expressed ADSC specific markers CD29, CD44, CD59 and CD105. When ADSC‐LCs labelled with lipophilic red dye (PKH26) were injected into rat testes which were selectively eliminated endogenous LCs using ethylene dimethanesulfonate (EDS, 75 mg/kg), the transplanted ADSC‐LCs could survive and function in the interstitium of testes, and accelerate the recovery of blood testosterone levels and testis weights. These results demonstrated that ADSCs could be differentiated into Leydig‐like cells by few defined molecular compounds, which might lay the foundation for further clinical application of ADSC‐LC transplantation therapy.

African star apple fruit pulp-supplemented diet modulates fertility-related biomolecules in the testis and epididymis of high-fat diet/streptozotocin-induced diabetic rats.

This study evaluated the modulatory effect of African star apple fruit (ASAF) pulp inclusive diet on biomolecules associated with reproductive function in the testis and epididymis of high-fat diet/streptozotocin-induced diabetic male rats. The rats were divided into seven groups: control, diabetic control, diabetic rats treated with metformin, diabetic rats served with diet having 5 and 10% ASAF, respectively, and control rats served with diet containing 5%, and 10% ASAF respectively for 14 days. There were noticeable decrease in sperm parameters, reproductive hormone, glycogen, nitric oxide, total thiol, nonprotein thiol levels, and testicular 3β- and 17β-hydroxysteroid dehydrogenase activities and concomitant increase in cholesterol, reactive oxygen species, malondialdehyde levels, and arginase activity compared to the control. Nevertheless, ASAFs reversed all these parameters toward the control levels. Therefore, these findings suggest that ASAF pulp-supplemented diet might be an active approach in controlling male reproductive dysfunction induced by diabetes. PRACTICAL APPLICATIONS: The results suggest that ASAF pulp-supplemented diet might be an active approach in controlling male reproductive dysfunction induced by diabetes through alterations in the levels of blood glucose, glycogen, cholesterol, nitric oxide, reproductive hormones, activities of steroidogenic enzymes, arginase, and sperm characteristics as well as the antioxidant status in the testes and epididymis.

Development of fetal and adult Leydig cells.

BackgroundIn mammals, two distinct Leydig cell populations, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs), appear in the prenatal and postnatal testis, respectively. Although the functional differences between these cell types have been well described, the developmental relationship between FLCs and ALCs has not been fully understood. In this review, I focus on the cellular origins of FLCs and ALCs as well as the developmental and functional links between them.MethodsI surveyed previous reports about FLC and/or ALC development and summarized the findings.Main findingsFetal Leydig cells and ALCs were identified to have separate origins in the fetal and neonatal testis, respectively. However, several studies suggested that FLCs and ALCs share a common progenitor pool. Moreover, perturbation of FLC development at the fetal stage induces ALC dysfunction in adults, suggesting a functional link between FLCs and ALCs. Although the lineage relationship between FLCs and ALCs remains controversial, a recent study suggested that some FLCs dedifferentiate at the fetal stage, and that these cells serve as ALC stem cells.ConclusionFindings obtained from animal studies might provide clues to the causative mechanisms of male reproductive dysfunctions such as testicular dysgenesis syndrome in humans.

PH and male fertility: making sense on pH homeodynamics throughout the male reproductive tract.

In the male reproductive tract, ionic equilibrium is essential to maintain normal spermatozoa production and, hence, the reproductive potential. Among the several ions, HCO3- and H+ have a central role, mainly due to their role on pH homeostasis. In the male reproductive tract, the major players in pH regulation and homeodynamics are carbonic anhydrases (CAs), HCO3- membrane transporters (solute carrier 4-SLC4 and solute carrier 26-SLC26 family transporters), Na+-H+ exchangers (NHEs), monocarboxylate transporters (MCTs) and voltage-gated proton channels (Hv1). CAs and these membrane transporters are widely distributed throughout the male reproductive tract, where they play essential roles in the ionic balance of tubular fluids. CAs are the enzymes responsible for the production of HCO3- which is then transported by membrane transporters to ensure the maturation, storage, and capacitation of the spermatozoa. The transport of H+ is carried out by NHEs, Hv1, and MCTs and is essential for the electrochemical balance and for the maintenance of the pH within the physiological limits along the male reproductive tract. Alterations in HCO3- production and transport of ions have been associated with some male reproductive dysfunctions. Herein, we present an up-to-date review on the distribution and role of the main intervenient on pH homeodynamics in the fluids throughout the male reproductive tract. In addition, we discuss their relevance for the establishment of the male reproductive potential.

Baillonella toxisperma improves sexual performance and protects against stress-induced reproductive dysfunction in male Wistar rats

Baillonella toxisperma Pierre (Sapotaceae) is a medicinal plant widely used in Central Africa against several diseases including erectile dysfunction and male infertility. However, no study dealing with these male reproductive dysfunctions has been published until now. Accordingly, the present study was undertaken. It evaluated the capacity of an aqueous extract of stem bark of B. toxisperma (BT) at 75, 150 and 300 mg/kg/d to induce aphrodisiac effects and prevent the stress-induced reproductive dysfunction in males using normal non-experienced (an 8-day oral treatment) and stressed (a 6-h/day immobilization stress for 35 consecutive days)male Wistar rats. Both in normal and stressed animals, BT at the doses of 150 and 300 mg/kg decreased (p < 0.05) the mount and intromission latencies, and increased (p < 0.05) the number of total penile licking, mount and intromission as well as ejaculation frequencies. In stressed animals, a significant (p < 0.05) increase in sperm levels, sperm mobility as well as in the relative weight of androgen-dependent organs (testis, epididymis and seminal vesicles) was observed at the same doses compared with the stressed control. These results suggest that this aqueous extract of B. toxisperma might endow with aphrodisiac and androgenic properties in normal and stressed male Wistar rats.

Effect of Spirulina platensis suspension on quality and quantity of sperm and expression of caspase-3 of testis in diabetic wistar rats induced by streptozotocin

Diabetes is metabolic disorders caused by oxidative stress that has always been linked to male reproductive dysfunction. Spirulina platensis has been used for therapeutic supplements for diabetes and repairing reproduction organs based on its antioxidant effects. The aim of this study was to examine the effect of Spirulina platensis suspension (SP) on quality and quantity of sperm also the expression of caspase-3 on testis in male Wistar rats induced by streptozotocin (STZ). This study used 30 adult male Wistar rats that divided into 6 groups of K1 (normal), K2 (single injection of STZ 45 mg/kg BW), K3 (normal rats treated with SP 36/kg BW/day) and treatment group K4, K5 and K6 were diabetic rats given with SP 36 mg/kgBW, 72 mg/kgBW and 144 mg/kg BW. The treatment was given orally for 28 days. Blood glucose level levels were measured using the biochemical analyzer. Quality and quantity of sperm were analyzed using Neubauer slide under the microscope. Apoptosis of Leydig cells was detected by immunohistochemical staining using Caspase-3 polyclonal antibodies. The result showed that there were significant differences between groups (p < 0.05) in final blood glucose level, quality, and quantity of spermatozoa and expression of caspase-3. Our findings clearly highlight the role of Spirulina platensis as an antidiabetes and protective agent for reproducton organs of STZ-induced in diabetic male Wistar rats that improves quality and quantity of sperm cells and reproductive organs.

Endoscopy and Cannulation as Non-Invasive Tools to Identify Sex and Monitor Reproductive Development in Arapaima gigas

The lack of tools for sex identification and assessment of gonadal development are hindering our ability to study the reproductive dysfunction of Arapaima gigas in captivity. This study initially aimed to validate a non-surgical endoscopy procedure to identify sex in juveniles and assess stage of ovary development in female broodstock under field operational conditions. Cannulation, assisted through the description of the genital anatomy, made ovarian biopsy possible to describe oocyte development from primary growth to pre-ovulation, providing a first classification scheme for oogenesis in the species including description of the micropyle morphology using scanning electron microscopy. Cannulation was also successfully performed without endoscopic guidance, which allowed monitoring of ovarian development along the reproductive season together with profiling of plasma sex steroids (17β-estradiol [E2] and 11-ketotestosterone [11-KT] in females and males, respectively). The monitoring of our study population showed females paired with males in earthen ponds sexually matured and reached oocyte maturation during the spawning season. However, since no spawning was recorded, eggs had either been resorbed or released and not fertilized by the male. Plasma E2 levels remained high in females, as expected in an asynchronous species during the spawning season with multiple batches of oocytes being recruited. Plasma 11-KT showed a tendency to decrease, suggesting a male reproductive dysfunction or the end of the reproductive season with a lack of synchronization between sexes. In conclusion, endoscopy and cannulation are tools that can be promptly applied to aid sex identification, assessment of reproductive function, and overall broodstock management in wild and captive stocks. These tools will greatly help future studies looking at the effects of environmental, social, and hormonal cues on reproductive development with the aim of developing a spawning induction protocol for the species.

Protective Effect of Resveratrol on Benzo(a)Pyrene Induced Dysfunctions of Steroidogenesis and Steroidogenic Acute Regulatory Gene Expression in Leydig Cells.

Benzo(a)pyrene [B(a)P] is the toxic environmental Polycyclic Aromatic Hydrocarbon (PAH), that exerts male reproductive dysfunctions. In this study the molecular mechanism of B(a)P induced Leydig cell steroidogenic dysfunctions and its protective mechanism of action with a natural Aryl hydrocarbon receptor (AhR) antagonist and anti-oxidant, Resveratrol (Res) has been investigated. B(a)P exposure induced ROS mediated steroidogenic imbalance via activation of p38MAPK and repression of testosterone level as well as other steroidogenic enzymes like CYPIIA1, 3β-HSD, 17β-HSD expressions. B(a)P exposure decreased StAR protein expression along with increased DAX-1, a transcriptional repressor of StAR gene. Along with that B(a)P decreased the expression of SF-1 that acts as a transcriptional inducer of StAR gene expression. The study has established Resveratrol as a potential agent combating the deleterious effect of B(a)P on Leydig cell steroidogenesis. Resveratrol treatment resulted significant protection against B(a)P by scavenging ROS and modulating the transcriptional regulation of anti-oxidant enzymes. Furthermore, Resveratrol also prevented stress kinase like p38 MAPK activation and increased StAR protein expression through the reduction of DAX-1 expression. Moreover, the testosterone production was efficiently restored with Resveratrol treatment. ChIP assay also revealed that resveratrol improved SF-1expression which further increased the StAR gene expression. Resveratrol acted efficiently against B(a)P, through its anti-oxidative properties as well as inhibits p38MAPK and increased steroidogenesis and StAR expression through the modulation of SF-1 gene expression.

Cyanidin-3-O-glucoside protects against cadmium-induced dysfunction of sex hormone secretion via the regulation of hypothalamus-pituitary-gonadal axis in male pubertal mice

Cadmium (Cd) has been generally recognized as an endocrine-disrupting chemical for its toxic effects on the hypothalamus-pituitary-gonadal (HPG) axis accompanied by dysfunction in sex hormone secretion. Particularly, exposure to Cd during puberty versus post-puberty exhibits differing age-dependent effects that require further examination. This study sought to determine if cyanidin-3-O-glucoside (C3G), a typical anthocyanin with neuroprotective bioactivity, could protect against Cd-induced sex hormone-disorder in Pubertal male mice. C3G treatment reversed the disruption of hormone levels and increased Gnrh1 gene expression in the hypothalamus. In addition, the levels of gonadotropins, including luteinizing hormone (LH) and follicle stimulating hormone (FSH), were reversed by C3G. Interestingly, C3G improved the expression of LH and FSH receptor in the testis in mice exposed to Cd. Furthermore, C3G activated the signaling pathway related to the synthesis of testosterone processing. In conclusion, C3G protected against Cd-induced dysfunction of sex hormone secretion through the regulation of the HPG axis in male mice during puberty. The results of this study suggest that consumption of anthocyanins can be protective against metal-induced male reproductive dysfunction.

Sulforaphane ameliorates high-fat diet-induced spermatogenic deficiency in mice†.

Sulforaphane (SFN), a dietary isothiocyanate that is mainly found in cruciferous vegetables, possesses anti-oxidative and anticancer activity and modulates inflammation. However, little is known about the role of SFN in obesity-related male reproductive defects. The present study aimed to investigate the effects of SFN on high-fat diet (HFD)-induced male spermatogenic impairment and further clarify the possible underlying mechanisms. In this study, 8-week-old mice were randomly divided into four groups. Mice were fed a normal diet or an HFD with or without SFN supplementation. Sulforaphane was subcutaneously injected at a dose of 0.5 mg/kg 5 days/week for 4 weeks beginning 8 weeks after initiation of the HFD. The results demonstrated that SFN could protect against HFD-induced reproductive dysfunction in male mice. Moreover, SFN also improved reproductive ability, as demonstrated by an increased pregnancy rate and decreased embryo resorption rate in comparison to the corresponding HFD group. We also observed a decrease in apoptosis and an attenuation of endoplasmic reticulum (ER) stress after SFN treatment. In vitro studies of mouse and human sperm samples also revealed that SFN protects against the palmitic acid-induced reduction in sperm viability and motility by inhibiting ER stress in an AMP-activated protein kinase (AMPK)-dependent manner. AMPK-dependent ER stress attenuation by SFN was further confirmed using AMPK knockout mice. Taken together, these data show that SFN protects against HFD-induced male reproductive dysfunction by inhibiting ER stress and apoptosis. These findings may be helpful for identifying new therapeutic methods to treat male infertility.

Vitamin C mitigates heat damage by reducing oxidative stress, inducing HSP expression in TM4 Sertoli cells.

Heat stress is a major stressor that can lead to male reproductive dysfunction. Sertoli cells play a crucial role in spermatogenesis by providing germ cells with structural and nutritional support, and contributing to blood-testis barrier formation. Vitamin C (Vc) is an antioxidant capable of neutralizing reactive oxygen species and preventing lipid peroxidation widely used because it is inexpensive and highly accessible. In the present study, we investigated the protective effect of Vc on TM4 cells following heat stress. Pretreatment with Vc could effectively inhibit apoptosis (p < 0.01), lipid peroxidation, and lactate dehydrogenase (LDH) activity. However, a significant increase in the malondialdehyde (MDA) level and LDH activity (p < 0.01) was observed in TM4 cells without Vc-pretreatment, in conjunction with vacuole degeneration and karyopyknosis. In addition, both the messenger RNA and protein levels of CryAB, Hsp27, Hsp70, and Hsp110 substantially increased in the 3 and 12 hr recovery groups (p < 0.01). Vc also prevented microtubule aggregation following heat stress. These results suggest that pretreatment with Vc-protected TM4 cells against heat stress by reducing the level of oxidative stress and inducing heat shock protein expression.

Effects of perfluorooctanoic acid on stem Leydig cell functions in the rat

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic (PFOS) are two perfluorinated chemical products widely existing in the environment. Evidence suggested that PFOA might relate to male reproductive dysfunction in rats and humans. PFOA exposure inhibited the function of Leydig cells. However, it is still unknown whether PFOA affects stem Leydig cells (SLCs). In the present study, we examined the effects of a short-term exposure to PFOA on Leydig cell regeneration and also explored the possible mechanism involved. Thirty-six adult Sprague-Dawley rats were randomly divided into three groups and intraperitoneally injected with a single dose of 75 mg/kg ethane dimethyl sulfonate (EDS) to eliminate all Leydig cells. From post-EDS day 7, the 3 group rats received 0, 25 or 50 mg/kg/day PFOA (n = 12 per group) for 9 consecutive days. Exposure to PFOA significantly decreased serum testosterone levels by day 21 and day 56 post-EDS treatment. Also, the expression levels of Leydig cell specific genes (Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Hsd11b1 and Cyp17a1) and their protein levels were all down-regulated. PFOA exposure may also affect proliferation of SLCs or their progeny since the numbers of PCNA-positive Leydig cells were reduced by post-EDS day 21. These in vivo observations were also confirmed by in vitro studies where the effects of PFOA were tested by culture of seminiferous tubules. In summary, PFOA exposure inhibits the development of Leydig cells, possibly by affecting both the proliferation and differentiation of SLCs or their progeny.

Neonatal Estrogen Causes Irreversible Male Infertility via Specific Suppressive Action on Hypothalamic Kiss1 Neurons.

Aberrant exposure to estrogen-like compounds during the critical developmental period may cause improper hypothalamic programming, thus resulting in reproductive dysfunction in adulthood in male mammals. Kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the arcuate nucleus (ARC) have been suggested to govern tonic GnRH/gonadotropin release to control reproduction in male mammals. In this study, we report that chronic exposure to supraphysiological levels of estrogen during the neonatal period caused an irreversible suppression of KNDy genes in the ARC, resulting in reproductive dysfunction in male rats. Daily estradiol benzoate (EB) administration from days 0 to 10 postpartum caused smaller seminiferous tubules, abnormal spermatogenesis, and a decrease in plasma testosterone in adult male rats. The neonatal EB treatment profoundly suppressed LH pulse and ARC KNDy gene expression at adulthood, but it failed to affect the number of GnRH gene-expressing cells in male rats. The EB treatment failed to affect gene expression of other neuropeptides, such as GHRH, proopiomelanocortin, and agouti-related protein in the ARC, suggesting that ARC KNDy neurons would be a specific target of neonatal estrogen to cause male reproductive dysfunction. Because LH secretory responses to kisspeptin challenge and GnRH expression were spared in male rats with the EB treatment, LH pulse suppression is most probably due to ARC KNDy deficiency. Taken together, the current study indicates that chronic exposure to estrogenic chemicals in the developing brain causes a defect of ARC KNDy neurons, resulting in an inhibition of pulsatile GnRH/LH release and the failure of spermatogenesis and steroidogenesis.

Nonalcoholic Fatty Liver Disease, Male Sexual Dysfunction, and Infertility: Common Links, Common Problems.

Nonalcoholic fatty liver disease (NAFLD) is considered a hallmark of metabolic syndrome (MetS) and a significant contributor to cardiovascular disease (CVD). With the alarming rates of obesity in the United States and worldwide, efforts at understanding, preventing, and treating MetS and its components are being increasingly undertaken by scientists and clinicians. A strong association between MetS and male sexual problems is already well established. More recent animal and human studies have further evaluated the relationship of NAFLD with male sexual problems and infertility. The molecular and physiological mechanisms correlating these conditions are incompletely established at this time, however. To review and analyze current literature associating NAFLD with andrologic disorders, including erectile dysfunction (ED), infertility, and hypogonadism. The PubMed database was searched using terms "erectile dysfunction," "hypogonadism," "male infertility," and "nonalcoholic fatty liver disease" for articles published between January 1980 and June2018. We present a summary of the recent clinical and experimental evidence and discuss the possible pathophysiological mechanisms relating NAFLD development and progression to ED, a hypogonadal state, and infertility. A total of 132 articles were reviewed. These included human observational and clinical studies and animal and basic science research relating NAFLD to the development and progression of ED, hypogonadism, and infertility in men. There is growing evidence linking NAFLD to male sexual and reproductive dysfunction. A complex interplay of pathophysiological processes underlying these entities and further relating them to the MetS components may ultimately aid the identification and development of novel diagnostic and therapeutic approaches. Hawksworth DJ, Burnett AL. Nonalcoholic Fatty Liver Disease, Male Sexual Dysfunction, and Infertility: Common Links, Common Problems Sex Med Rev 2020;8:274-285.

Attenuation of reproductive dysfunction in diabetic male rats with timber cultured Antrodia cinnamomea ethanol extract.

Diabetes mellitus together with the oxidative stress affects the process of spermatogenesis and leads to male infertility. Antrodia cinnamomea (AC) is a mushroom found unique in Taiwan and commonly used for the treatment of several types of cancers and inflammatory disorders. This study was aimed to investigate the anti-oxidative and the ameliorative effects of Antrodia cinnamomea ethanol extract (ACEE) on reproduction dysfunction in male diabetic rats. The diabetic condition was induced by administrating the combination of streptozotocin (STZ) (65 mg/kg) and nicotinamide (NA) (230 mg/kg). Three different doses of ACEE were tested (385, 770, 1540 mg/kg) for 5 weeks. The results indicated that the ACEE improved STZ-NA induced hyperglycemia, oxidative stress, and insulin resistance. In addition to this, ACEE reduced the degree of lipid peroxidation, recovered the abnormal structure of the seminiferous tubules, and improved sperm parameters. Moreover, the DNA damages and mitochondrial membrane potential were improved in sperm. Our study confirmed that the ACEE has anti-inflammatory and ameliorative effects to prevent diabetes-induced male reproductive dysfunction.

Differentiation of Human Adipose Derived Stem Cells into Leydig-Like Cells with Molecular Compounds

Background: Leydig cells (LCs) are the primary source of testosterone in the testis, and testosterone deficiency caused by LC functional degeneration can lead to male reproductive dysfunction. LC replacement transplantation is a very promising approach for this disease therapy. Methods: Here, we report that human adipose derived stem cells (ADSCs) can be differentiated into Leydig-like cells using a novel differentiation method based on molecular compounds. Findings: The isolated human ADSCs expressed positive CD29, CD44, CD59, CD105, negative CD34, CD45, HLA-DR by flow cytometryn, and had adipogenic and osteogenic differentiation capacity. The ADSCs derived Leydig-like cells (ADSC-LCs) acquired testosterone synthesis capabilities, and positively expressed Leydig cell lineage specific markers LHCGR, STAR, SCARB1, SF-1, CYP11A1, HSD3B1, CYP17A1, and HSD17B3 as well as negatively expressed ADSC specific markers CD29, CD44, CD59, and CD105. When ADSC-LCs labeled with lipophilic red dye (PKH26) were injected into rat testes which were selectively eliminated endogenous LCs using ethylene dimethanesulfonate (EDS, 75 mg/kg), the transplanted ADSC-LCs could survive and function in the interstitium of testes, and accelerate the recovery of blood testosterone levels and testis weights. Interpretation: These findings demonstrated that the ADSCs were able to be differentiated into Leydig-like cells by few defined molecular compounds, which may lay the foundation for further clinical application of ADSC-LC transplantation therapy. Funding Statement: This work was supported by the National Nature Science Foundation of China (81701426, 81771636, and 81771555), the Medical and Health Research Science and Technology Plan Project of Zhejiang Province (2018KY523 and 2017KY473), and the Public Welfare Science and Technology Plan Project of Wenzhou City (Y20180097, Y20160069, and ZS2017012). Declaration of Interests: There is no conflict of interest. Ethics Approval Statement: Informed consent was acquired from each donor, and this research was approved by Human Research and Ethical Committee of Wenzhou Medical University.

Serum Bisphenol A concentrations in men with idiopathic infertility

BackgroundBisphenol A (BPA) has been associated with male reproductive dysfunction. However, few studies have assessed BPA according to the cause of male infertility. AimTo investigate serum BPA concentrations in infertile men according to infertility cause. Patients and methodsMen with infertility (n = 55) [non-obstructive azoospermia (n = 23), cryptorchidism (n = 12), varicocele (n = 20)] compared with fertile men (n = 25). Serum BPA concentrations were measured along with clinical and hormonal assessment. ResultsBPA was detected in all men, with no difference between infertile and control groups [median (IQR) 0.19 (0.45) vs. 0.18 (0.28) ng/ml, p = 0.689] or among the infertility cause [azoospermia 0.30 (0.69), cryptorchidism 0.12 (0.39), varicocele 0.17 (0.23) ng/ml, p = 0.316]. High concentrations of BPA (>3 ng/ml) were observed only in infertile men. Α negative correlation was observed between ΒΡΑ concentrations and AMH (r = −0.320, p < 0.01). ConclusionsAlthough male infertility cannot be attributed to exposure to BPA, high concentrations of BPA could contribute to infertility.

Dietary protocatechuic acid abrogates male reproductive dysfunction in streptozotocin-induced diabetic rats via suppression of oxidative damage, inflammation and caspase-3 activity

Clinical and experimental studies demonstrated that reproductive dysfunction is a non-lethal complication of diabetes. Protocatechuic acid (PCA) reportedly elicited several pharmacological effects in diabetic animals. However, there is paucity of information on the role of PCA in reproductive dysfunction associated with diabetes. The present study investigated the influence of PCA on the functional changes along the hypothalamic-pituitary-testicular axis in male diabetic rats. Streptozotocin (STZ)-induced diabetic rats were orally treated with PCA at 25 and 50 mg/kg body weight for 45 consecutive days. Results showed that PCA treatment significantly dwindled blood glucose level as well as prevented diabetes mediated decrease in body weight gain and organo-somatic indices of the testes and epididymis in the treated rats. Moreover, PCA increased the reproductive hormone levels, marker enzymes of testicular function and sperm functional characteristics in the treated rats. Further, PCA augmented the antioxidant status, inhibited lipid peroxidation and suppressed pro-inflammatory biomarkers including myeloperoxidase (MPO) activity, nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) levels as well as caspase-3 activity inhypothalamus, testes and epididymis of diabetic rats. Collectively, PCA effectively abrogated reproductive deficits in diabetic rats via mechanisms involving suppression of oxidative stress, inflammation and caspase-3 activity along with enhancement of sperm functional parameters. Thus, PCA may preserve reproductive health in humans suffering from diabetes.