Search Results (80)

Triptolide (TP) is a diterpenoid compound extracted from the traditional Chinese medicinal herb Tripterygium wilfordii. It has antitumor and anti-inflammatory effects and stimulates immunity. However, its serious side effects, especially reproductive toxicity, limit its clinical application. This study employed a testicular injury model established by intraperitoneally injecting TP (0.2 mg/kg) in C57BL/6J male mice (age = 7–8 weeks) for 14 days. The control and TP mice’s testicular tissues were subjected to transcriptome sequencing to assess potential testicular damage mechanisms. Based on the transcriptome sequencing results and relevant literature reports, further experiments were performed. In addition, to alleviate triptolide-induced testicular damage, we treated the mice with N-acetyl-L-cysteine (NAC). The acquired data revealed that compared with the control mice, the TP-treated mice’s testes indicated severe damage. Transcriptome sequencing identified differentially expressed genes that showed enrichment in cell differentiation, apoptotic process, cell cycle, glutathione (GSH) metabolism, and the p53 signaling pathway. Furthermore, TUNEL assays and Western blot analysis showed that in the TP mice’s testicular tissues, the spermatocytes had mitochondrial pathway apoptosis as well as abnormal mitochondrial morphology and structure. Triptolide induces oxidative stress in testicular tissue by enhancing pro-oxidative systems and inhibiting antioxidant systems. NAC reduced testicular damage and apoptosis by alleviating TP-induced oxidative stress. This study also employed a GC2 cell line for in-vitro analyses, and the results were consistent with the in vivo experiments. This study provides evidence for alleviating TP’s adverse effects on the male reproductive system for better clinical application. Full article

Cisplatin (CIS) is a widely used chemotherapeutic agent, but its side effects, such as oxidative stress, inflammation, and apoptosis, often lead to male reproductive damage. Oxidative stress, primarily caused by the excessive generation of reactive oxygen species (ROS), plays a critical role in disrupting testicular homeostasis, resulting in spermatogenic impairment and tissue injury. L-cysteine (CYS), a semi-essential amino acid with potent antioxidant and anti-inflammatory properties, may offer protection against CIS-induced oxidative damage. This study aimed to assess the protective potential of CYS against CIS-induced male reproductive toxicity using in vivo and in vitro models. In vitro, treatment of TM3 (Leydig) and TM4 (Sertoli) cells with CIS led to increased ROS levels, reduced cell viability, and elevated apoptosis and inflammation, all of which were significantly ameliorated by subsequent CYS exposure. In vivo, CIS-treated male rats displayed heightened oxidative stress, impaired spermatogenesis, and histopathological damage in reproductive organs. However, CYS administration for 21 days significantly reduced oxidative stress, improved sperm viability, and protected testicular tissues from damage. These findings suggest that CYS has a protective effect against CIS-induced oxidative stress and male reproductive damage, making it a promising therapeutic agent for mitigating CIS-induced reproductive toxicity. Full article

PTD-FNK, a synthetic anti-apoptotic protein, has been shown to potently alleviate cellular injuries. However, the effects of PTD-FNK on oxidative defense in boar testicular Sertoli cells (SCs) against oxidative injury has not been explored. In this study, we show that exposure of SCs to 100 mg/L lipopolysaccharide (LPS) for 12 h leads to decreased survival rate, superoxide dismutase (SOD) activity, and increased malondialdehyde (MDA). Treatment with 0.01 nmol/L PTD-FNK for 4 h significantly enhanced the activity of SOD, catalase (CAT), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) in SCs. Concurrently, PTD-FNK treatment effectively reduced the production of reactive oxygen species (ROS) and the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in SCs. Moreover, using His pull-down and LC-MS techniques, we identified PTD-FNK-interacting proteins and confirmed that this protective effect may be mediated by the regulation of the Keap1-Nrf2 signaling pathway by PTD-FNK. Therefore, PTD-FNK alleviates LPS-induced oxidative stress via the Keap1/Nrf2 pathway, providing novel insights for the development of therapeutic agents targeting testicular oxidative damage. Full article

The impact of ionizing radiation on the male reproductive system is gaining increasing attention, particularly when it comes to testicular damage, which may result in decreased sperm quality and hormonal imbalances. Finding effective protective measures to mitigate testicular damage caused by radiation has become a focal point in the biomedical field. S1P, an essential biological signaling molecule, has garnered significant interest due to its multiple roles in regulating cellular functions and its protective effects against radiation-induced testicular injury. S1P not only effectively reduces the generation of ROS induced by radiation but also alleviates oxidative stress by enhancing the activity of antioxidant enzymes. Furthermore, S1P inhibits radiation-induced cell apoptosis by regulating the expression of anti-apoptotic and pro-apoptotic proteins. Additionally, S1P alleviates radiation-induced inflammation by inhibiting the production of inflammatory factors, thereby further protecting testicular tissue. In summary, S1P effectively reduces radiation-induced testicular damage through multiple mechanisms, offering a promising therapeutic approach to safeguard male reproductive health. Future research should explore the specific mechanisms of action and clinical application potential of S1P, aiming to contribute significantly to the prevention and treatment of radiation damage. Full article

Polyethylene terephthalate (PET) is a type of polymer plastic that is often used to make plastic bags, bottles, and clothes. However, the waste of such plastic products is decomposed into microplastics (MPs), which are plastic fragments smaller than 5 mm, by various external forces such as wind, UV radiation, mechanical wear, and biodegradation. PET MPs have been widely detected in the environment and human tissue samples; however, the toxicity and mechanism of PET MPs in mammals are still unclear. In this study, we investigated the male reproductive toxicity of PET MPs and their underlying mechanism. A total of 80 male mice were orally exposed to 0.01, 0.1, and 1 mg/d of PET MPs (with a diameter of 1 μm) for 42 days. The results showed that 1 μm PET MPs induced different degrees of pathological damage to testicular tissues, decreased sperm quality, and increased the apoptosis of spermatogenic cells via oxidative stress and p38 signaling pathway activation. To further illustrate and verify the mechanistic pathway, oxidative stress was antagonized using N-acetylcysteine (NAC), and the activation of the p38 signaling pathway was blocked using SB203580. The results revealed that the male reproductive injury effects after exposure to PET MPs were significantly ameliorated. Specifically, the testicular tissue lesions were relieved, the sperm quality improved, and the apoptosis of spermatogenic cells decreased. These results demonstrated that PET MP exposure induced male reproductive toxicity through oxidative stress and the p38 signaling pathway. This study provides new insights into the reproductive toxicity of MPs in males, as well as valuable references for public health protection strategies. Full article

Oxidative stress triggered by testicular torsion and detorsion in young males could negatively impact future fertility. Using a rat animal model for testicular IRI (tIRI), we aim to study the induction of autophagy (ATG) during testicular ischemia and tIRI and the role of oxidative-stress-induced c-Jun N-terminal Kinase (JNK) as a cytoprotective mechanism. Sixty male Sprague-Dawley rats were divided into five groups: sham, ischemia only, ischemia+SP600125 (a JNK inhibitor), tIRI only, and tIRI+SP600125. The tIRI rats underwent an ischemic injury for 1 h followed by 4 h of reperfusion, while ischemic rats were subjected to 1 h of ischemia only without reperfusion. Testicular-ischemia-induced Beclin 1 and LC3B expression was associated with decreased p62/SQSTM1 expression, increased ATP and alkaline phosphatase (AP) activity, and slightly impaired spermatogenesis. SP600125 treatment improved p62 expression and reduced the levels of Beclin 1 and LC3B but did not affect ATP or AP levels. The tIRI-induced apoptosis lowered the expression of the three ATG proteins and AP activity, activated caspase 3, and caused spermatogenic arrest. SP600125-inhibited JNK during tIRI restored sham levels to all investigated parameters. This study emphasizes the regulatory role of JNK in balancing autophagy and apoptosis during testicular oxidative injuries. Full article

Blood–testis barrier (BTB) genes are crucial for the cellular mechanisms of spermatogenesis as they protect against detrimental cytotoxic agents, chemicals, and pathogens, thereby maintaining a sterile environment necessary for sperm development. BTB proteins predominantly consist of extensive tight and gap junctions formed between Sertoli cells. These junctions form a crucial immunological barrier restricting the intercellular movement of substances and molecules within the adluminal compartment. Epithelial tight junctions are complex membrane structures composed of various integral membrane proteins, including claudins, zonula occludens-1, and occludin. Inter-testicular cell junction proteins undergo a constant process of degradation and renewal. In addition, the downregulation of genes crucial to the development and preservation of cell junctions could disrupt the functionality of the BTB, potentially leading to male infertility. Oxidative stress and inflammation may contribute to disrupted spermatogenesis, resulting in male infertility. L-cysteine is a precursor to glutathione, a crucial antioxidant that helps mitigate damage and inflammation resulting from oxidative stress. Preclinical research indicates that L-cysteine may offer protective benefits against testicular injury and promote the expression of BTB genes. This review emphasizes various BTB genes essential for preserving its structural integrity and facilitating spermatogenesis and male fertility. Furthermore, it consolidates various research findings suggesting that L-cysteine may promote the expression of BTB-associated genes, thereby aiding in the maintenance of testicular functions. Full article

Male fertility is strongly affected by the overexpression of free radicals induced by heavy metals. The aim of this study was to evaluate the potential antioxidant, anti-inflammatory, and gonado-protective effects of natural compounds. Biochemical and morphological assays were performed on male albino rats divided into five groups: a control group (water only), a group orally exposed to a metal mixture of Pb-Cd-Hg-As alone and three groups co-administered the metal mixture and an aqueous extract of the Nigerian medicinal plant, Anonychium africanum (Prosopis africana, PA), at three different concentrations (500, 1000, and 1500 mg/kg) for 60 days. The metal mixture induced a significant rise in testicular weight, metal bioaccumulation, oxidative stress, and pro-inflammatory and apoptotic markers, while the semen analysis indicated a lower viability and a decrease in normal sperm count, and plasma reproductive hormones showed a significant variation. Parallel phytochemical investigations showed that PA has bioactive compounds like phlobatannins, flavonoids, polyphenols, tannins, saponins, steroids, and alkaloids, which are protective against oxidative injury in neural tissues. Indeed, the presence of PA co-administered with the metal mixture mitigated the toxic metals’ impact, which was determined by observing the oxido-inflammatory response via nuclear factor erythroid 2-related factor 2, thus boosting male reproductive health. Full article

Diabetes mellitus (DM) induces the production of reactive oxygen species, which may lead to cell injury and death. This study aimed to assess the effects of rosmarinic acid (RA) on testicular damage, oxidative stress, and apoptosis in streptozotocin (STZ)-induced diabetic albino mice. DM in four- to six-week-old BALB/c male albino mice was induced via 50 mg/kg STZ, IP for 5 days. Twelve mice were randomly assigned into each of following groups: a control group, a diabetic (DM) group, RA5 mg/kg and RA15 mg/kg groups, and DM + RA5 mg/kg and DM + RA15 mg/kg groups. RA doses were intraperitoneally injected six times a week for seven weeks. Diabetes increased blood sugar and HbA1c levels and decreased all assessed sperm parameters. Testicular tissues of the diabetic mice showed increased lipid peroxidation, decreased reduced glutathione levels and catalase and superoxide dismutase activities, and increased apoptosis associated with histological abnormalities. Both RA doses had no effects on final body weight, blood sugar, and HbA1c in the diabetic mice. It is concluded that the administration of the potent antioxidant RA to diabetic mice improved the redox status in testicular tissues, protected them from diabetes-induced oxidative damage, and improved the quality of spermatozoa, mostly in a dose-dependent manner, which suggests a potential application value of RA in treating DM-related testicular injury and perhaps other complications. Full article

Ruminants exhibit stronger tolerance to gossypol, an anti-nutritional factor, compared to monogastric animals. We transplanted Hu sheep rumen microbiota into male mice to investigate the role of rumen microbiota in animal gossypol tolerance. Thirty specific-pathogen-free (SPF) male C57BL/6 mice were randomly divided into three groups: normal diet (CK group), gossypol diet (FG group), and rumen microbiota transplantation (FMT group, gossypol diet). The pathological changes in the liver and small intestine of the mice, the organ coefficient, and sperm parameters were analyzed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the blood and lactate dihydrogen-X (LDH-X) levels in the testicular tissue were also measured. The results showed that body weight, feed intake, sperm concentration, sperm motility, and LDH-X levels in the FMT group increased (p < 0.05) compared with the FG group, while the enzyme activities of ALT, AST, and AST/ALT decreased (p < 0.05). In the FMT group, the injury to liver cells was alleviated, the structure of the small intestine was intact, and the villus height and the ratio of villus height to crypt depth (V/C) were higher than those in the FG group (p < 0.05). And there were no differences in various organ coefficients and sperm deformity rates among the three groups (p > 0.05), but compared with the FG group, mice in the FMT group showed tendencies closer to those in the CK group. Rumen microbiota transplantation relieved the reproductive toxicity and liver damage induced by gossypol in male mice and improved the tolerance of recipient animals to gossypol. Additionally, rumen microbes improved the intestinal structural integrity of recipients. Full article

Chemotherapy is an important factor leading to male infertility. It is crucial to discover safe and effective treatments to prevent male reproductive injury caused by chemotherapy. The Ganoderma lucidum polysaccharide peptide (GLPP) has multiple pharmacological activities. The purpose of this study was to determine whether GLPP could protect the male sperm production from chemotherapeutic injury using a mouse model, with testicular damage induced by cyclophosphamide (CP). CP (50 mg/kg/day) was injected intraperitoneally into male ICR mice gavaged with different doses of GLPP at certain spermatogenic stages. The experimental results showed that GLPP alleviated the CP-induced reduction in reproductive organ coefficients and sperm parameters and reduced the morphological damage of testicular tissues in a dose-dependent manner. GLPP significantly improved the reproductive index, sperm-related parameters, sex hormone levels, and histological testis architecture at different spermatogenic stages. Furthermore, GLPP significantly increased superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), Nrf2, and HO-1, and decreased malondialdehyde (MDA) and Keap-1 in the testicular tissue, indicating reduced oxidative stress. In addition, GLPP limited CP-induced apoptosis via a reduction in Bax expression and increase in Bcl-2 expression. This study suggests that GLPP plays a protective role in spermatogenesis by reducing chemotherapeutic injury and might be developed into drug for male patients receiving chemotherapy. Full article

The reproductive system of males is adversely impacted by lead (Pb), a toxic heavy metal. The present study examined arbutin, a promising hydroquinone glycoside, for its potential ameliorative impact against Pb-induced testicular impairment in rats. The testicular injury was induced by the intraperitoneal administration of Pb acetate (20 mg/kg/day) for 10 consecutive days. Thirty-six rats were divided into six experimental groups (n = 6 per group): control, control treated with oral arbutin (250 mg/kg), control treated with intraperitoneal arbutin (75 mg/kg), untreated Pb, Pb treated with oral arbutin, and Pb treated with intraperitoneal arbutin. The treatments were administered daily for 10 days. Arbutin was administered by the oral and intraperitoneal routes to compare the efficacy of both routes in mitigating Pb acetate-induced testicular dysfunction. The current data revealed that both oral and intraperitoneal administration of arbutin significantly enhanced serum testosterone and sperm count/motility, indicating the amelioration of testicular dysfunction. In tandem, both routes lowered testicular histopathological aberrations and Johnsen’s damage scores. These favorable outcomes were driven by dampening testicular oxidative stress, evidenced by lowered lipid peroxidation and increased glutathione and catalase antioxidants. Moreover, arbutin lowered testicular p-JAK2 and p-STAT3 levels, confirming the inhibition of the JAK2/STAT3 pro-inflammatory pathway. In tandem, arbutin suppressed the testicular NLRP3/caspase-1/NF-B axis and augmented the cytoprotective PK2/PKR2 pathway. Notably, intraperitoneal arbutin at a lower dose prompted a more pronounced mitigation of Pb-induced testicular dysfunction compared to oral administration. In conclusion, arbutin ameliorates Pb-evoked testicular damage by stimulating testicular antioxidants and the PK2/PKR2 pathway and inhibiting the JAK2/STAT3 and NLRP3/caspase-1 pro-inflammatory pathways. Hence, arbutin may be used as an adjunct agent for mitigating Pb-induced testicular impairment. Full article

Busulfan, an indispensable medicine in cancer treatment, can cause serious reproductive system damage to males as a side effect of its otherwise excellent therapeutic results. Its widespread use has also caused its accumulation in the environment and subsequent ecotoxicology effects. As a Chinese medicine, Wulingzhi (WLZ) has the effects of promoting blood circulation and improving female reproductive function. However, the potential effects of WLZ in male reproduction and in counteracting busulfan-induced testis damage, as well as its probable mechanisms, are still ambiguous. In this study, busulfan was introduced in a mouse model to evaluate its production of the testicular damage. The components of different WLZ extracts were compared using an untargeted metabolome to select extracts with greater efficacy, which were further confirmed in vivo. Here, we demonstrate abnormal spermatogenesis and low sperm quality in busulfan-injured testes. The WLZ extracts showed a strong potential to rehabilitate the male reproductive system; this effect was more prominent in room-temperature extracts. Additionally, both water and ethanol WLZ extracts at room temperature alleviated various busulfan-induced adverse effects. In particular, WLZ recovered spermatogenesis, re-activated arginine biosynthesis, and alleviated the increased oxidative stress and inflammation in the testis, ultimately reversing the busulfan-induced testicular injury. Collectively, these results suggest a promising approach to protecting the male reproductive system from busulfan-induced adverse side effects, as well as those of other similar anti-cancer drugs. Full article

Lead (Pb) is a common pollutant that is not biodegradable and gravely endangers the environment and human health. Annona squamosa fruit has a wide range of medicinal uses owing to its phytochemical constituents. This study evaluated the effect of treatment with A. squamosa fruit extract (ASFE) on testicular toxicity induced in male rats by lead acetate. The metal-chelating capacity and phytochemical composition of ASFE were determined. The LD₅₀ of ASFE was evaluated by probit analysis. Molecular docking simulations were performed using Auto Dock Vina. Forty male Sprague Dawley rats were equally divided into the following groups: Gp1, a negative control group; Gp2, given ASFE (350 mg/kg body weight (b. wt.)) (1/10 of LD₅₀); Gp3, given lead acetate (PbAc) solution (100 mg/kg b. wt.); and Gp4, given PbAc as in Gp3 and ASFE as in Gp2. All treatments were given by oro-gastric intubation daily for 30 days. Body weight changes, spermatological parameters, reproductive hormone levels, oxidative stress parameters, and inflammatory biomarkers were evaluated, and molecular and histopathological investigations were performed. The results showed that ASFE had promising metal-chelating activity and phytochemical composition. The LD₅₀ of ASFE was 3500 mg/kg b. wt. The docking analysis showed that quercetin demonstrated a high binding affinity for JAK-1 and STAT-3 proteins, and this could make it a more promising candidate for targeting the JAK-1/STAT-3 pathway than others. The rats given lead acetate had defective testicular tissues, with altered molecular, biochemical, and histological features, as well as impaired spermatological characteristics. Treatment with ASFE led to a significant mitigation of these dysfunctions and modulated the JAK-1/STAT-3/SOCS-1 axis in the rats. Full article

Tert-butylhydroquinone (tBHQ) has emerged as a promising candidate for mitigating the adverse effects of T-2-induced reproductive toxicity. The protective effects of tBHQ on rat sperm quality, testicular injury, apoptosis, and inflammation induced by T-2 toxin exposure were investigated. Histopathological examination of testicular tissues revealed severe damage in the T-2-treated group, characterized by disorganized germ cell arrangement, thinning of the convoluted seminiferous tubule walls, and significant cellular necrosis. However, tBHQ administration, either as a preventive or therapeutic measure, mitigated this structural damage. Image analysis confirmed an increase in the cross-sectional area and height of the convoluted seminiferous tubules in the tBHQ-treated groups compared to the T-2-treated group (p < 0.05), indicating tBHQ’s efficacy in alleviating testicular damage. Additionally, tBHQ treatment significantly inhibited T-2-induced apoptosis of testicular tissue cells, as evidenced by the results showing reduced apoptotic cell counts and downregulation of the BAX/BCL2 ratio and caspase-3 expression (p < 0.05). tBHQ significantly increased the concentrations of the antioxidant factors SOD, CAT, TAC, and GSH-PX. Furthermore, tBHQ attenuated the inflammatory response induced by T-2 exposure, as indicated by the decreased mRNA expression of the proinflammatory cytokines Tnf, Il1, and Il10 in testicular tissue (p < 0.05). Additionally, tBHQ treatment alleviated the decline in serum testosterone induced by the T-2 and promoted testosterone synthesis gene expression, including for the genes 17β-HSD and Cyp11a1, in rat testes (p < 0.05). These findings underscore tBHQ’s role as a therapeutic agent combatting T-2-induced reproductive toxicity, highlighting its antioxidative, anti-apoptotic, and anti-inflammatory properties. Further elucidation of tBHQ’s mechanisms of action may offer novel strategies for preventing and treating reproductive disorders induced by environmental toxins. Full article