Inflammation In Testis Research Articles

Protective impact of Betanin against noise and scrotal hyperthermia on testicular toxicity in Wistar rat: Role of apoptosis, oxidative stress and inflammation

The heat exposure and white noise can induce damage on reproductive organs. The main objective of this study is to observe, if betanin administration could ameliorate oxidative stress, apoptosis and inflammation in testis of rodents following noise and scrotal hyperthermia exposure. Wistar rats were divided into 6 groups; control, betanin, noise, hyperthermia and two treatment groups. Scrotal hyperthermia model was performed by heat exposure of rat testicular (43 °C) for 15 min and 3 times per weeks for 14 days. Noise induction model was done following exposure of rats with 100-dB noise level for 14 days and 8 h daily similar to real exposure condition in human. Betanin was administrated at the sub-effective dose (15 mg/kg) by gavage route for 4 weeks (5 times a week) to male rats. The animals were euthanized and testis were dissected and stored at −80 °C. Then, the oxidative stress biomarkers (MDA and GSH), apoptosis (cytochrome c & Annexin V), and inflammatory cytokines (TNF-α & IL-6) were measured by the real time polymerase chain reaction (RT-PCR) of testis collected samples. The data output demonstrates the impact of noise and hyperthermia in testicular toxicity induction by mitigating oxidative damage, apoptosis and inflammatory mediators. Following treatment with 15 mg/kg per day of betanin, lipid peroxidation and GSH content have been modulated, and TNF-α and IL-6 gene expression has been declined. Our results revealed that in Wistar rats, betanin displays protective effects against noise and scrotal hyperthermia-induced acute testicular toxicity through the inhibition of oxidative stress, apoptosis, and inflammation.

Cadmium activates the innate immune system through the AIM2 inflammasome

Cadmium (Cd) is a widely used heavy metal and has recently been recognized as a possible source of human toxicity due to its ability to accumulate in organs. Accumulation of heavy metals has several adverse effects, including inducing inflammation, in multiple organs, such as the testis. However, how Cd ions are sensed by host cells and how tissue inflammation eventually occurs remains unclear. Here, we show that Cd activates the AIM2 inflammasome by mediating genomic DNA release into the cytoplasm after DNA damage via oxidative stress, to trigger IL-1β secretion and pyroptosis. Specifically, the toxicity effects induced by Cd in cells were prevented by melatonin, which served as an antagonist of oxidative stress. Accordingly, in a mouse model, Cd-induced inflammation in the testis and consequential male reproductive dysfunction were effectively reversed by melatonin. Thus, our results suggest a function of AIM2 in Cd-mediated testis inflammation and identify AIM2 as a major pattern recognition receptor in response to heavy metal Cd ions.

Exploration of Lactiplantibacillus plantarum P101 ameliorated the alcohol-induced testicular dysfunction based on metabolome analysis

The decline in male sperm quality caused by multiple factors has become a widespread concern. Alcohol excessive consumption is one of the factors that induce testicular dysfunction. Testicular dysfunction caused by alcohol abuse is related to oxidative stress and inflammation. Probiotics can ameliorate alcohol-induced testicular dysfunction. However, the specific mechanism is not explicit. This study aimed to elucidate the underlying mechanism by which Lactiplantibacillus plantarum P101 ameliorates the alcohol-induced testicular dysfunction. The model of alcohol-induced testicular dysfunction in C57B/6 male mice was established according to the National Institute on Alcohol Abuse and Alcoholism, and Lactiplantibacillus plantarum P101 supplementation was orally administered to mice during the experiment. The results showed that Lactiplantibacillus plantarum P101 promoted androgen production, reduced testis inflammation, and improved testis antioxidant capacity, thereby improving sperm quality and sperm motility and ultimately ameliorating alcohol-induced testicular disorder. Three key metabolite pathways and six key metabolites were identified by metabolome analysis.

Ferroptosis Is Crucial for Cisplatin Induced Sertoli Cell Injury via N6-Methyladenosine Dependent Manner.

This study aimed to investigate the effect of the N6-methyladenosine (m6A) dependent ferroptosis on cisplatininduced Sertoli cell injury. A cisplatin exposure mouse model was established by intraperitoneal injection of cisplatin in our study. TM4 cell lines was used for in vitro study. Ferroptosis was detected according to metabolomic analysis and a series of assays, including malondialdehyde, glutathione, and glutathione disulfide concentration detection, 2',7'-dichlorodihydrofluorescein diacetate and BODIPY 581/591 C11 probe detection, and transmission electron microscope imaging. Key ferroptosis-related genes were identified via transcriptomic analysis, western blot and immunohistochemistry. The m6A modification was demonstrated via m6A RNA immunoprecipitation and luciferase reporter assays. Immune cell infiltration was detected by mass cytometry, and verified by flow cytometry and immunofluorescence. Ferroptosis, but not other types of programmed cell death, is a significant phenomenon in cisplatin-induced testis damage and Sertoli cell loss. Ferroptosis induced by cisplatin in Sertoli cell/TM4 cell is GPX4 independent but is regulated by SLC7A11 and ALOX12. Both SLC7A11 and ALOX12 are regulated via m6A dependent manner by METTL3. Furthermore, overexpressed ALOX12-12HETE pathway may result in macrophage polarization and inflammatory response in cisplatin exposure testis. Cisplatin-induced Sertoli cell injury via ferroptosis and promoted ferroptosis in an m6A dependent manner. m6A modification of both SLC7A11 and ALOX12 mRNA could result in ferroptosis in our in vitro model. Further, overexpressed ALOX12 can cause more production of 12-HETE, which may be responsible for testis inflammation caused by cisplatin.

The male reproductive toxicity after nanoplastics and microplastics exposure: Sperm quality and changes of different cells in testis

Nanoplastics (NPs) and Microplastics (MPs) pollution has become a severe threat to the planet and is a growing concern. However, their effects on male reproductive toxicity remain poorly understood. In this study, a series of morphological analyses were completed to explore the influence of NPs and MPs exposure on the testis in mice. After 12-weeks exposure, although both NPs and MPs exposure can lead to reproductive toxicity, compared with NPs exposure, exposure to MPs leads to a more significant increase in reproductive toxicity dependent on some particle size. Moreover, increased reproductive toxicities, including increased spermatogenesis disorders, and sperm physiological abnormality, oxidative stress, testis inflammation was more associated with MPs group than NPs group. Ultra-pathological structure observed by transmission electron microscopy indicated that both NPs and MPs have different effects on spermatogonia, spermatocytes and Sertoli cells. Exposure to MPs resulted in decreased Sertoli cell numbers and reduced Leydig cell area, and showed no effects on differentiation of Leydig cells by the expression level of the Insulin-Like factor 3 (INSL3) in Leydig cells. Transcriptomic sequencing analysis provided valuable insights into the differential effects of NPs and MPs on cellular processes. Specifically, our findings demonstrated that NPs were predominantly involved in the regulation of steroid biosynthesis, whereas MPs primarily influenced amino acid metabolism. This study demonstrates the effect of adult-stage reproductive toxicity in mice after exposure to NPs and MPs, which will deep the understanding of the NPs and MPs induced toxicity.

Eif2s3y alleviated LPS-induced damage to mouse testis and maintained spermatogenesis by negatively regulating Adamts5

Eif2s3y (eukaryotic translation initiation factor 2, subunit 3, structural gene Y-linked, Eif2s3y) is an essential gene for spermatogenesis. Early studies have shown that Eif2s3y can promote the proliferation of spermatogonial stem cells (SSCs) and can replace the Y chromosome together with sex-determining region Y (Sry) to transform SSCs into round spermatozoa. We injected lentiviral particles into the seminiferous tubules of mouse testes by sterile surgery surgically to establish overexpressing Eif2s3y testes. And then the mice were intraperitoneally injected with LPS to established the model of testis inflammation. Through RNA sequencing, qRT–PCR analysis, Western blot, co-culture etc., we found that Eif2s3y alleviated LPS-induced damage in mouse testes and maintained spermatogenesis. In testes with Eif2s3y overexpression, the seminiferous tubules were more regularly organized after exposure to LPS compared with the control. Eif2s3y performs its function by negatively regulating Adamts5 (a disintegrin and metalloproteinase containing a thrombospondin-1 motif), an extracellular matrix-degrading enzyme. ADAMTS5 shows a disruptive effect when the testis is exposed to LPS. Overexpression of Eif2s3y inhibited the TLR4/NFκB signaling pathway in the testis in response to LPS. Generally, our research shows that Eif2s3y protects the testis from LPS and maintains spermatogenesis by negatively regulating Adamts5.

5-Aminolevulinic acid combined with ferrous iron ameliorates scrotal heat stress-induced spermatogenic damage by enhancing HO-1 expression

To explore whether 5-Aminolevulinic acid combined with ferrous iron(5-ALA/Fe2+) could protect testicular tissues damage of mice subjected to heat stress (HS) and provide its underlying mechanisms. 5-ALA/Fe2+ was administered intragastrically to mice for 10days, then exposed to a scrotal heat stress at 43°C for 20min on third day. Testes were harvested for morphologic and histopathological examination, oxidative stress, apoptosis, heme oxygenase-1 (HO-1) and inflammation detection. The mitogen-activated protein kinases (MAPK) signaling pathway in testis and CD4+FoxP3+regulatory T (Treg) cells in spleen were also investigated. Compared to control group, the testis weight decreased and histological damage severed in HS group. Besides, HS also increased the oxidative stress, apoptosis and inflammation in testis. However, these indicators were ameliorated after 5-ALA/Fe2+ treatment but deteriorated after receiving ZnPPIX. The expression of HO-1 was increased both in HS group and 5-ALA/Fe2+ group. The protein expression levels of MAPK proteins were activated by HS and inhibited by 5-ALA/Fe2+. The CD4+FoxP3+ Treg generation was reduced by HS and increased by 5-ALA/Fe2+. In this study, we have demonstrated that 5-ALA/Fe2+ ameliorated the spermatogenic damage induced by scrotal heat stress via up-regulating the expression of HO-1 and inhibiting MAPK mediated oxidative stress and apoptosis and inducing CD4+Foxp3+ Tregs to inhibit the inflammation induced by HS in mice.

Gouqizi () seed oil reduces D-galactose induced inflammation in testis of rats Janus kinase 1/signal transducerand activator of transcription 1/nuclear factor-κB and.

To investigate the efficacy of Gouqizi () seed oil (FLSO) on D-gal induced inflammation in testis of rats and . In aging Sertoli cells (TM4 cells) induced by D-galactose (D-gal), the expression of upregulated aging-related proteins. The number of cells counted by cell counting kit (CCK)-8 assay showed a high number of cells disposed with FLSO at 50, 100 and 150 μg/mL compared to that for the aging model. , male Sprague-Dawley rats ( = 50, 8-week-old, 230-255 g) were randomly categorized into control, aging model, and FLSO (low-, medium-, and high-dose) groups. The expression of nuclear factor-κB (NF-κB) and its upstream factors [Janus kinase 1 (JAK1) and signal transducerand activator of transcription 1 (STAT1)] was detected by Western blot and immunofluorescence, related inflammatory factors quantified by enzyme-linked immunosorbent assay. Evaluation of testicular tissue by Johnsen score, the spermatogenic function was explored. The expression of interleukin-1β (IL-1β) ( < 0.05), IL-6 ( < 0.001), and tumor necrosis factor α (TNF-α) ( < 0.05) was decreased significantly, while that of heme oxygenase-1 (HO-1) ( < 0.001) and IL-10 ( < 0.05) was increased in cells disposed with FLSO 100 μg/mL. FLSO inhibited the expression of NF-B and declined p-p65/p65 ( < 0.01), as detected by Western blotting. In, the levels in serum of IL-1β ( < 0.001), IL-6 ( < 0.05), and TNF-( < 0.01) declined while IL-10 ( < 0.05) was upregulated post-FLSO treatment. In addition, the expression of JAK-1 and STAT1 increased significantly in testicular tissue of rats treated with FLSO as compared to the aging model of rats ( < 0.001), while the expression of NF-κB ( < 0.001) declined in the testis in the FLSO group, as assessed by immunofluorescence. The levels of inhibor B and testosterone in serum both increased (< 0.05). In conclusion, this study determined the protective effects of FLSO to tolerate inflammatory injury in the testis, indicating that FLSO alleviates inflammation JAK-1/STAT1/NF-κB pathway.

MP01-14 THE LOSS OF HISTONE READER PHF7 LEADS TO IMMUNE PATHWAYS ACTIVATION VIA ENDOGENOUS RETROVIRUSES DURING SPERMIOGENESIS

You have accessJournal of UrologyCME1 Apr 2023MP01-14 THE LOSS OF HISTONE READER PHF7 LEADS TO IMMUNE PATHWAYS ACTIVATION VIA ENDOGENOUS RETROVIRUSES DURING SPERMIOGENESIS Jianxing Cheng, Haocheng Lin, and Hui Jiang Jianxing ChengJianxing Cheng More articles by this author , Haocheng LinHaocheng Lin More articles by this author , and Hui JiangHui Jiang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003212.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Genetic studies have elucidated critical roles of the Phf7 in germline development in animals, but whether PHF7 is an actual disease gene in human infertility remains unknown. To investigate the role of PHF7 on infertility in humans and explore its mechanism. METHODS: The blood and testicular samples from azoospermia patients were collected and used for genome sequencing western blot and immunohistology. The Phf7 knockout mice model were established and used for animal study. RT-PCR, Immunohistology, and western blotting were used for phenotypic identification. Transcriptome of testicular haploid cells of Phf7 knockout mice were analyzed, and the differentially expressed ERV was further used for coverage analysis; Quantitative PCR and Western blot were performed to verification. Mouse germ cell lines GC-1 and GC-2 with ERV target knockouts were constructed for experiment in vitro. The chromatin accessibility and epigenetic changes of mouse testicular cells after Phf7 deletion were analyzed by ATAC-seq and ChIP-seq data. Targeted drugs for PPARα to treat Phf7 knockout mice. RESULTS: We report a germline mutation of human PHF7 in azoospermic patients and our findings to demonstrate that PHF7 is a potential etiological factor in non-obstructive azoospermic patients. By modeling such mutations in Phf7 knockout mice, we show that the genetic defects are directly responsible for male infertility that prevent histone-to-protamine exchange as previously reported. More importantly, the deficiency of spermatogenesis caused by the deletion of Phf7 through ERV-mediated activation of the immune pathway is a common mechanism of infertility. Moreover, PPARα is an emerging target of immunity and inflammation in testis which ERV suppressed, we further demonstrate that Astaxanthin is a promising drug for treating male infertility. CONCLUSIONS: Our findings identify Phf7 as a target in human infertility and reveal its role as an epigenetic reader, while the loss of Phf7 lead to immune pathways activation which can be rescued by PPARα agonist Astaxanthin. Source of Funding: This work was supported by: Natural Science Foundation of Beijing (General #7212134), National Natural Science Foundations of China (#81601272) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e7 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jianxing Cheng More articles by this author Haocheng Lin More articles by this author Hui Jiang More articles by this author Expand All Advertisement PDF downloadLoading ...

Chlorogenic acid alleviated testicular inflammation and apoptosis in tunicamycin induced endoplasmic reticulum stress

Chlorogenic acid (CA) is a polyphenolic compound, found in many herbs and foods including coffee, berries and potatoes. Anti-inflammatory, anti-oxidant, anti-cancer and anti-apoptotic effects of CA have been proven in many tissues. Testicular inflammation and apoptosis are essential factors in male infertility that could result from endoplasmic reticulum (ER) stress. ER stress leads to unfolding and misfolding of nascent proteins and thereby provokes cellular inflammatory and apoptotic pathways. This study was designed to assess the effects of CA on ER stress-induced testis inflammation and apoptosis. To do this, male mice were divided into six groups. The control, vehicle and CA groups received saline, DMSO and 50 mg kg-1 CA. Tunicamycin (TM (was injected to induce ER stress (TM group). In the CA20-TM and CA50-TM groups, 20 mg kg-1 CA and 50 mg kg-1 CA were administered one hour before TM injection. After thirty hours, animals were sacrificed and testes were removed. Hematoxylin & eosin staining, ELISA assay and real-time PCR were performed. CA administration significantly downregulated gene expression of TNFα, IL6, P53, Bax/Bcl2 ratio and caspase3. It also reduced testis levels of ALP, NF-κB, TNFα and caspse3. Finally, CA relieved structural changes in seminiferous tubules. This study demonstrated that the positive effects of CA on the attenuation of ER-stress induced inflammation and apoptosis might be due to the inhibition of NF-κB and thereby suppression of inflammatory and apoptotic pathways.

Protective effects of Nigella sativa oil against bisphenol A-induced testicular toxicity in rats

The study investigated the protective effect of Nigella sativa (NS) oil against testicular damage induced by bisphenol A (BPA). A total of 36 Wistar Albino rats were divided into 4 groups: control (1ml olive oil), NS (5 ml/kg NS), BPA (100 mg/kg BPA in 1 ml olive oil), BPA+NS (100 mg/kg BPA + 5 ml/kg NS). During the 30-day experiment, all substances were administered by oral gavage. The levels of testosterone and LH in serum, as well as MDA, GSH, SOD, TNF-α, IL-6 and IL-10 levels in testicular tissue were measured by ELISA. Spermatological examinations and histopathological analyses of testicular tissue were also performed. BPA was found to raise LH while reducing the serum testosterone level. BPA caused a decrease in GSH, SOD, TNF-α and IL-6, but an increase in MDA and IL-10. BPA also reduced sperm motility, plasma membrane integrity, mitochondrial activity and acrosome membrane integrity. Oedema, hyperaemia, mononuclear cell infiltration in the interstitial tissue, as well as giant cell formations, degeneration and necrosis in the seminiferous tubules were seen in the BPA group. In addition, reductions in germinative epithelium, tubule diameter and the Johnson testicular score were noted. In rats receiving NS, hormonal profile, oxidative stress markers and cytokine levels were within normal limits. NS improved sperm motility, mitochondrial activity (JC1), plasma membrane integrity (SYBR-14) and partially acrosome membrane integrity (FITC-PNA). NS reduced testis inflammation, significantly ameliorated the testicular score and, to a lesser extent, increased germinative epithelium thickness and tubule diameter. It was concluded that NS has a protective effect against BPA-induced testicular toxicity.

Effects of Rosmarinus officinalis on orchitis following spermatic cord torsion-detorsion in male mice with emphasis on anti-inflammatory and antioxidant properties.

Orchitis as inflammation of testis occurs following traumatic injuries such as testicular torsion leading to high levels of oxidative stress and inflammation. Rosmarinus officinalis is a herb with anti-inflammatory and antioxidant properties. This study assessed therapeutic effects of rosemary following testicular torsion. A total of 36 male mice were categorised; control, torsion, rosemary (100 and 200mg/kg) and torsion+rosemary groups. Torsion was induced surgically, and rosemary was gavaged. Total antioxidant capacity of extract was approved by Ferric Reducing Ability of Plasma. Malondialdehyde and Griess protocols were hired to assess oxidative stress. Finally, sperm parameters and testosterone levels were analysed. Immunofluorescent (of Tumour Necrosis Factor Alpha), hematoxylin and eosin stainings and expression of inflammatory genes (Interleukin-1α, Interleukin-1β, Interferon-γ) were also assessed. Data were analysed using SPSS (v. 19), and graphs were drawn by GraphPad Prism (v. 9). Significantly (p<.05), oxidative stress indices and inflammatory genes expression were increased in torsion group, and total antioxidant capacity was increased in rosemary groups. In torsion+rosemary groups, total antioxidant capacity, sperm parameters and testosterone levels were increased, and inflammatory gene expression decreased significantly (p<.05). Rosemary with anti-inflammatory and antioxidant properties accelerates testicular healing in torsion cases, especially in therapeutic dose of 200mg/kg.

Fluoride Induces Autoimmune Orchitis Involved with Enhanced IL-17A Secretion in Mice Testis

Fluoride (F) widely exists in the water and food. Recent studies reported that F induced testicular toxicity via inflammation reaction. This study was aimed to explore the mechanism of F-induced inflammation in testis. 100 healthy male mice (BALB/cJ strain) were randomly divided into five groups including: control, experimental autoimmune orchitis (EAO), and three F groups (25, 50, and 100 mg/L sodium fluoride (NaF)). After 150 d, the results showed a significant increase in testicular cytokines levels including of IL-17A, IL-6, IFN-γ, and TNF-α in NaF and EAO groups compared with control group. Interestingly, the presence of specific antisperm autoantibodies in antitesticular autoantibodies and the notable recruitment of immunocyte (T cells and dendritic cells) were also observed in NaF and EAO groups. In addition, findings showed that in NaF and EAO groups macrophages and T cells both significantly secreted IL-17A, and the protein and mRNA levels of cytokines (IL-6 and TGF-β) were significantly increased. From these results, it can be concluded that autoimmune orchitis and IL-17A are implicated in F-induced testicular inflammation.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin promotes inflammation in mouse testes: The critical role of Klotho in Sertoli cells

Increasing evidence shows that 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) enhances inflammation, and inflammation has a significant negative impact on fertility. Therefore, the aim of this study was to investigate the effects of TCDD on testis inflammation. Pregnant mice and primary Sertoli cells were treated with TCDD, and male offspring and Sertoli cells were treated with lipopolysaccharides(LPS). We then measured testis apoptotic cells, proinflammatory cytokines, and observed the Klotho/PDLIM2/p65 pathway. In vivo results revealed that TCDD further enhanced LPS-increased testis apoptotic cells and concentrations of testicular proinflammatory cytokines (IL1β, IL18, and IL12) (p < 0.05). An in vitro investigation showed the levels of proinflammatory cytokines were increased in TCDD + LPS-treated cells compared with LPS-treated cells (p < 0.05). Compared with the LPS-treated cells, expression of Klotho and PDLIM2 was significantly decreased in TCDD + LPS-treated cells (p < 0.05), while expression of p65 and NLRP3 were significantly increased in the cotreatment cells (p < 0.05). However, the addition of Klotho to the TCDD + LPS-cotreated cells significantly increased PDLIM2 and decreased p65 activation and NLRP3 (p < 0.05). Meanwhile, mRNA levels and the secretion of proinflammatory cytokines were both suppressed by exogenous Klotho (p < 0.05). Administration of Klotho decreased TCDD + LPS-induced cytokines and apoptosis in mice (p < 0.05). Taken together, TCDD may increase testicular inflammation by affecting the secretion of proinflammatory cytokines in Sertoli cells via the Klotho/PDLIM2/p65 pathway, which influences the testicular microenvironment and induces germ cell apoptosis.

Primary high grade testicular leiomyosarcoma: A rare malignancy in a young male.

A 27-year-old male presented with a gradually increasing left scrotal mass. There was no significant past medical history. Ultrasonography of the left scrotum showed a hypoechoic, intratesticular mass with solid and cystic components. Laboratory investigations revealed normal serum levels of alpha-fetoprotein, beta human chorionic gonadotropin and lactate dehydrogenase. He underwent left high inguinal orchidectomy due to suspicion of testicular malignancy. After histopathologic examination and immunostaining, a diagnosis of high-grade primary testicular leimyosarcoma was ascertained. Only a few cases of primary intratesticular leiomyosarcoma have been reported in literature with the mean age of presentation of 50 years. In younger individuals, these tumors have been reported in a setting of predisposing factors like anabolic steroid use, testicular germ cell tumors, chronic inflammation of testis and testicular field radiation for treatment of leukemia. We present a case of high grade leiomyosarcoma of testis in a young male without any known predisposing factors.

Aluminum exposure for 60 days at human dietary levels impairs spermatogenesis and sperm quality in rats

Concerns about environmental aluminum (Al) and reproductive health have been raised. We investigated the effects of Al exposure at a human relevant dietary level and a high level exposure to Al. Experiment 1 (Lower level) rats were treated orally for 60 days: a) controls – ultrapure water; b) aluminum at 1.5mg/kg bw/day and c) aluminum at 8.3mg/kg bw/day. Experiment 2 (High level) rats were treated for 42 days: a) controls – ultrapure water; b) aluminum at 100mg/kg bw/day. Al decreased sperm count, daily sperm production, sperm motility, normal morphological sperm, impaired testis histology; increased oxidative stress in reproductive organs and inflammation in testis. Our study shows the specific presence of Al in the germinative cells and, that low concentrations of Al in testes (3.35μg/g) are sufficient to impair spermatogenesis and sperm quality. Our findings provide a better understanding of the reproductive health risk of Al.

MP07-13 THERAPEUTIC EFFECT OF RIPK1 INHIBITOR IN TESTICULAR ISCHEMIA-REPERFUSION

You have accessJournal of UrologyInfertility: Basic Research & Pathophysiology I1 Apr 2017MP07-13 THERAPEUTIC EFFECT OF RIPK1 INHIBITOR IN TESTICULAR ISCHEMIA-REPERFUSION Shin Ohira, Ryoei Hara, Shigenobu Tone, Seitetsu Kin, Shinjiro Shimizu, Tomohiro Fujii, Yoshiyuki Miyaji, and Atsushi Nagai Shin OhiraShin Ohira More articles by this author , Ryoei HaraRyoei Hara More articles by this author , Shigenobu ToneShigenobu Tone More articles by this author , Seitetsu KinSeitetsu Kin More articles by this author , Shinjiro ShimizuShinjiro Shimizu More articles by this author , Tomohiro FujiiTomohiro Fujii More articles by this author , Yoshiyuki MiyajiYoshiyuki Miyaji More articles by this author , and Atsushi NagaiAtsushi Nagai More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.279AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Testicular torsion makes testis ischemic. Surgery is immediately needed to reestablish blood flow. Even if the surgery succeed, testicular atrophy is often appear and lead to spermatic dysfunction. However, the etiology is still controversial in terms of pathophysiological changes. Recently it was reported that loss of the formation in any tissue after ischemia-reperfusion (IR) was involved in necroptosis, which is one of programmed cell death series. Necrostatin-1 (Nec-1) blocks both necroptosis and indoleamine 2,3-dioxygenase (IDO). In our previous research, we elucidated that IDO inhibitor decrease inflammation in testis and epididymis. First, we investigated pathophysiological change of testicular IR researching histological and biochemical phase in this study. Subsequently to the analysis, we tried to inhibit Receptor-interacting protein kinase 1 (RIPK1) and clarify a function of necroptosis in testicular IR. METHODS Twelve weeks old ICR male mice were used in this study. Their unilateral testicular artery was clamped under general anesthesia. Declamping three hours later, their testicular blood flow were resumed. After the procedure, bilateral testes were removed in time dependent manner (at day 1, 3, 5 and 7). Histological and biochemical change were evaluated by immunostaining and ELISA methods. Spermatic analysis from the epididymal cauda were evaluated by computer aided sperm analysis (CASA). In the following research, Nec-1 4 μg/g was administrated (iv) after declamping testicular blood flow. After the treatment, bilateral testes were removed in time dependent manner. Then, histological, biochemical and semen analysis were evaluated. Sham surgery was performed as control. Their experiments were duplicated at least. RESULTS Regarding histological change, invasion of lymphocyte-predominant inflammatory cells accumulated at day 3, 5 and destruction of seminiferous structure were observed at day 5, 7. Necroptosis cell using RIPK staining was abundantly expressed. In semen analysis, significant decreased spermatic concentration was observed at day 5 and 7 compared to control (p<0.05). Significant decreased spermatic motility was observed at day 1, 3, 5 and 7 compared to control (p<0.05). Interestingly, in contralateral (unaffected side) testes, significant decreased spermatic motility was observed at day 5 and 7 compared to control (p<0.05). Some candidates were picked up as molecular marker. Significant increased E-selectin expression, which is a marker of leukocyte-endothelial cell adhesion molecule, was observed at day 1 compared to control (p<0.05). Significant increased IL-6 expression, which is a marker of inflammation, was observed at day 3 compared to control (p<0.05). Significant increased 8-OHdG expression, which is a biomarker of oxidative stress, was observed at day 7 compared to control (p<0.05). Interestingly, significant increased the highest expression of E-selectin, IL-6 and 8-OHdG were observed in contralateral testes. Same results were introduced in immunohistochemical staining. After treatment of Nec-1, testicular structure were maintained and little invasion of inflammatory cells were observed. Significant decreased germ cell death (necroptosis) in seminiferous tubules were statistically observed. Significant decreased E-selectin, IL-6 and 8-OHdG were also observed. Importantly, Spermatic motility also maintained in both treated testis and contralateral testes. CONCLUSIONS Oxidative stress via inflammation and necroptosis should induce spermatogenetic dysfunction in IR testis. First, prominent inflammation was occurred in testicular ischemia-reperfusion model and not only expression of cytokines were increased, but also in contralateral testes. Subsequently, oxidative stress highly expressed and cell death appeared. Therefore, their change of bilateral testis would be one of pathophysiology in patients with ischemic testis. To inhibit RIPK1 would be contribute to protection of testicular tissue and spermatogenesis in IR model. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e86-e87 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Shin Ohira More articles by this author Ryoei Hara More articles by this author Shigenobu Tone More articles by this author Seitetsu Kin More articles by this author Shinjiro Shimizu More articles by this author Tomohiro Fujii More articles by this author Yoshiyuki Miyaji More articles by this author Atsushi Nagai More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MKP-1 attenuates LPS-induced blood-testis barrier dysfunction and inflammatory response through p38 and IκBα pathways.

Sertoli cells create a local tolerogenic microenvironment to maintain testicular immune privilege especially through the formation of a blood-testis barrier (BTB). However, the molecular mechanisms underlying the immune modulation function and BTB dynamics of Sertoli cells remained elusive. MAP phosphatase (MKP)-1 acts as a crucial negative regulator of the inflammatory response. Nevertheless, the role of MKP-1 in regulating Sertoli cells has not been elucidated. In this study, we have for the first time uncovered distinct cellular localization of MKP-1 in the cells at different stages of mouse testis, and the level of MKP-1 expression was significantly up-regulated by LPS-induced acute testis inflammation. In addition, MKP-1 staining was strongly detected in nuclei and peri-nuclear regions of cytoplasm in the Sertoli cells, and it was presented at Sertoli cell tight junctions (TJs) at stages VII-VIII after LPS treatment. Moreover, we demonstrated that MKP-1 was capable of attenuating LPS-induced decrease of occludin by interaction with p38 MAP kinase and IκBα molecules. Taken together, our data highlight that MKP-1 was an important endogenous suppressor of innate immune responses involved in the regulation of BTB barrier dynamic. This study thus might offer novel targets for treating inflammatory diseases in the testis.

GLP-1 Receptor Agonist Exenatide Attenuates the Detrimental Effects of Obesity on Inflammatory Profile in Testis and Sperm Quality in Mice.

Male obesity has been linked to subfecundity. This study is to investigate the effects of GLP-1 receptor (GLP-1R) agonist exenatide on sperm quality in high-fat diet (HFD)-induced obese mice. After 12 weeks of chow diet (CD) or HFD challenge, mice on HFD were allocated to either saline or exenatide (24 nmol/kg/day) interventions for 8 weeks. Sperm quality and the inflammatory profile of testis were compared among three groups. Obesity reduced the quality of sperm and changed the inflammatory profile characterized by increased mRNA expression levels of TNF-α, MCP-1, and F4/80 in testis. Exenatide intervention reduced the expression of pro-inflammatory cytokines and improved the quality of sperm. HFD-induced obesity leads to the impairment of sperm quality and increased inflammation of testis in mice, and the abnormal physiology can be attenuated by exenatide treatment. Exenatide treatment may bring additional profits to obese and diabetes men by improving sperm function.

Dual roles of endogenous and exogenous galectin-1 in the control of testicular immunopathology.

Galectin-1 (Gal-1), a proto-type member of galectin family, is highly expressed in immune privileged sites, including the testis. However, in spite of considerable progress the relevance of endogenous and exogenous Gal-1 in testis pathophysiology have not yet been explored. Here we evaluated the in vivo roles of Gal-1 in experimental autoimmune orchitis (EAO), a well-established model of autoimmune testicular inflammation associated with subfertility and infertility. A significant reduction in the incidence and severity of EAO was observed in mice genetically deficient in Gal-1 (Lgals1−/−) versus wild-type (WT) mice. Testicular histopathology revealed the presence of multifocal testicular damage in WT mice characterized by an interstitial mononuclear cell infiltrate and different degrees of germ cell sloughing of seminiferous tubules. TUNEL assay and assessment of active caspase-3 expression, revealed the prevalence of apoptotic spermatocytes mainly localized in the adluminal compartment of seminiferous tubules in EAO mice. A significant increased number of TUNEL-positive germ cells was detected in EAO testis from WT compared with Lgals1−/− mice. In contrast, exogenous administration of recombinant Gal-1 to WT mice undergoing EAO attenuated the severity of the disease. Our results unveil a dual role of endogenous versus exogenous Gal-1 in the control of autoimmune testis inflammation.