Cisplatin-induced Testicular Toxicity Research Articles

Transmembrane BAX Inhibitor Motif-6 (TMBIM6) protects against cisplatin-induced testicular toxicity.

Is the Transmembrane BAX Inhibitor Motif-6 (TMBIM6) involved in the molecular mechanism by which cisplatin causes reproductive toxicity? TMBIM6 protects against cisplatin-induced testicular toxicity through up-regulation of heme oxygenase-1 (HO-1),-which maintains the levels of steroidogenic enzymes by decreaseing oxidative stress in the endoplasmic reticulum (ER). Testosterone production is highly suppressed as a main complication of cisplatin (cis-diamminedichloroplatinum) anticancer therapy. Groups of seven wild type or Tmbim6 KO C57BL/6J mice were given a single i.p., injection of cisplatin (30 mg/kg body wt) and testis and serum were collected 3 days later. Tmbim6-lentivirus-mediated testicular expression-rescued KO mice were analyzed to confirm function was restored. Tmbim6-over expressing TM3 mouse Leydig cells were exposed to cisplatin in vitro. After collection of the specimens serum testosterone level and testicular weight and structure were compared between the groups. Quantitative PCR, immunoblot, and assays for ROS, HO-1 activity and protein disulfide isomerase (PDI) carbonylation were performed. Phospho protein kinase B (p-Akt), nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), and its downstream gene product HO-1 and the levels of testosterone synthesis-associated enzymes, including steroidogenic acute regulatory protein (StAR), a rate limiting enzyme for testosterone production, were significantly expressed in the presence of Tmbim6 and maintained after cisplatin treament. Excessive post-translational oxidation of protein disulfide isomerase (PDI), altered folding capacitance and ROS accumulation, and ER stress were also decreased in the presence of Tmbim6. Higher levels of ER stress and protein hypercarbonylation were consistently observed in KO testis, compared with WT testis. In the Tmbim6 KO mice, lentivirus-mediated testicular expression of Tmbim6 rescued the above phenotypes. Furthermore, the protective role of Tmbim6 against testicular toxicity was consistently shown in Tmbim6-overexpressing TM3 Leydig cells (testosterone producing cells). We conclude that TMBIM6 protects against cisplatin-induced testicular toxicity by inducing HO-1 and enhancing ER folding capacitance. N/A. This study was performed using a short, 3-day cisplatin treatment condition. Therefore, the results need to be cautiously interpreted with regard to cisplatin-associated chronic toxicity. Moreover, to determine the clinical relevance of the role of TMBIM6, further studies in testicular cancer are needed. Cisplatin-associated ER stress and redox imbalance might be implicated as toxicity mechanisms associated with anticancer therapy. This study was supported by the National Research Foundation of Korea (2015R1A2A1A13001849). The authors have no competing interests to disclose.

Evaluation of the Effect of Pentoxifylline on Cisplatin-Induced Testicular Toxicity in Rats

Chemotherapy is associated with male infertility. Cisplatin (cis-diamminedichloro-platinum (II) (CDDP) as a chemotherapy medication used to treat a number of cancers has been reported to most likely induce testicular toxicity. Administration of antioxidants, such as pentoxifylline (PTX) may reduce some Adverse Drug Reactions (ADRs) of CDDR Therefore, this study investigated the potentially protective effects of PTX on CDDP-induced testicular toxicity in adult male rats. For this purpose, 42 male rats were randomly divided into 7 groups. The rats were orally preheated with PTX at the 3 doses of 75, 150, and 300 mg/kg once a day for 14 successive days. On the 14th day of the study, they were intraperitoneally (IP) administered with a single dose of CDDP (7 mg/kg). Finally, the sperm/testis parameters, serum levels of reproductive hormones, including testosterone, Luteinizing Hormone (LH), and Follicle Stimulating Hormone (FSH) as the pivotal endocrine factors controlling testicular functions, and histopathological changes of testis tissue were examined. Pretreatment with the two doses of 75 and 150 mg/kg PTX indicated significant increases in the sperm count and motility induced by CDDP administration. The right and significantly left testis weights were decreased following the treatment with 300 mg/kg of PTX plus CDDP. However, 75 mg/kg of PTX plus CDDP showed the best near-to-normal histopathological features. The results demonstrated that PTX alone enhanced some parameters, such as the sperm count, while reducing other parameters, including sperm fast motility and germ layer thickness. Furthermore, despite testosterone or LH levels, the mean serum FSH level was significantly augmented by the doses of 75 and 150 mg/ kg. It was concluded that PTX administration cannot reduce CDDP-induced testicular toxicity even at high doses (e.g., 300 mg/kg), while it seemed to partially intensify CDDP toxicity effects at a dose of 75 mg/kg. Thus, further research is required in this regard.

Induction of heme oxygenase-1 with hemin alleviates cisplatin-induced reproductive toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line

Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells.

Cetuximab intensifies cisplatin-induced testicular toxicity

Epidermal growth factor receptor (EGFR) has proliferative properties in the testis. Cetuximab, an anti-EGFR, is administered together with chemotherapy to patients with various types of cancer. This studies aim was to investigate the effect of cetuximab on testicular function. Adult male mice were injected with cetuximab (10 mg/kg), cisplatin (8 mg/kg) or a combination of both, and killed one week or one month later. The doses were chosen by human equivalent dose calculation. Testicular function was evaluated by epididymal-spermatozoa total motile count and sperm motility, weights of testes and epididymides, and the level of anti-Müllerian hormone (AMH) in the serum. Immunohistochemistry was performed to examine germ cell proliferation (Ki-67), apoptosis (Terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labelling), reserve (DAZL-Deleted in azoospermia-like, Promyelocytic leukaemia zinc-finger), blood vessels (CD34) and Sertoli cells (GATA-4). Administration of cetuximab alone increased testicular apoptosis and decreased epididymal-spermatozoa total motile count over time. When added to cisplatin, cetuximab exacerbated most of the recorded testicular parameters, compared with the effect of cisplatin alone, including testis and epididymis weights, epididymal-spermatozoa total motile count, AMH concentration, meiosis and apoptosis. In conclusion, cetuximab has only a mild effect on testicular reserve, but when added to cisplatin, it exacerbates cisplatin-induced testicular toxicity.

PROTECTIVE EFFECT OF L-CARNITINE AGAINST CISPLATIN-INDUCED TESTICULAR TOXICITY IN RATS

Testicular damage is one of the most deleterious effects whenever cisplatin (CIS) is employed in cancer chemotherapy. Oxidative stress has been proven to be involved in CIS induced toxicity. Thus, the current study explored the possible protective effect of L-carnitine (L-CAR) against cisplatin-induced testicular damage in rats. L-carnitine (500 mg/kg/day; i.p.) was injected for 15 days, whereas cisplatin (10 mg/kg; i.p.) was injected as a single dose at the 12th day to induce testicular damage in adult male Sprague-Dawley rats. In the current study, CIS reduced the reproductive organs weight, sperm count, sperm motility and serum testosterone level beside a marked increase in the incidence of sperm abnormalities. In addition, it significantly increased malondialdehyde (MDA) and nitric oxide (NO) along with a marked decrease in testis reduced glutathione (GSH) content and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. At the same time, CIS administration resulted in marked elevation in tumor necrosis factor-α (TNF-α) production and nuclear factor-kabba B (NF-κB) expression. These results were confirmed by histopathological examination. Treatment with L-CAR markedly attenuated cisplatin-induced injury by suppression of oxidative/nitrosative stress and inflammation, amendment of antioxidant defenses, as well as improvement of steroidogenesis, spermatogenesis and testicular histological features. This study suggests a novel therapeutic application for L-carnitine as a protective agent against cisplatin-induced testicular toxicity through its promising anti-inflammatory and antioxidant capacities.

Protective effects of resveratrol against cisplatin-induced testicular and epididymal toxicity in rats

This study investigated the probable protective effect of resveratrol against cisplatin-induced testicular and epididymal toxicity in rats. Body weights of the animals showed no significant changes after cisplatin administration. Conversely, the weights of testis, and accessory sex organs reduced significantly. The daily sperm production and epididymal sperm quantity and quality were decreased in cisplatin treated rats. The circulatory levels of testosterone and activity levels of testicular 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase were significantly decreased after cisplatin treatment. The activity levels of superoxide dismutase and catalase were decreased with an increase in the levels of lipid peroxidation and H2O2 generation in the testis and epididymis of cisplatin treated rats, suggesting the cisplatin-induced oxidative stress. The biochemical findings were supplemented by histological examination of testis. Reduced tubular size, decreased spermatogenesis and deterioration in architecture were observed after cisplatin treatment. Administration of resveratrol alone has no significant effect on testicular and epididymal metabolism. On the other hand, administration of resveratrol ameliorated cisplatin-induced alterations in testicular and epididymal oxidative damage, suppressed steroiodgenesis and spermatogenesis and restored testicular architecture. In conclusion, resveratrol possesses multimechanistic protective activity that can be attributed to its steroidogenic and antioxidant actions.

Anti-oxidative and anti-apoptotic roles of spermatogonial stem cells in reversing cisplatin-induced testicular toxicity

Background aimsBecause of reproductive toxic effects of chemotherapy, researchers have taken some techniques to preserve fertility potential. The present study was designed to point out the potential role of spermatogonial stem cell (SSC) therapy in reversing cisplatin (CP)-induced testicular toxicity and restore the spermatogenesis. MethodsSixty rats were randomly divided into three groups: group 1, control group; group 2, rats received CP in a dose of 7 mg/kg/day for 5 consecutive days; group 3, CP was injected at 7 mg/kg per day for 5 consecutive days, and, on the 6th day of the experiment, rats were treated with SSC. Forty days after receiving the last dose of CP, rats were euthanized under anesthesia; testes were collected, and gene expression using real-time polymerase chain reaction for P53, Bax, caspase 9 and cytochrome c, testicular histological findings and oxidative status were determined. ResultsAdministration of cisplatin caused significant increases in malondialdehyde levels, Bax and caspase 9 genes expression levels concomitant with significant decreases in anti-oxidant enzyme activities, p53 and cytochrome c gene expression levels, along with some histopathological lesions in testicular tissue. SCC attenuated the disturbance in oxidant/anti-oxidant status and testicular apoptosis; this is associated with improvements in the histopathological view of the testicular tissue. ConclusionsThe current study highlights evidence that the SCC has anti-oxidative and anti-apoptotic properties that could reverse CP-induced testicular toxicity, in addition to their role in spermatogenesis.

Abstract 3840: Cetuximab-induced testicular toxicity

Abstract Background: Cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC) in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic disease, in association with cisplatin-based chemotherapy. We aimed to study the effect of cetuximab on testicular function and reserve. Methods: Male mice were injected intraperitoneally with cetuximab (1mg), or cisplatin (8mg/kg) or the combination of both and sacrificed either 1 week or 6 weeks later. Saline-injected mice served as controls. Testes were excised, weighed and further processed. Glutathione and apoptosis assays were performed on 6 weeks samples for determination of oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effect of cetuximab, cisplatin and their combination on the testis histology as well as on the spermatogonial reserve. Results: Cetuximab induced mild apoptosis in the testis. Cisplatin induced enhanced apoptosis and depleted spermatogonial reserve, reflected by reduced DAZL staining (early spermatocyte marker). The combined treatment resulted in further decline in testicular weight compared with cisplatin-only treated mice at 1-month post treatment (p<0.05). Cetuximab enhanced cisplatin-induced oxidative stress, and further depletion of spermatogonial reserve (p<0.05). Conclusions: Cetuximab has a mild effect on testicular reserve. Nevertheless, the addition of cetuximab to cisplatin exacerbates cisplatin-induced testicular toxicity. Citation Format: Mattan Levi, Aaron Popovtzer, Moran Tzabari, Salomon M. Stemmer, Ruth Shalgi, Irit Ben-Aharon. Cetuximab-induced testicular toxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3840. doi:10.1158/1538-7445.AM2014-3840

Cisplatin-induced testicular toxicity in rats: the protective effect of arjunolic acid.

In the present study, the effect of arjunolic acid on testicular damage induced by intraperitoneal injection of rats with 7 mg/kg cisplatin was studied. Cisplatin induced a significant reduction in testicular weights, plasma testosterone, and testicular reduced glutathione levels in addition to a significant elevation of testicular malondialdehyde levels and testicular gene expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and p38 mitogen-activated protein kinase (MAPK) when compared with the control group (p < 0.05). Lower tubular diameters and depletion of germ cells and irregular small seminiferous tubules with Sertoli cells only were observed in the cisplatin group. Arjunolic acid administration significantly corrected the changes in both biochemical and histopathological parameters. Arjunolic acid plays a significant protective role against cisplatin-induced testicular injury by attenuating oxidative stress parameters along with downregulation of iNOS, TNF-α, and p38-MAPK testicular expressions.

Abrogation by Curcumin on Testicular Toxicity Induced by Cisplatin in Rats

Cisplatin is one of the most effective and widely-used antineoplastic agents for the treatment of testicular germ cell tumors. The present study was conducted to examine the possible modifying effects of curcumin against testicular toxicity induced by cisplatin in male rats. 60 male albino rats were equally divided into six groups; the first and second groups were the control and curcumin treated group respectively while the 3rd group was cisplatin treated group; the 4th and 5th groups were co- and post treated cisplatin rat with curcumin respectively and the 6th group was self treated cisplatin rat group. Many side effects were observed in animals injected with cisplatin such as loosing of body weight, loss of activity, weakness, yellowish body hair. A significant decrease in the body and testicular weights,, sperm counts, sperm motility, plasma testosterone, luteinizing hormone reduced glutathione, total antioxidant capacity, and total protein levels in cisplatin and cisplatin self treated groups when compared with the control group. On the other hand; a significant increase in the MDA and NO in cisplatin and cisplatin self treated groups when compared with the control group. sperm count and sperm motility, GSH and TAC exhibited significant increased in cisplatin treated with curcumin when compared with cisplatin groups, moreover, sperm abnormality, MDA, NO and total protein exhibited significant decrease in cisplatin treated groups with curcumin when compared with cisplatin groups. A significant decrease in sperm abnormality, MDA, NO and total protein and a significant increase in GSH and TAC in Co-treated group when compared with post treated cisplatin with curcumin. Our recommendation, administration of curcumin caused ameliorative effect against cisplatin-induced testicular toxicity.

Histological study on the role of ginger against cisplatin-induced testicular toxicity in albino rats

Aim of the work Chemotherapy with cisplatin has adverse effects on spermatogenesis. Therefore, this work aimed at investigating the protective role of ginger against cisplatin-induced testicular toxicity in male albino rats. Materials and methods Twenty-four adult albino rats were used in this study. They were divided into three groups. The first group served as the control group; the second group was injected with cisplatin (12 mg/kg once); and the third group was injected with cisplatin (12 mg/kg once) and then given ginger (310 mg/kg orally) for 26 days. Testicular specimens were processed for light microscopic examination using H&E. Other specimens were processed for electron microscopic examination. Results Cisplatin had damaging effects on the seminiferous tubules. Some areas of the tubules showed complete depletion of germ cells. Other areas showed some spermatogonia or primary spermatocytes. Sertoli cells showed a variable degree of degenerative changes in the form of destruction of cellular processes and cell junction. Interruption of the nuclear envelope of spermatids and loss of intercellular bridges were noticed. Treating with ginger resulted in normal Sertoli cells and cell junctions. The germ cells lining the tubules were more or less normal except for some intercellular vacuolations. Conclusions The use of ginger has some protective effects on the testicular structure; hence, a larger number of experiments with higher doses of ginger or longer administration period could be beneficial for patients taking chemotherapeutic drugs.

Selenium and Lycopene Attenuate Cisplatin-induced Testicular Toxicity Associated With Oxidative Stress in Wistar Rats

To investigate the potential protective effects of selenium and lycopene, either alone or in combination, for cisplatin-induced oxidative stress and testicular dysfunction in male rats. A total of 50 adult male Wistar rats were divided into 5 groups of 10 animals each, as follows: control group (treated with placebo); cisplatin-alone group; cisplatin + lycopene group; cisplatin + selenium group; and cisplatin + selenium + lycopene group. The weights and dimensions of testes, epididymes, and accessory glands as well as sperm concentration, motility, and proportion of normal morphology were assessed. Testicular tissue malondialdehyde (MDA) and glutathione (GSH) levels, as well as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, and plasma testosterone were determined. Cisplatin treatment caused significant reductions in weights and dimensions of testes, epididymes, and accessory glands, sperm concentration, motility, and proportion of normal morphology, enzymatic and nonenzymatic antioxidants, and plasma testosterone levels. There was significantly increased MDA. The co-administration of selenium and lycopene, either separately or in combination, significantly attenuated the harmful effects of cisplatin-induced lipid peroxidation, oxidative stress, loss of genital organ weight and dimensions, as well as function of reproductive organs collectively in the Wistar rat model. The combination of selenium and lycopene was more effective than supplementation of either agent alone in preventing cisplatin-induced testicular damage. Selenium and lycopene supplementation reduced cisplatin-induced testicular toxicity, improved testicular function and prevented cisplatin-related injury to the rat testes by suppression of oxidative stress.

Protective effect of speman on cisplatin-induced testicular and epididymal toxicity in mice

Testicular cancer is the most common cancer affecting men of reproductive age. Advances in treatment of the disease, which includes the administration of cisplatin, have brought the 5-year survival rate to over 90%. This high cure rate, coupled with young age of patients, makes elucidation of the impact of the treatment on reproduction become increasingly important. The objective of the present study was to investigate the protective effect of speman, a non-hormonal herbal formulation, on cisplatin-induced suppressed male reproductive health in mice. Male mice were treated with cisplatin or speman alone or in combination and assessed for spermatogenesis and steroidogenesis. Significant decrease in the weights of testes and epididymis was observed in cisplatin treated animals. Injection of cisplatin significantly decreased epididymal sperm count, viable sperms, motile sperms and hypo-osmotic swelling (HOS)-tail coiled sperms with a significant reduction in the testicular steroidogenic enzyme activities and serum testosterone levels, whereas co-administration of speman with cisplatin showed a significant improvement in the selected reproductive parameters over cisplatin alone treated mice indicating the beneficial effect of speman to combat cisplatin-induced suppressed reproduction in male mice. Key words: Cisplatin, male mice, speman, sperm, steroidogenesis

Protective effect of speman on cisplatin-induced testicular and epididymal toxicity in mice

Protective effect of speman on cisplatin-induced testicular and epididymal toxicity in mice

Protective Effects of Erdosteine on the Testes of Cisplatin- Treated Adult Male Albino Rats: A Light and Scanning Electron Microscopic Study

Background: Cisplatin is considered a potent chemotherapeutic drug used in clinical oncology but causes testicular damage as a side effect. Erdosteine is a mucolytic drug possessing an antioxidant capacity. Aim of the Work: The present study was planned to evaluate the possible protective effect of erdosteine against cisplatin-induced testicular toxicity in rats. Material and Methods: Forty adult male albino rats were divided into four groups, ten rats each: control, erdosteine-treated (50 mg/kg body weight/day, orally for 7 days), cisplatin-treated (a single dose of 7mg/ kg intraperitoneally) and erdosteine/cisplatin-treated. Erdosteine was administered 24h before cisplatin injection and was continued until animal sacrifice. Six days after cisplatin administration, all rats were anaesthetized with ether. The scrotum of each animal was incised and the testes were removed and processed to be examined by both the light and scanning electron microscopy. Results: Examination of the testicular specimens of the cisplatin-treated group revealed severe testicular damage with significant reduction in the tubular diameter and germinal epithelium thickness compared to the control group. Shrunken tubules, germ cell loss and apoptotic changes in most of the cells, especially the primary spermatocytes and round spermatids were noticed. The mature spermatids appeared markedly decreased in number and the existing ones showed abnormal forms. Increased interstitial edema and apparent decrease in the Leydig cells were also observed. Erdosteine administration before cisplatin showed amelioration of the testicular architecture. Despite the mild degenerative changes in some spermatogenic cells, cell loss was markedly decreased and most of the tubular lumina were full of mature spermatids. Apparent increase in the Leydig cells and decreased interstitial edema was also noticed. Conclusions: Erdosteine partially protected the rat testes against the cisplatin-induced toxicity most probably via its potent antioxidant and radical scavenging activities.

Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats

To evaluate the effect of melatonin on cyclophosphamide (CP)- and cisplatin-induced testicular toxicity with use of sperm parameters and biochemical and histopathologic approaches. Experimental study. Vakif Gureba Hospital, Istanbul, Turkey. Six-week-old adult male Wistar albino rats (N = 48). Cyclophosphamide was administered to rats by gavage at a single dose of 100 mg/kg body weight, only once. Cisplatin was injected intraperitoneally at single doses of 7 mg/kg/d for five consecutive days. Melatonin was both administered separately and coadministered with CP and cisplatin intraperitoneally at a dose of 10 mg/kg body weight. Body and testicular weight, epididymal sperm characteristics, plasma T, and histopathologic structure of the testicular tissue were determined. Malondialdehyde (MDA) and reduced glutathione (GSH) levels and glutathione peroxidase (GSH-Px) activity were assessed in testicular tissue. Body and testicular weight, epididymal sperm count, motility and morphology, plasma T levels, the activities of GSH-Px, and GSH levels were significantly decreased whereas the level of MDA was significantly increased in rats of the CP and cisplatin group. Melatonin treatment increased GSH levels and GSH-Px activity, decreased MDA level in testicular tissue, and increased plasma T level. Cyclophosphamide and cisplatin caused irregular seminiferous tubules, reduction of seminiferous epithelial layers, significant maturation arrest, and perivascular fibrosis. Melatonin significantly improved histopathologic changes. Melatonin may prevent CP- and cisplatin-induced testicular damage.