Efficacy of relaxin for cisplatin-induced testicular dysfunction and epididymal spermatotoxicity

Abstract

Background: Cisplatin (CP) is an extremely effective anticancer agent widely used to treat various cancer types, however, the potential side effects include testicular dysfunction. This study was to investigate, using a rat model of CP-induced testicular dysfunction, the protective effects of relaxin (RLN) against oxidative stress, testicular function, histological damage, spermatogenesis, germ-cell apoptosis, and sperm output, and to explore the usefulness of RLN as a potential protective drug for use with CP in chemotherapeutic treatments. Methods: Sprague-Dawley male rats were used, which were divided into three groups: sham control, CP, and CP + RLN. Porcine RLN (500 ng/h) or saline was infused for 5 days using an implanted osmotic mini-pump following intraperitoneal injection of CP (6 mg/kg). RLN dose was chosen based on previous studies showing that it resulted in serum relaxin levels comparable to those in rats at the middle of pregnancy. At 5 days after CP administration, samples were collected and assessment of testicular histopathology, germ-cell apoptosis, oxidative stress, lipid peroxidation, and sperm quality was performed as main measures. Results: The testicular CP model showed reduced testis weight and significantly decreased spermatogenesis scores. Additionally, CP administration induced a 4.6-fold increase in the apoptotic index associated with a significant increase in oxidative stress and upregulation of pro-apoptotic Casp3 and downregulation of anti-apoptotic Bcl2 levels, resulting in a marked reduction in sperm concentration. However, RLN administration caused a significant reduction in CP-mediated damage by attenuating oxidative stress and cell apoptosis. RLN administration efficiently scavenged ROS via the activation of SOD, CAT, and GPx and upregulation of GSH to prevent lipid peroxidation and decreased apoptosis by altering Bcl2 and Casp3 expression, thereby reducing histopathological damage and restoring spermatogenesis. Furthermore, RLN ameliorated attenuated sperm motility in the cauda epididymis resulting from CP treatment. Conclusions: This study clearly indicates that RLN exerts a protective effect against CP-induced testicular damage through attenuation of oxidative stress and suppression of apoptosis. Our findings suggest RLN as a potentially efficacious drug for use with cisplatin chemotherapy in order to ameliorate CP-induced side effects and testicular injury adversely affecting spermatogenesis, sperm quality, and oxidative-stress parameters.

Panax ginseng’in sıçanlarda sisplatin ile oluşturulan testis hasarı üzerine etkileri

“…When gonadotropin luteinizing hormone is released, it results in cAMP release and protein kinase A activation, which initiates a series of enzyme cascade reactions (Liu et al, 2015). In various studies examining the effects of CP on testicular and reproductive function, it has been shown that plasma or testicular total and free testosterone levels are also reduced; these results have often been associated with oxidative stress (Azab et al, 2020;Ceylan et al, 2020;Famurewa et al, 2020;Jourabi et al, 2020;Kohsaka et al, 2020;Majd et al, 2021;Saad et al, 2020;. In the present study, we also demonstrated that CPinduced oxidative stress significantly decreased total and free testosterone levels in rats' plasma.…”

“…This result indicated that Pnx might promote the testosterone secretion of Leydig cells via suppressing oxidative stress which was induced by CP in rat testes. Kohsaka et al reported that CP causes an increase in TUNEL (+) spermatogenic and Leydig cells apoptotic index; however, it reduces Johnsen's score in rats' testes (Kohsaka et al, 2020). Research on the protective effect of caffeic acid phenethyl ester on testicular damage caused by CP showed that CP decreased Johnsen's score and damaged spermatogenic cells (Ceylan et al, 2020).…”

“…On the other hand, CP caused lower testosterone levels and induced apoptosis via enhanced Bcl-2-associated X protein (Bax) and decreased B-cell lymphoma 2 (Bcl-2) levels in the testis of rats (Azab et al, 2020). Generally, CP-induced animals also exhibited lower sperm count and motility as well as higher abnormal sperm; however, testicular injury adversely affects spermatogenesis, sperm quality, and oxidative stress parameters in the related studies (Ceylan et al, 2020;Kohsaka et al, 2020;Saad et al, 2020;. These findings showed the CP-induced genotoxicity and reproductive toxicity, which might be closely related to oxidative stress.…”

The Ameliorative Effects of Caffeic Acid Phenethyl Ester in Cisplatin-Induced Nephrotoxicity: Assessment of the Oxidative Stress an Inflammation

“…Thus, it is the most commonly known chemotherapeutic among chemotherapy drugs (Dasari & Tchounwou, 2014;Hanif & Hartinger, 2018). Although CP is used in many cancer treatments, it has many side effects including neurotoxicity, nephrotoxicity, hepatotoxicity, gonadotoxicity (Lu et al, 2006;Santos et al, 2008;Melli et al, 2008;Quintanilha et al, 2017;Kohsaka et al, 2020).…”

iTRAQ-Based Sperm Proteomic Analyses Reveals Candidate Proteins Affecting the Quality of Spermatozoa From Boar on Plateaus

“…But the sperm quality analysis of TP and YP raised at high altitudes have not yet been conduced. Proteomic data enable a better understanding of sperm biochemistry [5]. In-depth proteomic analysis of boar spermatozoa was implemented using shotgun and gel-based methods [6].…”