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Testicular and epididymal toxicity induced by benzo(a)pyrene, alcohol, and their combination in Wistar rats.

ABSTRACT: Alcoholism and cigarette smoking are pervasive problems that have been implicated in human health. In this study, independent and combinative toxicities of alcohol and benzo(a)pyrene (BaP) were tested for reproductive toxicity in rats. Male Wistar rats were exposed to BaP (100 ?g per kg body weight) on alternative days and alcohol (2 g per kg body weight per day) daily, either individually or in combination for 60 days. Exposure to BaP or alcohol significantly decreased the fertility index and reduced the number of implantations associated with elevated pre- and post-implantation losses. The relative weights of testes, epididymis, seminal vesicles, and prostate gland were significantly decreased in BaP or alcohol administered rats. Exposure to BaP or alcohol significantly decreased daily sperm production, sperm density, percentages of motile, viable, HOS-tail swelled sperm, testicular 3?- and 17?-hydroxysteroid dehydrogenase activity levels, mRNA levels of steroidogenic acute regulatory protein, and serum testosterone levels. Further, in silico studies revealed the binding of BaP at the hydrophobic tunnel of StAR protein. Additional studies disclosed stable interactions of BaP with the amide group of ASN150 and the hydroxyl group of THR263 by forming three hydrogen bonds. Our results also showed that treatment of rats with BaP or alcohol caused a marked increase in levels of superoxide anions, hydrogen peroxide, and lipid peroxidation in testis and epididymis. Conversely, glutathione levels and activity levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in testis as well as epididymis decreased significantly in the experimental rats. Under the same conditions, increased fragmented DNA levels were observed in sperm. The results of the present study indicate that exposure to BaP or alcohol adversely affected the male reproductive functions, which may be, at least in part, due to androgen deficiency and/or oxidative stress-related mechanisms. Consistently, the present results also showed higher reproductive toxicity upon exposure to combinations of BaP and alcohol than upon their individual treatments. Therefore, this combination was classified as additive and synergistic responses of BaP and alcohol.

SUBMITTER: Reddy KP

PROVIDER: S-EPMC6062366 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Testicular and epididymal toxicity induced by benzo(a)pyrene, alcohol, and their combination in Wistar rats.

Reddy K Pratap KP Reddy P Sreenivasula PS

Toxicology research 20151125 2

Alcoholism and cigarette smoking are pervasive problems that have been implicated in human health. In this study, independent and combinative toxicities of alcohol and benzo(a)pyrene (BaP) were tested for reproductive toxicity in rats. Male Wistar rats were exposed to BaP (100 μg per kg body weight) on alternative days and alcohol (2 g per kg body weight per day) daily, either individually or in combination for 60 days. Exposure to BaP or alcohol significantly decreased the fertility index and r ...[more]

PMID: 30090357

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Project description:BackgroundCisplatin (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.MethodsSprague-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.ResultsThe 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.ConclusionsThis 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.

Project description:Doxorubicin (DOX) is a powerful chemotherapeutic agent used in many types of malignancies. However, its use results in testicular damage. DOX-induced testicular damage results in low level of serum testosterone which may affect cognitive function. The current study investigated the protective effect of liraglutide (50, 100 μg/kg/day) in testicular toxicity and the consequent cognitive impairment induced by DOX. DOX treatment reduced sperm count (62%) and sperm motility (53%) and increased sperm abnormalities (786%), as compared to control group. DOX also reduced serum testosterone level (85%) and the gene expression of testicular 3β-HSD (68%) and 17β-HSD (82%). Moreover, it increased testicular oxidative stress (MDA and GSH) by 103% and 59%, respectively, apoptotic (caspase-3 and P53) by 996% and 480%, respectively. In addition, DOX resulted in increasing autophagic markers including PAKT, mTOR, and LC3 by 48%, 56%, and 640%, respectively. Additionally, rats' behavior in Y-maze (60%) and passive avoidance task (85%) was disrupted. The histopathological results of testis and brain supported the biochemical findings. Treatment with liraglutide (100 μg/kg/day) significantly abrogated DOX-induced testicular damage by restoring testicular architecture, increasing sperm count (136%) and sperm motility (106%), and decreasing sperm abnormalities (84%) as compared to DOX group. Furthermore, liraglutide increased serum testosterone (500%) and steroidogenesis enzymes 3β-HSD (105%) and 17β-HSD (181%) along with suppressing oxidative stress (MDA and GSH) by 23% and 85%, respectively; apoptotic (caspase-3 and P53) by 59% and55%, respectively; and autophagic markers including PAKT, mTOR, and LC3 by 48%, 97%, and 60%, respectively. Moreover, it enhanced the memory functions in passive avoidance and Y-maze tests (132%). In conclusion, liraglutide is a putative agent for protection against DOX-induced testicular toxicity and cognitive impairment through its antioxidant, antiapoptotic, and antiautophagic effects.

Dataset Information

Testicular and epididymal toxicity induced by benzo(a)pyrene, alcohol, and their combination in Wistar rats.

Publications

Testicular and epididymal toxicity induced by benzo(a)pyrene, alcohol, and their combination in Wistar rats.

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