BackgroundAmifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs. Doxorubicin, a potent anticancer anthracycline, is known to produce spermatogenic damage even in low doses. Although some studies have suggested that amifostine does not confer protection to doxorubicin-induced testicular damage, schedules and age of treatment have different approach depending on the protocol. Thus, we proposed to investigate the potential cytoprotective action of amifostine against the damage provoked by doxorubicin to prepubertal rat testes (30-day-old) by assessing some macro and microscopic morphometric parameters 15, 30 and 60 days after the treatment; for fertility evaluation, quantitative analyses of sperm parameters and reproductive competence in the adult phase were also carried out.MethodsThirty-day-old male rats were distributed into four groups: Doxorubicin (5 mg/kg), Amifostine (400 mg/kg), Amifostine/Doxorubicin (amifostine 15 minutes before doxorubicin) and Sham Control (0.9% saline solution). "Standard One Way Anova" parametric and "Anova on Ranks" non-parametric tests were applied according to the behavior of the obtained data; significant differences were considered when p < 0.05.ResultsThe rats killed 30 and 60 days after doxorubicin treatment showed diminution of seminiferous epithelium height and reduction on the frequency of tubular sections containing at least one type of differentiated spermatogonia; reduction of sperm concentration and motility and an increase of sperm anomalous forms where observed in doxorubicin-treated animals. All these parameters were improved in the Amifostine/Doxorubicin group only when compared to Doxorubicin group. Such reduction, however, still remained below the values obtained from the Sham Control group. Nevertheless, the reproductive competence of doxorubicin-treated rats was not improved by amifostine pre-administration.ConclusionsThese results suggest that amifostine promotes a significant reduction of the doxorubicin long-term side effects on the seminiferous epithelium of prepubertal rats, which is reflected in the epidydimal fluid parameters in the adult phase. However, fertility status results suggest that such protection may not be effective against sperm DNA content damage. Further investigation of sperm DNA integrity must be carried out using amifostine and doxorubicin-treated experimental models.
These results raise a concern about the effects of the association of these two drugs on the germ cell genome. Amifostine-doxorubicin-exposed rat spermatogonia produced long-term damage on sperm DNA, compromised conceptus development and reduced pregnancy outcome.
The progression of diabetes mellitus leads to several complications including overproduction of reactive oxygen species and reproductive alterations. As resveratrol (RES) is a powerful anti-oxidant and an anti-apoptotic compound, we hypothesized that side effects of type-1 diabetes (DM1) on male reproduction could be reduced by the RES treatment. Eighty-four prepubertal male rats were distributed into seven groups: sham-control (SC), RES-treated (R), resveratrol-vehicle-treated (RV), diabetic (D), diabetic-insulin-treated (DI), diabetic-RES-treated (DR), diabetic-insulin and RES-treated (DIR). DM1 was induced by a single intraperitoneal streptozotocin (STZ) injection (65 mg/kg) on the 30th day postpartum (dpp). Animals of DR, DIR and R groups received 150 mg/day of RES by gavage for 43 consecutive days (from the 33 to 75 dpp). DI and DIR rats received subcutaneous injections of insulin (1 U/100 g b.w./day) from 5th day after the DM1 induction. The blood glucose level was monitored. At 75 dpp, the euthanasia was performed for morphometric and biometric testicular analyses, spermatic evaluation and hormonal doses. In the D group, the blood glucose level was higher than in the DR, DI and DIR groups. Besides morphometric testicular measurements, testosterone and estradiol doses were lower in D group than in DR and DIR groups; LH dose was also lower than in DR. The preputial separation age was delayed in diabetes-induced groups. The DR and DIR groups showed an improvement in sperm mitochondrial activity, epididymal sperm counts and the frequency of morphologically normal sperms. RES treatment improved glycaemic level, sperm quantitative and qualitative parameters and the hormonal profile in DM1-induced rats and seems to be a good reproductive protector.
The aim of this study was to investigate the protective action of resveratrol against the reproductive damage caused by left-sided experimental varicocele. There was a reduction of testicular major axis in the varicocele group when compared with the other groups; the testicular volume was reduced in varicocele group in comparison to the sham-control and resveratrol groups. The frequency of morphologically abnormal sperm was higher in varicocele and varicocele treated with resveratrol groups than in sham-control and resveratrol groups. The frequency of sperm with 100% of mitochondrial activity and normal acrosome integrity were lower in varicocele group than in varicocele treated with resveratrol, sham-control and resveratrol groups. Sperm motility was also reduced in varicocele group than in other groups. The sperm DNA fragmentation was higher in varicocele group than in other groups.
Doxorubicin has been largely used in anticancer therapy in adults, adolescents, and children. The efficacy of l-carnitine as an antioxidant substance has been confirmed both in humans and rats. Carnitine, present in testis and epididymis, is involved in sperm maturation. It is also effective in infertility treatment. As a continuation of a previous study, we evaluated whether some spermatic qualitative parameters, DNA integrity, chromatin structure, and fertility status, could be ameliorated by the carnitine treatment in adult rats, which were subsequently exposed to doxorubicin at pre-puberty. Pre-pubertal male rats were distributed into four groups: Sham Control; Doxorubicin; l-carnitine; l-carnitine + Doxorubicin (l-carnitine injected 1 h before doxorubicin). At 100 days of age, all groups were reassigned into two sets: One set was submitted to the evaluation of sperm motility, acrosome integrity, mitochondrial activity, sperm chromatin structure analysis (SCSA), and evaluation of the oxidative stress. The other set of rats was destined to the evaluation of reproductive competence. The percentage of spermatozoa with intact acrosome integrity was higher in the Carnitine+Doxorubicin group when compared with the Doxorubicin group. However, sperm motility and mitochondrial activity were not improved by carnitine pre-treatment. Both values of malondialdehyde and nitrite (indirect measurement of nitric oxide) concentrations were statistically higher in the only doxorubicin-treated group when compared to the Carnitine + Doxorubicin group. Fertility index and implantation rate were lower in Doxorubicin group, when compared to Carnitine + Doxorubicin group. Moreover, the percentage of spermatozoa with damaged DNA was higher in the Doxorubicin-treated group when compared to the Carnitine+Doxorubicin group. l-carnitine, when administered before doxorubicin, partially preserved the acrosome integrity, an important feature related to sperm fertilization ability that positively correlated with the reproductive competence and sperm DNA integrity at adulthood. In conclusion, l-carnitine attenuated the long-term alterations caused by doxorubicin in the germ cells and improved male reproductive capacity in adulthood.
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