Abstract
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.
Highlights
Amifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs
Histopathology of the seminiferous epithelium Amifostine-treated rats of the A and AD groups showed preserved seminiferous epithelium, with normal morphology, similar to those observed in rats of the Sham control group, at the corresponding ages (Figs. 1A, B, E, 2A, B, E, F, 3A, B, E and 3F)
Round spermatid nuclei with condensed peripheral chromatin suggesting apoptosis were observed in tubular sections where the seminiferous epithelium was apparently more preserved (Fig. 2D)
Summary
Amifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs. A perfect chemotherapeutic treatment would selectively attack tumor cells without causing toxicity on normal tissues This ideal selectivity has not yet been reached by traditional chemotherapy, which is known to affect both neoplastic and proliferating normal. Doxorubicin has recognized effectiveness against solid and non-solid malignant tumors and is used in oncology protocols against malignancies such as Hodgkin disease, childhood leukemia and testicular cancer, which commonly affect young patients and children [3,6]. It is responsible for long and shortterm male infertility [7,8]. It has been recently found that doxorubicin interferes with an important molecule involved in chromosome stability and transcription, the DNA methyl-transferase 1 - DNMT1 [11], inducing apoptosis
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