بررسی اثرات محافظتی سیمواستاتین بر روی تغییرات ناشی از دوکسوروبیسین در بافت بیضه و توان باروری آزمایشگاهی (IVF) موش سفید کوچک آزمایشگاهی

Therapeutic utilities of doxorubicin (DOX), an anticancer anthracycline antibiotic, are limited by its serious dose-dependent toxicity to non-target tissues such as testis. The aim of the present study was to elucidate the potential of simvastatin (SIM), a lipid lowering agent with antioxidant and anti-inflammatory activities, to attenuate DOX-induced reproductive toxicity in male mice. Male mice of 20±2 g after 7 days of acclimation were randomly divided into four groups of six mice each. DOX was administered to two groups of mice in 5 equal intraperitoneal injections over a period of 4 weeks (accumulated dose of 20 mg/kg). One of these groups received 5 equal oral doses of SIM (accumulated dose of 60 mg/kg) along with DOX. A vehicle-treated control group and a SIM control group were also included. Animals were euthanized by CO2 exposure in a special device following anesthesia with ketamine 24 hours after the last treatment. Testes and epididymides were quickly dissected out, cleared of adhering connective tissue and weighed. Further to sperm characteristics analysis, histological alterations, stereological parameters and spermatogenesis indices in histological sections of testis as well as in vitro fertilizing capacity of epididymal sperms and embryo development were also evaluated. The DOX-treated group showed significant decreases in the testes weight, spermatogenic activities (tubule differentiation, spermiation and repopulation indices) and stereological parameters (seminiferous tubules diameters and their epithelial heights) as well as many histological alterations included atrophy of seminiferous tubules, severe reduction in number of germ cells, intraepithelial vacuolization and rupture, vacuolization, vascular congestion, inflammatory cells infiltration, oedematous fluid accumulation and interstitial space widening of intertubular connective tissue. Moreover, DOX significantly decreased sperm concentration, motility and viability as well as fertilization, blastocysts and hatched blastocysts rates. Also, incidence of embryo arrest and sperm abnormality was significantly higher in DOX group. In contrast, SIM co-administration provided marked normalization in above-mentioned parameters when compared to the DOX-only treated group. These findings indicate that SIM exerts protective effects against DOX-induced reproductive disorders. Mechanisms may involve suppressing inflammation and reducing oxidative stress induced by DOX treatment.