Dose-Dependent Adverse Effects of Salinomycin on Male Reproductive Organs and Fertility in Mice

Abstract

Salinomycin is used as an antibiotic in animal husbandry. Its implication in cancer therapy has recently been proposed. Present study evaluated the toxic effects of Salinomycin on male reproductive system of mice. Doses of 1, 3 or 5 mg/kg of Salinomycin were administered daily for 28 days. Half of the mice were sacrificed after 24 h of the last treatment and other half were sacrificed 28 days after withdrawal of treatment. Effects of SAL on body and reproductive organ weights were studied. Histoarchitecture of testis and epididymis was evaluated along with ultrastructural changes in Leydig cells. Serum and testicular testosterone and luteinizing hormones were estimated. Superoxide dismutase, reduced glutathione, lipid peroxidation, catalase and lactate dehydrogenase activities were measured. Spermatozoa count, morphology, motility and fertility were evaluated. Expression patterns of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side chain cleavage proteins (CYP11A1) were assessed by Western blotting. Salinomycin treatment was lethal to few mice and retarded body growth in others with decreased weight of testes and seminal vesicles in a dose dependent manner. Seminiferous tubules in testes were disrupted and the epithelium of epididymis showed frequent occurrence of vacuolization and necrosis. Leydig cells showed hypertrophied cytoplasm with shrunken nuclei, condensed mitochondria, proliferated endoplasmic reticulum and increased number of lipid droplets. Salinomycin decreased motility and spermatozoa count with increased number of abnormal spermatozoa leading to infertility. The testosterone and luteinizing hormone levels were decreased in testis but increased in serum at higher doses. Depletion of superoxide dismutase and reduced glutathione with increased lipid peroxidation in both testis and epididymis indicated generation of oxidative stress. Suppressed expression of StAR and CYP11A1 proteins indicates inhibition of steroidogenesis. Spermatogenesis was however observed in testis 28 days after Salinomycin withdrawal. The results indicate reversible dose-dependent adverse effects of Salinomycin on male reproductive system of mice.

Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells

“…Interestingly, SAL 5 mg/kg had low systemic toxicity but induced neurotoxic effects which could be reduced using mitochondrial Na + /Ca 2+ exchanger inhibitors without affecting the antitumor effects. In line with this, studies in mice indicated that SAL has reversible dose-dependent adverse effects on the male reproductive system [67]. Therefore, the poor water solubility and its toxicity still represent important limitations for clinical use of SAL, pointing out that SAL derivatives and/or nanoparticles are to be developed to reach higher local concentrations at tumor site [68].…”

The Effect of Indonesian Velvet Bean Extract on the Fertility of Albino Male Mice

“…Believed to have relatively lower negative side effects, herbal is more preferable than synthetic medicine [16][17][18]. L-Dopa is an important component of velvet beans [22].…”

T-2 toxin inhibits gene expression and activity of key steroidogenesis enzymes in mouse Leydig cells

“…Along with some important enzymes, like cholesterol side-chain cleavage enzyme (P450scc) and 3b-hydroxysteroid dehydrogenase/isomerase (3b-HSD), several proteins play key roles in steroidogenesis. Among these, the role of steroidogenic acute regulatory (StAR) protein appears to transfer cholesterol from cellular stores to the inner mitochondrial membrane, where cholesterol is enzymatically converted to pregnenolone by P450scc (Ojo et al, 2013;Anuka et al, 2013;Stocco and Clark, 1996;Stocco, 1999;Strauss et al, 1999;Bose et al, 2002). The conversion of pregnenolone to progesterone is a step metabolized by 3b-HSD.…”