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.
Highlights
Salinomycin (SAL), an ionophore has been shown as an effective anti-cancer agent [1]
As chemotherapy drugs are more likely to lead to infertility and have lasting effects on reproductive health it was thought opportune to evaluate SAL toxicity on male reproductive system of mice; an excellent model to monitor the potential damage induced by chemical agents [21]
Chemicals and reagents Salinomycin (≥98%), Dimethyl sulphoxide (DMSO), Nitro blue tetrazolium (NBT), Nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt (NADPH), Nicotinamide adenine dinucleotide disodium salt, (NADH), Oxidized Glutathione, Glutathione, 2-Thiobarbituric acid, Potassium dichromate, Acetone, Ethanol, Benzene, Formaldehyde, Hematoxylin and Eosin, Toluidine blue, 5,5, Dithiobis (2-nitrobenzoicacid),1-Chloro-2,4-dinitrobenzene, Protease inhibitor cocktail, N,N,N’,N’-Tetra methyl ethylenediamine (TEMED), Acrylamide, N,N’-Methylene bisacrylamide, Ponceau S, Ammonium persulphate (APS), Bromophenol blue (BPB), Sodium dodecyl sulphate (SDS), Osmium tetroxide, Paraformaldehyde, Glutaraldehyde, Phenazine methosulfate were purchased from Sigma Chemical CO (St Louis MO,USA)
Summary
Salinomycin (SAL), an ionophore has been shown as an effective anti-cancer agent [1]. It has been demonstrated that SAL is more than 100 times efficient than paclitaxel in eliminating human cancer stem cells (CSCs) [1]. Recent evidence shows that SAL is able to arrest cell cycle progression, induce apoptosis, break mitochondrial membrane potential, reverse multidrug resistance (MDR) and act synergistically with other anticancer drugs [5]. SAL effectively eliminates CSCs [1] and induces partial regression of chemotherapy-resistant cancers [7]. As chemotherapy drugs are more likely to lead to infertility and have lasting effects on reproductive health it was thought opportune to evaluate SAL toxicity on male reproductive system of mice; an excellent model to monitor the potential damage induced by chemical agents [21]
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