Abstract

Epirubicin is an anthracycline drug used in the treatment of different cancers and in combination with other medications. Toxicity of this drug have been reported but little is known about its effect on epididymis thus, this study aimed at evaluating the possible adverse effect of epirubicin on the epididymis tissue using mouse model. Potential ameliorating effect of quercetin from onion extract was also investigated. In this study, the mice used were divided into six groups. Mice in group I received vehicle and served as control; group II-5 mg/kg/bwt/day, III-10 mg/kg/bwt & group IV- 20 mg/kg/bwt. Mice in group V received 10 mg/kg/bwt Quercetin (standard) + 20 mg/kg/bwt while group VI were co-treated with 10 mg/kg/bwt Onion extracts + 20 mg/kg/bwt for fourteen days. Activities of some vital biochemical biomarker enzymes, sperm parameters and epididymal histology were evaluated. In this study, significant (p<0.05) depletion of sperm count and motility was measured, raised ROS and MDA with simultaneous depletions of the antioxidant enzymes was evaluated. Disruption of epithelium and vacuolization were observed in the cauda epididymis. However, appreciable recovery was seen in both groups V and VI that were co-treated with either quercetin or onion extract. Conclusively, this study reports generation of oxidative stress in epididymis leading to spermotozoa cytotoxicity in epirubicin treated mice. The studies also revealed that quercetin from onion extract can help to reduce the deleterious effect of epirubicin treatment.

Keywords: Epididymal Cytotoxicity; Quercetin; Epirubicin; Swiss Albino Mice

References

1. Gewirtz DA. “A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin”. Biochemical Pharmacology7 (1999): 727-741.
2. Attia SM., et al. “Aneugenic effects of epirubicin in somatic and germinal cells of male mice”. PloS one10 (2014): e109942.
3. Smith LA., et al. “Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials”. BMC Cancer 10 (2010): 337.
4. Praga C., et al. “Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide”. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology18 (2005): 4179-4191.
5. R Lahtinen., et al. “Cardiotoxicity of epirubicin and doxorubicin: A double‐blind randomized study”. European Journal of Haematology5 (1991).
6. Sen AK., et al. “Genotoxic effect of epirubicin in mouse bone marrow in vivo. Zeitschrift fur Naturforschung C”. Journal of Biosciences3-4 (2010): 211-217.
7. Arung ET., et al. “Anti- melanogenesis properties of quercetin- and its derivative-rich extract from Allium cepa”. Food Chemistry3 (2011): 1024-1028.
8. Hamauzu Y., et al. “Physicochemical characteristics of rapidly dried onion powder and its anti-atherogenic effect on rats fed high-fat diet”. Food Chemistry 3 (2011): 810-815.
9. Jimenez L., et al. “Effect of γ- radiation on green onion DNA integrity: role of ascorbic acid and polyphenols against nucleic acid damage”. Food Chemistry 3 (2011): 735-741.
10. Tripathi PC and Lawande KE. “Onion storage in tropical region: A review”. Current Horticulture2 (2019): 15-27.
11. Slimestad R., et al. “Onions: a source of unique dietary flavonoids”. Journal of Agricultural and Food Chemistry 25 (2007): 10067-10080.
12. Fujiwara Y., et al. “Onionin A, a sulfur-containing compound isolated from onions, impairs tumor development and lung metastasis by inhibiting the protumoral and immunosuppressive functions of myeloid cells”. Molecular Nutrition and Food Research 11 (2016): 2467-2480.
13. Junko Tsuboki., et al. “Onionin A inhibits ovarian cancer progression by suppressing cancer cell proliferation and the protumour function of macrophages”. Scientific Reports 6 (2016): 29588.
14. Mahmoud Hashemzaei., et al. “Anticancer and apoptosis‑inducing effects of quercetin in vitro and in vivo”. Oncology Reports 2 (2017): 819-828.
15. Junjian Wang and Shaoxiang Huang. “Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway”. Experimental and Therapeutic Medicine 3 (2017): 2667-2673.
16. Ojo OO., et al. “Therapeutic effect of Quercetin against Methotrexate-induced male infertility”. Journal of Toxicology and Pharmacology 1 (2019): 023.
17. Guo-Qing S., et al. “Isolation of flavonoids from onion skin and their effects on K562 cell viability”. Bangladesh Journal of Pharmacology 11 (2016): S18-S25.
18. Marklund S and Marklund G. “Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase”. European Journal of Biochemistry 47 (1974): 469-474.
19. Sedlak J and Lindsay RH. “Estimation of Total Protein-Bound, and Nonprotein Sulfhydryl Groups in Tissue with Ellman’s Reagent”. Analytical Biochemistry 25 (1968): 1192-1205.
20. Hayashi M Sutou., et al. “Difference between intraperitoneal and oral gavages application in the micronucleus test The 3rd collaborative study by CSGMT/JEMS MMS”. Mutation Research 223 (1989): 329-344.
21. Verma RJ and Nair A. “Ameliorative effect of vitamin E on aflatoxin-induced changes in accessory sex organs of male mice”. Toxicology International2 (2003): 76-80.
22. , et al. “Metabolism and testicular toxicity of 1,3-dinitrobenzene in rats of different ages”. Fundamental and Applied Toxicology 23 (1994): 439-446.
23. , et al. “Normal mice develop from oocytes injected with spermatozoa with grossly misshapen heads”. Biology of Reproduction 55 (1996): 709-714.
24. Vidal O. “Histology of the human testis from neonatal period to adolescence”. In: Rosemberg E, Paulsen, C.A., eds. The human testis. Advances in experimental medicine and biology. New York, Plenum Press. 10 (1970): 95-111.
25. Ojo OO., et al. “Dose-Dependent Adverse Effects of Salinomycin on Male Reproductive Organs and Fertility in Mice”. PLoS ONE7 (2013): e69086.
26. Lokendra Kushwah., et al. “Evaluating the Ameliorative Potential of Quercetin against the Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats”. Pulmonary Medicine (2013): 921724.
27. Olajumoke Omolara Ojo., et al. “Therapeutic Effect of Quercetin against Methotrexate - Induced Male Infertility”. Journal of Toxicology and Pharmacology 3 (2019): 023.
28. Olajumoke Omolara Ojo., et al. “Protective effect of onion extract and quercetin on capecitabine induced cytotoxicity and genotoxicity in germ cells of mice”. European Journal of Pharmaceutical and Medical Research7 (2020): 19-28.
29. Martin RH., et al. “Analysis of aneuploidy for chromosomes 13, 21, X and Y by multicolour fluorescence in situ hybridisation (FISH) in a 47,XYY male”. Zygote 2 (1999): 131-134.
30. Attia SM., et al. “Utility of Dexrazoxane for the Attenuation of Epirubicin-Induced Genetic Alterations in Mouse Germ Cells”. PLoS ONE 9 (2016): e0163703.
31. Cavallini G. “Male idiopathic oligoasthenoteratozoospermia”. Asian Journal of Andrology 2 (2006): 143-157.
32. Grankvist K and Henriksson R. “Doxorubicin and epirubicin iron-induced generation of free radicals in vitro. A comparative study”. Bioscience Reports8 (1987): 653-658.
33. Sekar Suresh., et al. “Effect of Mucuna pruriens on oxidative stress mediated damage in aged rat sperm”. International Journal of Androlog1 (2010): 22-32.
34. Giorgio M., et al. “Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals?” Nature Reviews Molecular Cell Biology 8 (2007): 722-728.
35. Syntin P and Robaire B. “Sperm structural and motility changes during aging in the brown Norway rat”. Journal of Andrology 22 (2001): 235-244.