Vitamin D: An effective way to combat methotrexate-induced testis injury

Methotrexate (MTX) is a frequently used anticancer drug in the treatment of several diseases. However, MTX therapy causes significant cytotoxicities in testicular tissue. In this experimental study, the therapeutic utility of vitamin D (VD) on MTX induced testicular injury was investigated. Twenty-eight Wistar rats were randomly divided into four equal groups; Control, VD, MTX, and MTX+VD. Following the treatment, the rats were sacrificed and testicular tissues were removed. Testicular tissues were analyzed for routine histopathology and apoptosis. The activities of glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were evaluated by enzyme-linked immunosorbent assay and malondialdehyde (MDA) levels were measured spectrophotometrically. MTX-treatment group exhibited degeneration of spermatogenic cells, desquamation of the epithelial cells into the lumen of the tubules, lack of spermatozoa in tubule lumen, edema at interstitial area, a statistically significant decrease in both height and diameter of the tubules (p < 0.05). These values were also concordant with the Johnsen’s testicular biopsy score (JTBS). In addition, a significantly increased caspase-3 immunoreactivity was observed. Serum and testicular tissue SOD, and GSH-Px enzyme activities were found to be decreased while MDA increased in the MTX group compared to control group (p < 0.05). In the MTX + VD group, the histological injury was reduced, the caspase-3 positivity and MDA level decreased whereas activities of SOD, and GP-x enzymes were significantly increased compared to those in MTX group (p < 0.05). VD supplement may have a therapeutic utility in reducing the MTX-induced cytotoxicities in testicular tissue.

___

1. Padmanabhan S, Tripathi DN, Vikram A, et al. Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: Intervention of folic and folinic acid. Mutat Res. 2009;673:43-52.

2. Saxena AK, Dhungel S, Bhattacharya S, et al. Effect of chronic low dose of methotrexate on cellular proliferation during spermatogenesis in rats. Arch Androl. 2004;50:33-5.

3. Armagan A, Uzar E, Uz E, et al. Caffeic acid phenethyl ester modulates methotrexate-induced oxidative stress in testes of rat. Hum Exp Toxicol. 2008;27:547-52.

4. Işık A, Işılay L, Erdemli EA, et al. Methotrexate effects on rat testis using light and electron microscope. Ankara Üniversitesi Tıp Fakültesi Dergisi. 1997;50:125-9.

5. Nouri HS, Azarmi Y, Movahedin M. Effect of growth hormone on testicular dysfunction induced by methotrexate in rats. Andrologia. 2009;41:105-10.

6. Yüncü M, Bükücü N, Bayat N, et al. The effect of vitamin E and L-carnitine against methotrexate-induced injury in rat testis. Turk J Med Sci. 2015;45:517–25.

7. Wimalawansa SJ. Vitamin D deficiency: Effects on oxidative stress, epigenetics, gene regulation, and aging. Biology (Basel). 2019;8:30.

8. Norman AW, Nemere I, Zhou LX, et al. 1,25(OH)2-vitamin D3, a steroid hormone that produces biologic effects via both genomic and nongenomic pathways. J Steroid Biochem Mol Biol. 1992;41:231-40.

9. Wang H, Chen W, Li D, et al. Vitamin D and chronic diseases. Aging Dis. 2017;8:346-53.

10. Wiseman H. Vitamin D is a membrane antioxidant Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action. FEBS Lett. 1993;326:285-8.

11. Liu Y, He Y, Wang Q, et al. Vitamin D 3 supplementation improves testicular function in diabetic rats through peroxisome proliferator-activated receptor-γ/transforming growth factor-beta 1/nuclear factor-kappa B. J Diabetes Investig. 2019;10:261-71.

12. Câmara AB, Brandão IA. The relationship between vitamin D deficiency and oxidative stress can be independent of age and gender. Int J Vitam Nutr Res. 2019:1-16.

13. Hilger J, Friedel A, Herr R, et al. A systematic review of vitamin D status in populations worldwide. Br J Nutr. 2014;111:23-45.

14. Sönmez MF, Çilenk KT, Karabulut D, et al. Protective effects of propolis on methotrexate-induced testis injury in rat. Biomed Pharmacother. 2016;79:44-51.

15. El-Sheikh AA, Morsy MA, Al-Taher AY. Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexateinduced testicular damage. Life Sci. 2014;119:40-6.

16. Dabak DO, Kuloglu T, Ozercan MR. Effects of vitamin D3 (cholecalciferol) on adriamycin-induced nephrotoxicity. Renal Fail. 2009;31:400-5.

17. Johnsen SG. Testicular biopsy score count–a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones. 1970;1:2-25.

18. Keles H, Yalcin A, Aydin H. Protective effect of Vitamin D on imidaclopridinduced testicular injury in rats. Arch Med Sci. 2019;15:1-4.

19. Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-hydroxynonenal. Methods Enzymol. 1990;186:407-21.

20. Pınar N, Çakırca G, Özgür T, et al. The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats. Biomed Pharmacother. 2018;97:1486–92.

21. Yaman T, Uyar A, Kaya MS, et al. Protective effects of silymarin on methotrexate-induced damages in rat testes. Braz J Pharm Sci. 2018;54:e17529.

22. Daggulli M, Dede O, Utangac MM, et al. Protective effects of carvacrol against methotrexate-induced testicular toxicity in rats. Int J Clin Exp Med. 2014;7:5511-6.

23. Koc F, Erısgın Z, Tekelıoglu Y, et al. The effect of beta glucan on MTX induced testicular damage in rats. Biotech Histochem. 2018;93:70-5.

24. Sayılmaz A, Karabulut YY, Özgörgülü A. The histopathological evaluation of healing effects of vitamin c administered before methotrexate therapy on testicular injury induced by methotrexate. Turk J Urol. 2016;42:235-9.

25. Kim SH, Lee IC, Baek HS, et al. Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats. Food Chem Toxicol. 2014;64:110-8.

26. Eldutar E, Kandemir FM, Kucukler S, et al. Restorative effects of Chrysin pretreatment on oxidant–antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamolinduced hepatotoxicity in rats: An experimental and biochemical study. J Biochem Mol Toxicol. 2017;31:e21960.

27. Vardi N, Parlakpinar H, Ates B, et al. Antiapoptotic and antioxidant effects of β-carotene against methotrexate-induced testicular injury. Fertil Steril. 2009;92:2028-33.

28. Morsy MA, Abdel-Aziz AM, Abdel-Hafez S, et al. The possible contribution of P-glycoprotein in the protective effect of paeonol against methotrexateinduced testicular injury in rats. Pharmaceuticals (Basel). 2020;13:E223.

29. Prahalathan C, Selvakumar E, Varalakshmi P. Protective effect of lipoic acid on adriamycin-induced testicular toxicity. Clin Chim Acta. 2005;360:160-6.

30. Fujii J, Iuchi Y, Matsuki S, et al. Cooperative function of antioxidant and redox systems against oxidative stress in male reproductive tissues. Asian J Androl. 2003;5:231-42.

31. Jow WW, Schlegel PN, Cichon Z, et al. Identification and localization of copper-zinc superoxide dismutase gene expression in rat testicular development. J Androl. 1993; 14:439-47.

32. Türedi S, Yuluğ E, Alver A, et al. Effects of resveratrol on doxorubicin induced testicular damage in rats. Exp Toxicol Pathol. 2015;67:229-35.

33. Jahovic N, Cevik H, Sehirli AO, et al. Melatonin prevents methotrexateinduced hepatorenal oxidative injury in rats. J Pineal Res. 2003;34:282-7.

34. Luong KVQ, Nguyen LTH, Nguyen DNP. The role of vitamin D in protecting type 1 diabetes mellitus. Diabetes Metab Res Rev. 2005;21:338-46.

35. Menegaz D, Rosso A, Royer C, et al. Role of 1alpha, 25 (OH)2 vitamin D3 on alpha-[1-14C] MeAIB accumulation in immature rat testis. Steroids. 2009;74:264-9.

36. Jørgensen A, Jensen MB, Nielsen JE, et al. Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model. J Steroid Biochem Mol Biol. 2013;136:238-46.

37. Ding C, Wang Q, Hao Y, et al. Vitamin D supplement improved testicular function in diabetic rats. Biochem Biophys Res Commun. 2016;473:161-7.

38. Kinuta K, Tanaka H, Moriwake T, et al. Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads. Endocrinology. 2000;141:1317-24.

39. BaSalamah MA, Abdelghany AH, El-Boshy M, et al. Vitamin D alleviates lead induced renal and testicular injuries by immunomodulatory and antioxidant mechanisms in rats. Sci Rep. 2018;8:1-13.

40. Hamden K, Carreau S, Jamoussi K, et al. Inhibitory effects of 1alpha, 25dihydroxyvitamin D3 and Ajuga iva extract on oxidative stress, toxicity and hypo-fertility in diabetic rat testes. J Physiol Biochem. 2008;64:231-9..
Medicine Science-Cover
  • ISSN: 2147-0634
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 2012
  • Yayıncı: Effect Publishing Agency ( EPA )
Sayıdaki Diğer Makaleler

Single-center retrospective evaluation of short and long-term efficacy of intragastric balloon placement in obesity treatment

Ferit ÇELİK, Ali ŞENKAYA, Füsun SAYGILI, Özgür FIRAT, Hayriye ELBİ, Rukiye VARDAR

Approach of ACLS for stroke patients

Adel Hamed ELBAIH, Mahmoud DIBAS

Seroprevalence of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus in patients undergoing nasopharyngeal biopsy

Muhammet YILDIZ, Erdem Atalay ÇETİNKAYA, Ömer Tarık SELÇUK, Hülya EYİGÖR, N. Didem YILMAZ, Nuray ENSARİ, Nilgün GÜR, Özer Erdem GÜR

Vitamin D: An effective way to combat methotrexate-induced testis injury

Alper YALÇIN, Hasan AYDIN, Ahmet TÜRK, Mevlüt DOĞUKAN, Nadire ESER, Muhittin ÖNDERCİ, Fatih ÜÇKARDEŞ, Atila YOLDAS, Erkan YILMAZ, Hikmet KELEŞ

Domestic violence and affectıng factors among married women aged between 15-49 Years

Sema ÇİFTÇİ, Yasemin AÇIK

1800MHz Radiofrequency electromagnetic radiation: Does it affect heat shock genes expression levels in the rat brain?

Badel ARSLAN, Nurcan ARAS, Gül YAŞ, Ayşegül ÇETİNKAYA

Mid-term results after isolated digital nerve repair in patients presenting with hand injury

Sadullah TURHAN, Aydoğan AŞKIN, Özkan GÖRGÜLÜ

Attitudes of nursing and medical school students towards ageism

Medine KOÇ, Aygül KISSAL, Rıza ÇITIL, Yalçın ÖNDER

Research into Hepatitis B seroprevalence among children aged 1-18 years in Usak province and comparison with seroprevalence in other provinces and Turkey

Selçuk GÜREL, Mehmet UÇAR

Investigation of rotavirus and enteric adenovirus antigens in children between 0-14 years old

Fatma AVCIOĞLU, Mustafa BEHÇET