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Tajabadi, E., Javadi, A., Ahmadi Azar, N., Najafi, M., Shirazi, A., Shabeeb, D., & Eleojo Musa, A. (2020). Radioprotective effect of a combination of melatonin and metformin on mice spermatogenesis: A histological study. International Journal of Reproductive BioMedicine (IJRM), 18(12), 1073–1080. https://doi.org/10.18502/ijrm.v18i12.8029
https://doi.org/10.18502/ijrm.v18i12.8029
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- Cited by 5 articles
authors
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Elham Tajabadi
Elham Tajabadi
Department of Medical Radiation Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
-
Abdolreza Javadi
Abdolreza Javadi
Department of Pathology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Nasim Ahmadi Azar
Nasim Ahmadi Azar
Department of Medical Radiation Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
-
Masoud Najafi
Masoud Najafi
Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Alireza Shirazi
Alireza Shirazi
Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Dheyauldeen Shabeeb
Dheyauldeen Shabeeb
Department of Physiology, College of Medicine, University of Misan, Misan, Iraq
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Ahmed Eleojo Musa
Ahmed Eleojo Musa
Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Published Date
- Dec 21, 2020
Radioprotective effect of a combination of melatonin and metformin on mice spermatogenesis: A histological study
Abstract
Background: The spermatogenesis system includes highly radiosensitive cells. Hence, this system is a potential target for toxic effects of ionizing radiation during radiotherapy of abdomen and pelvis cancers, as well as after accidental radiation events. Accordingly, metformin and melatonin are two important radioprotectors that have shown an ability to prevent cell death through neutralization of free radicals and stimulating DNA damage responses.
Objective: To evaluate the radioprotective effects of melatonin and metformin on mice spermatogenesis when administered alone or as a combination.
Materials and Methods: In this histological Study, 40 (6-8 wk, 30 gr) NMRI mice were divided into 8 groups (n = 5/each) as control, metformin, melatonin, melatonin + metformin, radiation, radiation + melatonin, radiation + metformin, and radiation + melatonin + metformin. 37 days after the irradiation, the testicular tissues were collected for histological evaluation.
Results: Single administration of melatonin could ameliorate effectively radiation toxicity in mice testis. Metformin showed radioprotective effects on some parameters such as the numbers of spermatogonia and mature sperms. Interestingly, the melatonin and metformin combination reversed the reduced number of sperms rather than single drug administration.
Conclusion: The combination of melatonin with metformin can protect mice spermatogenesis against ionizing radiation more effectively compared to the single forms of these drugs.
Key words: Radiation, Testis, Leydig cells, Melatonin, Metformin, Spermatogenesis.
References
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[11] Farhood B, Aliasgharzadeh A, Amini P, Rezaeyan A, Tavassoli A, Motevaseli E, et al. Mitigation of radiationinduced lung pneumonitis and fibrosis using metformin and melatonin: A histopathological study. Medicina 2019; 55: 417–426.
[12] Mahdavi M, Mozdarani H. Protective effects of famotidine and vitamin C against radiation induced cellular damage in mouse spermatogenesis process. Iran J Radiat Res 2011; 8: 223–230.
[13] Asghari A, Akbari Gh, Meghdadi A, Mortazavi P. Effects of melatonin and metformin co-administration on testicular ischemia/reperfusion injury in rats. J Pediatr Urol 2016; 12: 410. e1–e7.
[14] Ghanbari E, Nejati V, Khazaei M. Antioxidant and protective effects of Royal jelly on histopathological changes in testis of diabetic rats. Int J Reprod Biomed 2016; 14: 519–526.
[15] Du Zh, Xu Sh, Hu Sh, Yang H, Zhou Zh, Sidhu K, et al. Melatonin attenuates detrimental effects of diabetes on the niche of mouse spermatogonial stem cells by maintaining Leydig cells. Cell Death & Disease 2018; 9: 968–982.
[16] Najafi M, Cheki M, Amini P, Javadi A, Shabeeb D, Eleojo Musa A. Evaluating the protective effect of resveratrol, Q10, and alpha-lipoic acid on radiation-induced mice spermatogenesis injury: A histopathological study. Int J Reprod BioMed 2019; 17: 907–914.
[17] Yamashiro H, Abe Y, Fukuda T, Kino Y, Kawaguchi I, Kuwahara Y, et al. Effects of radioactive caesium on bull testes after the Fukushima nuclear plant accident. Sci Reports 2013; 3: 2850–2855.
[18] Meistrich ML. Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril 2013; 100: 1180–1186.
[19] Farhood B, Mortezaee K, Haghi-Aminjan H, Khanlarkhani N, Salehi E, Shabani Nashtaei M, et al. A systematic review of radiation-induced testicular toxicities following radiotherapy for prostate cancer. J Cell Physiol 2019; 234: 14828–14837.
[20] Tamminga J, Kovalchuk O. Role of DNA damage and epigenetic DNA methylation changes in radiation-induced genomic instability and bystander effects in germline in vivo. Curr Mol Pharmacol 2011; 4: 115–125.
[21] Møller AP, Surai P, Mousseau TA. Antioxidants, radiation and mutation as revealed by sperm abnormality in barn swallows from Chernobyl. Proc Biol Sci 2005; 272: 247– 253.
[22] Kumar D, Salian SR, Kalthur G, Uppangala Sh, Kumari S, Challapalli S, et al. Semen abnormalities, sperm DNA damage and global hypermethylation in health workers occupationally exposed to ionizing radiation. PLoS One 2013; 8: e69927. 1–8.
[23] Songthaveesin C, Saikhun J, Kitiyanant Y, Pavasuthipaisit K. Radio-protective effect of vitamin E on spermatogenesis in mice exposed to g-irradiation: a flow cytometric study. Asian J Androl 2004; 6: 331–336.
[24] Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med 1998; 30: 122–130.
[25] Bonomini F, Borsani E, Favero G, Rodella LF, Rezzani R. Dietary melatonin supplementation could Be a promising preventing/therapeutic approach for a variety of liver diseases. Nutrients 2018; 10: 1135–1159.
[26] Aricigil M, Dundar MA, Yucel A, Eryilmaz MA, Aktan M, Alan MA, et al. Melatonin prevents possible radiotherapyinduced thyroid injury. Int J Radiat Biol 2017; 93: 1350– 1356.
[27] Zetner D, Andersen LPH, Rosenberg J. Melatonin as protection against radiation injury: A systematic review. Drug Res 2016; 66: 281–296.
[28] Take G, Erdogan D, Helvacioglu F, Göktas G, Ozbey G, Uluoglu C, et al. Effect of melatonin and time of administration on irradiation-induced damage to rat testes. Brazil J Med Biol Res 2009; 42: 621–628.
[29] Khan Sh, Adhikari JS, Rizvi MA, Chaudhury NK. Radioprotective potential of melatonin against 60 Co γ-ray-induced testicular injury in male C57BL/6 mice. J Biomed Sci 2015; 22: 61–75.
[30] Mohamad Ghasemi F, Faghani M, Khajehjahromi S, Bahadori M, Nasiri E E, Hemadi M. Effect of melatonin on proliferative activity and apoptosis in spermatogenic cells in mouse under chemotherapy. J Reprod Contracept 2010; 21: 79–94.
[31] Dogan Turacli I, Candar T, Yuksel EB, Kalay S, Oguz AK, Demirtas S. Potential effects of metformin in DNA BER system based on oxidative status in type 2 diabetes. Biochimie 2018; 154: 62–68.
[32] Ouslimani N, Peynet J, Bonnefont-Rousselot D, Thérond P, Legrand A, Beaudeux JL. Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism 2005; 54: 829–834.
[33] Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res 2019; 11: 3295–3313.
[34] Nasri H, Rafieian-Kopaei M. Metformin: current knowledge. J Res Med Sci 2014; 19: 658–664.
[35] Sarıbal D, Erdem E, Güngör-Ordueri NE, Usta A, Karakuş C, Karacan M. Metformin decreases testicular damages following ischaemia/reperfusion injury in rats. Andrologia 2020; 52: e13481.
[2] Barnett GC, West CML, Dunning AM, Elliott RM, Coles CE, Pharoah PDP, et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer 2009; 9: 134–142.
[3] Mahmood J, Jelveh S, Calveley V, Zaidi A, Doctrow SR, Hill RP. Mitigation of lung injury after accidental exposure to radiation. Radiat Res 2011; 176: 770–780.
[4] Dorr H, Meineke V. Acute radiation syndrome caused by accidental radiation exposure - therapeutic principles. BMC Med 2011; 9: 126–131.
[5] Marjault HB, Allemand I. Consequences of irradiation on adult spermatogenesis: Between infertility and hereditary risk. Mutat Res 2016; 770: 340–348.
[6] Grewenig A, Schuler N, Rübe CE. Persistent DNA damage in spermatogonial stem cells after fractionated low-dose irradiation of testicular tissue. Int J Radiat Oncol Biol Phys 2015; 92: 1123–1131.
[7] Takino S, Yamashiro H, Sugano Y, Fujishima Y, Nakata A, Kasai K, et al. Analysis of the effect of chronic and lowdose radiation exposure on spermatogenic cells of male large Japanese field mice (Apodemus speciosus) after the Fukushima Daiichi nuclear power plant accident. Radiat Res 2017; 187: 161–168.
[8] Fukunaga H, Butterworth KT, Yokoya A, Ogawa T, Prise KM. Low-dose radiation-induced risk in spermatogenesis. Int J Radiat Biol 2017; 93: 1291–1298.
[9] Shakhov AN, Singh VK, Bone F, Cheney A, Kononov Y, Krasnov P, et al. Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2). PloS One 2012; 7: e33044. 1–12.
[10] Najafi M, Cheki M, Hassanzadeh Gh, Amini P, Shabeeb D, Musa AE. The radioprotective effect of combination of melatonin and metformin on rat duodenum damage induced by ionizing radiation: A histological study. Adv Biomed Res 2019; 8: 51–61.
[11] Farhood B, Aliasgharzadeh A, Amini P, Rezaeyan A, Tavassoli A, Motevaseli E, et al. Mitigation of radiationinduced lung pneumonitis and fibrosis using metformin and melatonin: A histopathological study. Medicina 2019; 55: 417–426.
[12] Mahdavi M, Mozdarani H. Protective effects of famotidine and vitamin C against radiation induced cellular damage in mouse spermatogenesis process. Iran J Radiat Res 2011; 8: 223–230.
[13] Asghari A, Akbari Gh, Meghdadi A, Mortazavi P. Effects of melatonin and metformin co-administration on testicular ischemia/reperfusion injury in rats. J Pediatr Urol 2016; 12: 410. e1–e7.
[14] Ghanbari E, Nejati V, Khazaei M. Antioxidant and protective effects of Royal jelly on histopathological changes in testis of diabetic rats. Int J Reprod Biomed 2016; 14: 519–526.
[15] Du Zh, Xu Sh, Hu Sh, Yang H, Zhou Zh, Sidhu K, et al. Melatonin attenuates detrimental effects of diabetes on the niche of mouse spermatogonial stem cells by maintaining Leydig cells. Cell Death & Disease 2018; 9: 968–982.
[16] Najafi M, Cheki M, Amini P, Javadi A, Shabeeb D, Eleojo Musa A. Evaluating the protective effect of resveratrol, Q10, and alpha-lipoic acid on radiation-induced mice spermatogenesis injury: A histopathological study. Int J Reprod BioMed 2019; 17: 907–914.
[17] Yamashiro H, Abe Y, Fukuda T, Kino Y, Kawaguchi I, Kuwahara Y, et al. Effects of radioactive caesium on bull testes after the Fukushima nuclear plant accident. Sci Reports 2013; 3: 2850–2855.
[18] Meistrich ML. Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril 2013; 100: 1180–1186.
[19] Farhood B, Mortezaee K, Haghi-Aminjan H, Khanlarkhani N, Salehi E, Shabani Nashtaei M, et al. A systematic review of radiation-induced testicular toxicities following radiotherapy for prostate cancer. J Cell Physiol 2019; 234: 14828–14837.
[20] Tamminga J, Kovalchuk O. Role of DNA damage and epigenetic DNA methylation changes in radiation-induced genomic instability and bystander effects in germline in vivo. Curr Mol Pharmacol 2011; 4: 115–125.
[21] Møller AP, Surai P, Mousseau TA. Antioxidants, radiation and mutation as revealed by sperm abnormality in barn swallows from Chernobyl. Proc Biol Sci 2005; 272: 247– 253.
[22] Kumar D, Salian SR, Kalthur G, Uppangala Sh, Kumari S, Challapalli S, et al. Semen abnormalities, sperm DNA damage and global hypermethylation in health workers occupationally exposed to ionizing radiation. PLoS One 2013; 8: e69927. 1–8.
[23] Songthaveesin C, Saikhun J, Kitiyanant Y, Pavasuthipaisit K. Radio-protective effect of vitamin E on spermatogenesis in mice exposed to g-irradiation: a flow cytometric study. Asian J Androl 2004; 6: 331–336.
[24] Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med 1998; 30: 122–130.
[25] Bonomini F, Borsani E, Favero G, Rodella LF, Rezzani R. Dietary melatonin supplementation could Be a promising preventing/therapeutic approach for a variety of liver diseases. Nutrients 2018; 10: 1135–1159.
[26] Aricigil M, Dundar MA, Yucel A, Eryilmaz MA, Aktan M, Alan MA, et al. Melatonin prevents possible radiotherapyinduced thyroid injury. Int J Radiat Biol 2017; 93: 1350– 1356.
[27] Zetner D, Andersen LPH, Rosenberg J. Melatonin as protection against radiation injury: A systematic review. Drug Res 2016; 66: 281–296.
[28] Take G, Erdogan D, Helvacioglu F, Göktas G, Ozbey G, Uluoglu C, et al. Effect of melatonin and time of administration on irradiation-induced damage to rat testes. Brazil J Med Biol Res 2009; 42: 621–628.
[29] Khan Sh, Adhikari JS, Rizvi MA, Chaudhury NK. Radioprotective potential of melatonin against 60 Co γ-ray-induced testicular injury in male C57BL/6 mice. J Biomed Sci 2015; 22: 61–75.
[30] Mohamad Ghasemi F, Faghani M, Khajehjahromi S, Bahadori M, Nasiri E E, Hemadi M. Effect of melatonin on proliferative activity and apoptosis in spermatogenic cells in mouse under chemotherapy. J Reprod Contracept 2010; 21: 79–94.
[31] Dogan Turacli I, Candar T, Yuksel EB, Kalay S, Oguz AK, Demirtas S. Potential effects of metformin in DNA BER system based on oxidative status in type 2 diabetes. Biochimie 2018; 154: 62–68.
[32] Ouslimani N, Peynet J, Bonnefont-Rousselot D, Thérond P, Legrand A, Beaudeux JL. Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism 2005; 54: 829–834.
[33] Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res 2019; 11: 3295–3313.
[34] Nasri H, Rafieian-Kopaei M. Metformin: current knowledge. J Res Med Sci 2014; 19: 658–664.
[35] Sarıbal D, Erdem E, Güngör-Ordueri NE, Usta A, Karakuş C, Karacan M. Metformin decreases testicular damages following ischaemia/reperfusion injury in rats. Andrologia 2020; 52: e13481.