Effect of exogenous Melatonin administration on Spermatogenesis in chronic unpredictable stress rat model

• İshak Gökçek Hatay Mustafa Kemal University, Faculty of Veterinary Science, Department of Physiology. Hatay, Turkey https://orcid.org/
• Leyla Aydın Ankara Yıldırım Beyazıt University, Faculty of Medicine, Department of Physiology. Ankara, Turkey
• Mustafa Cellat Hatay Mustafa Kemal University, Faculty of Veterinary Science, Department of Physiology. Hatay, Turkey
• İlker Yavaş Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Reproduction and Artificial Insemination. Hatay, Turkey
• Tuncer Kutlu Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Pathology. Hatay, Turkey

DOI: https://doi.org/10.52973/rcfcv-e33288

Keywords: Chronic stress, spermatogenesis, Melatonin, antioxidant, anti–inflammatory cytokines

Abstract

This study investigated the hormonal, inflammatory, oxidant–antioxidant, and histopathological effects of exogenous Melatonin administration on Spermatogenesis in rats' chronic unpredictable stress model (CUSM). In the study, stress caused a decrease in follicle stimulating–hormone (FSH), luteinizing hormone (LH), Testosterone, Melatonin, Glutathione (GSH), Glutathione peroxidase (GSH–Px), catalase, interleukin 10 (IL–10) levels and motility, and an increase in Corticosterone, nuclear factor kappa beta (NF–kB), tumor necrosis factor–alpha (TNF–α), interleukin 1 beta (IL–1β), interleukin 6 (IL–6), abnormal sperm, dead/live sperm ratio and exogenous Melatonin reduced inflammatory cytokines and oxidative stress and improved spermatological parameters (P<0.05). Melatonin also partially corrected stress–induced changes in testicular morphology. As a result, using Melatonin in rats with CUSM may be effective in improving spermatological parameters through anti–inflammatory and antioxidant mechanisms.

References

Guo Y, Sun J, Li T, Zhang Q, Bu S, Wang Q, Lai D. Melatonin ameliorates restraint stress–induced oxidative stress and apoptosis in testicular cells via NF–κB/iNOS and Nrf2/HO–1 signaling pathway. Sci. Rep. [Internet]. 2017; 7(1):9599. doi: https://doi.org/kn8z

Liu B, Zhao L, Yue C, Qian M, Xie M. Changes in gonadal function at different stages of chronic restraint stress–induced depression animals. Physiol. Behav. [Internet]. 2019; 210:112656. doi: https://doi.org/kn82

Nirupama M, Devaki M, Nirupama R, Yajurvedi HN. Chronic intermittent stress–induced alterations in the spermatogenesis and antioxidant status of the testis are irreversible in albino rat. J. Physiol. Biochem. [Internet]. 2013; 69(1):59–68. doi: https://doi.org/gmgq7f

Kolbasi B, Bulbul MV, Karabulut S, Altun CE, Cakici C, Ulfer G, Mudok T, Keskin I. Chronic unpredictable stress disturbs the blood–testis barrier affecting sperm parameters in mice. Reprod. Biomed. Online. [Internet]. 2021; 42(5):983–95. doi: https://doi.org/gqfbdt

Gozer A, Bahan O, Dogruer G, Kutlu T. Serum antimüllerian hormone concentrations in female cats. Relation with ovarian remnant syndrome, ovarian cysts and gonadectomy status. Theriogenol. [Internet]. 2023; 200:106–13. doi: https://doi.org/kn83

Tuzlu T, Saribay MK, Ürer EK, Köse AM, Gözer A, Yakan A, Özsoy ŞY. Evaluation of blood omega–3 and omega–6 levels in healthy female dogs and female dogs with mammary tumours. J. Hellenic. Vet. Med. Soc. 2021; 72(2):2925–34.

Brotto L, Atallah S, Johnson–Agbakwu C, Rosenbaum T, Abdo C, Byers ES, Graham C, Nobre P, Wylie, K. Psychological and interpersonal dimensions of sexual function and dysfunction. J. Sex. Med. [Internet]. 2016; 13(4):538–71. doi: https://doi.org/gdzz9q

Choy JT, Eisenberg ML. Male infertility as a window to health. Fertil. Steril. [Internet]. 2018; 110(5):810–4. doi: 10.1016/j.fertnstert.2018.08.015.

Kumar N, Singh AK. Trends of male factor infertility, an important cause of infertility: A review of literature. J Hum Reprod Sci. [Internet]. 2015; 8(4):191–6. doi: https://doi.org/ghw9mq

Orr TE, Taylor MF, Bhattacharyya AK, Collins DC, Mann DR. Acute immobilization stress disrupts testicular steroidogenesis in adult male rats by inhibiting the activities of 17 alpha–hydroxylase and 17,20–lyase without affecting the binding of LH/hCG receptors. J. Androl. 1994; 15(4):302–8. PMID: 7982797.

Lin H, Yuan KM, Zhou HY, Bu T, Su H, Liu S, Zhu Q, Wang Y, Hu Y, Shan Y, Lian QQ, Wu XY, Ge RS. Time–course changes of steroidogenic gene expression and steroidogenesis of rat Leydig cells after acute immobilization stress. Intern. J. Mol. Sci. [Internet]. 2014; 15(11):21028–44. doi: https://doi.org/f6sf29

Leisegang K, Dutta S. Do lifestyle practices impede male fertility? Androl. [Internet]. 2021; 53(1):e13595. doi: https://doi.org/gpkvg6

Li R, Luo X, Li L, Peng Q, Yang Y, Zhao L, Ma M, Hou Z. The protective effects of Melatonin against oxidative stress and inflammation induced by acute cadmium exposure in mice testis. Biol. Trace. Elem. Res. [Internet]. 2016; 170(1):152–64. doi: https://doi.org/f79qs8

Zarezadeh M, Khorshidi M, Emami M, Janmohammadi P, Kord–Varkaneh H, Mousavi SM, Mohammed SH, Saedisomeolia A, Alizadeh S. Melatonin supplementation and pro–inflammatory mediators: a systematic review and meta–analysis of clinical trials. Eur. J. Nutr. [Internet]. 2020; 59(5):1803–13. doi: https://doi.org/kn84

Lin R, Wang Z, Cao J, Gao T, Dong Y, Chen Y. Role of Melatonin in intestinal mucosal injury induced by restraint stress in mice. Pharm. Biol. [Internet]. 2020; 58(1):342–51. doi: https://doi.org/ghxj6p

Fahim AT, Abd El–Fattah AA, Sadik NAH, Ali BM. Resveratrol and dimethyl fumarate ameliorate testicular dysfunction caused by chronic unpredictable mild stress–induced depression in rats. Arch. Biochem. Biophys. [Internet]. 2019; 665:152–65. doi: https://doi.org/kn85

Willner P, Muscat R, Papp M. Chronic mild stress–induced anhedonia: a realistic animal model of depression. Neurosci. Biobehav. Rev. [Internet]. 1992; 16(4):525–34. doi: https://doi.org/c4fpxj

Sakr HF, Abbas AM, Elsamanoudy AZ, Ghoneim FM. Effect of fluoxetine and resveratrol on testicular functions and oxidative stress in a rat model of chronic mild stress–induced depression. J. Physiol. Pharmacol. 2015; 66(4):515–27. PMID: 26348076.

Ramadan HM, Taha NA, Ahmed HH. Melatonin enhances antioxidant defenses but could not ameliorate the reproductive disorders in induced hyperthyroidism model in male rats. Environ. Sci. Pollut. Res. Intern. [Internet]. 2021; 28(4):4790–804. doi: https://doi.org/kn86

Galvao J, Davis B, Tilley M, Normando E, Duchen MR, Cordeiro MF. Unexpected low–dose toxicity of the universal solvent DMSO. FASEB. J. [Internet]. 2014; 28(3):1317–30. doi: https://doi.org/gfkjdb

Güvenç M, Cellat M, Gökçek İ, Yavaş İ, Yurdagül–Özsoy Ş. Effects of thymol and carvacrol on sperm quality and oxidant/antioxidant balance in rats. Arch. Physiol. Biochem. [Internet]. 2019; 125(5):396–403. doi: https://doi.org/gpwffw

Sönmez M, Türk G, Yüce A. The effect of ascorbic acid supplementation on sperm quality, lipid peroxidation and testosterone levels of male Wistar rats. Theriogenol. [Internet]. 2005; 63(7):2063–72. doi: https://doi.org/cn6kn5

Watson PF. Use of a Giemsa stain to detect changes in acrosomes of frozen ram spermatozoa. Vet. Rec. [Internet]. 1975; 97(1):12–5. doi: https://doi.org/cz5w9x

Bekhbat M, Glasper ER, Rowson SA, Kelly SD, Neigh GN. Measuring corticosterone concentrations over a physiological dynamic range in female rats. Physiol. Behav. [Internet]. 2018; 194:73–6. doi: https://doi.org/gd6xbs

Ateşşahin A, Sahna E, Türk G, Ceribaşi AO, Yilmaz S, Yüce A, Bulmuş O. Chemoprotective effect of Melatonin against cisplatin–induced testicular toxicity in rats. J. Pineal. Res. [Internet]. 2006; 41(1):21–7. doi: https://doi.org/d9bhz5

Kirby ED, Geraghty AC, Ubuka T, Bentley GE, Kaufer D. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc. Natl. Acad. Sci. USA. [Internet]. 2009; 106(27):11324–9 doi: https://doi.org/bk2nx9

Hardy MP, Gao HB, Dong Q, Ge R, Wang Q, Chai WR, Feng X, Sottas C. Stress hormone and male reproductive function. Cell. Tissue. Res. [Internet]. 2005; 322(1):147–53. doi: https://doi.org/bf5h6m

Liu B, Zhao L, Yue C, Qian M, Xie M. Changes in gonadal function at different stages of chronic restraint stress–induced depression animals. Physiol. Behav. [Internet]. 2019; 210:112656. doi: https://doi.org/kn82

Wu CS, Leu SF, Yang HY, Huang BM. Melatonin inhibits the expression of steroidogenic acute regulatory protein and steroidogenesis in MA–10 cells. J. Androl. 2001; 22(2):245–54. PMID: 11229798.

Voordouw BC, Euser R, Verdonk RE, Alberda BT, de Jong FH, Drogendijk AC, Fauser BC, Cohen M. Melatonin and Melatonin–progestin combinations alter pituitary–ovarian function in women and can inhibit ovulation. J. Clin. Endocrinol. Metab. [Internet]. 1992; 74(1):108–17. doi: https://doi.org/kn87

Cagnacci A, Elliott JA, Yen SS. Amplification of pulsatile LH secretion by exogenous Melatonin in women. J. Clin. Endocrinol. Metab. [Internet]. 1991; 73(1):210–2. doi: https://doi.org/dv6vrk

Ninomiya T, Iwatani N, Tomoda A, Miike T. Effects of exogenous Melatonin on pituitary hormones in humans. Clin. Physiol. [Internet]. 2001; 21(3):292–9. doi: https://doi.org/c9jtpq

Lang U, Aubert ML, Conne BS, Bradtke JC, Sizonenko PC. Influence of exogenous Melatonin on Melatonin secretion and the neuroendocrine reproductive axis of intact male rats during sexual maturation. Endocrinol. [Internet]. 1983; 112(5):1578–84. doi: https://doi.org/bnbw72

Zizzo J, Reddy R, Kulkarni N, Blachman–Braun R, Ramasamy R. Impact of low–dose Melatonin supplementation on testosterone levels in U.S. adult males. Urol. [Internet]. 2022; 169:92–5. doi: https://doi.org/kn88

Huleihel M, Lunenfeld E. Regulation of spermatogenesis by paracrine/autocrine testicular factors. Asian. J. Androl. 2004; 6(3):259–68. PMID: 15273877.

Bahrami N, Goudarzi M, Hosseinzadeh A, Sabbagh S, Reiter RJ, Mehrzadi S. Evaluating the protective effects of Melatonin on di(2–ethylhexyl) phthalate–induced testicular injury in adult mice. Biomed. Pharmacother. [Internet]. 2018; 108:515–23. doi: https://doi.org/gfpr6w

Koksal M, Oğuz E, Baba F, Eren MA, Ciftci H, Demir ME, Kurcer Z, Take G, Aral F, Ocak AR, Aksoy N, Ulas T. Effects of Melatonin on testis histology, oxidative stress and spermatogenesis after experimental testis ischemia–reperfusion in rats. Eur. Rev. Med. Pharmacol. Sci. 2012; 16(5):582–8. PMID: 22774397.

Torabi F, Malekzadeh–Shafaroudi M, Rezaei N. Combined protective effect of zinc oxide nanoparticles and Melatonin on cyclophosphamide–induced toxicity in testicular histology and sperm parameters in adult Wistar rats. Intern. J. Reprod. Biomed. 2017; 15(7):403–12. PMID: 29202124