The effect of fluoxetine on spermatogenesis and spermatogonial stem cells self-renewal in adult male rats

Authors

Abstract

Background and Objective: Fluoxetine (FLX) application as a selective serotonin reuptake inhibitor (SSRI) drug that accompanies side effects including reproductive dysfunctions. The current study was designed to explore the effects of FLX on rat spermatogenesis as well as spermatogonial stem cells self-renewal through evaluation of glial cell line-derived neurotrophic factor  family receptor alpha-1 (GFRα1) expression at mRNA level in testicular tissue.
 
Materials and Methods: Adult male Wistar rats were randomly allocated into experimental and control groups. The experimental group was subdivided into two groups which received 5 mg/kg/day and 10 mg/kg/day of FLX orally for 48 days. Testicular tissue samples were collected 24 hours after the last treatment and histological assessments and reverse transcription polymerase chain reaction were done to analyze spermatogenesis and mRNA expression of GFRα1, respectively.
 
Results: Treatment with FLX caused spermatozoa maturation arrest in a dose-dependent manner as was evident by significant decreases in spermatogenic indices. Moreover, FLX administration at a dose of 10 mg/kg/day resulted in significant reduction in mRNA expression of GFRα1 in testicular tissue.
 
Conclusion: These findings suggest that FLX induces male reproductive toxicities via disruption of spermatogonial stem cells self-renewal, bringing about the necessity of more researches about the precise mechanisms of SSRI antidepressants-induced spermatogenic failures.

Keywords


1. Balon R. SSRI-associated sexual dysfunction. The American Journal of Psychiatry 2006; 163: 1504-9. 2. Hajizadeh Z, Soleimani Mehranjani M, Najafi G, Shariatzadeh SMA, Shalizar Jalali A. Black grape seed extract modulates fluoxetine-induced oxidative stress and cytotoxicity in the mouse testis. Jundishapur Journal of Natural Pharmaceutical Products 11(2): e27512. 3. Grigoriadis S, VonderPorten EH, Mamisashvili L, Roerecke M, Rehm J, Dennis CL, et al. Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence. Journal of Clinical Psychiatry 2013; 74: e293–e308. 4. Huybrechts KF, Sanghani RS, Avorn J, Urato AC. Preterm birth and antidepressant medication use during pregnancy: a systematic review and meta-analysis. PLoS ONE 2014; 9: e92778. 5. Kumar VS, Sharma VL, Tiwari P, Singh D, Maikhuri JP, Gupta G, et al. 2006. The spermicidal and antitrichomonas activities of SSRI antidepressants. Bioorganic and Medicinal Chemistry Letters 2006; 16: 2509-12. 6. Alzahrani HA. Sister chromatid exchanges and sperm abnormalities produced by antidepressant drug fluoxetine in mouse treated in vivo. European Review for Medical and Pharmacological Sciences 2012; 16: 2154-61. 7. Bataineh HN, Daradka T. Effects of long-term use of fluoxetine on fertility parameters in adult male rats. Neuro Endocrinology Letters 2007; 28: 321–5. 8. Ferguson L, How JJ, Agoulnik AL. The fate of spermatogonial stem cells in the cryptorchid testes of RXFP2 deficient mice. PLoS ONE 2013; 8: e77351. 9. Hofmann MC. GDNF signaling pathways within the mammalian spermatogonial stem cell niche. Molecular and Cellular Endocrinology 2008; 288: 95-103. 10. Meng X, Lindahl M, Hyvönen ME, Parvinen M, de Rooij DG, Hess MW, et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 2000; 287(5457): 1489-93. 11. Pawluski JL, van Donkelaar E, Abrams Z, Houbart V, Fillet M, Steinbusch HW, et al. Fluoxetine dose and administration method differentially affect hippocampal plasticity in adult female rats. Neural Plasticity 2014; 2014: 123026. 12. 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. 13. Pilania M, Bairwa M, Kumar N, Khanna P, Kurana H. Elderly depression in India: An emerging public health challenge. Australasian Medical Journal 2013; 6(3):107-11. 14. Muller JC, Imazaki PH, Boareto AC, Lourenco EL, Golin M, Vechi MF, et al. In vivo and in vitro estrogenic activity of the antidepressant fluoxetine. Reproductive Toxicology 2012; 34(1): 80-5. 15. Silva J, Lins A, Amorim J, Pinto CF, Deiró TBJ, Oliveira JRM, et al. Neonatal administration of fluoxetine decreased final sertoli cell number in Wistar rats. International Journal of Morphology 2008; 26(1): 51-62. 16. Sciarra J. Infertility: an international problem. International Journal of Gynecology and Obstetrics 1994; 46(2): 155-63. 17. Safarinejad MR. Evaluation of endocrine profile and hypothalamic-pituitary-testis axis in selective serotonin reuptake inhibitor-induced male sexual dysfunction. Journal of Clinical Psychopharmacology 2008; 28(4): 418-23. 18. Sakr SA, Mahran HA, El-Deeb MM. Ameliorative effect of curcumin on fluoxetine-induced reproductive toxicity and oxidative stress in male albino rats. Oxidants and Antioxidants in Medical Science 2013; 2(1): 29-35. 19. Kasahara E, Sato EF, Miyoshi M, Konaka R, Hiramoto K, Sasaki J, et al. Role of oxidative stress in germ cell apoptosis induced by di(2-ethylhexyl)phthalate. Biochemical Journal 2002; 365(Pt 3): 849-56. 20. Oatley JM, Avarbock MR, Brinster RL. Glial cell line-derived neurotrophic factor regulation of genes essential for self-renewal of mouse spermatogonial stem cells is dependent on Src family kinase signaling. Journal of Biological Chemistry 2007; 282(35): 25842-51. 21. Lee J, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, et al. Akt mediates self-renewal division of mouse spermatogonial stem cells. Development 2007; 134(10): 1853-9. 22. Sariola H, Saarma M. Functions and signaling pathways for GDNF. Journal of Cell Science 2003; 116: 3855-62. 23. Mohammadi F, Jalali AS, Najafi G, Behfar M. Stereological, morphometric and morphological analyses of bilateral epididymal lipectomy induced changes in mouse testicular histoarchitecture. Journal of Kermanshah University of Medical Sciences 2017; 20(4): 141-6. 24. Nooraei A, Jalali AS, Razi M, Behfar M. Bilateral epididymal lipectomy disturbs mouse germline maintenance. Journal of Reproduction and Infertility 2017; 18: 212-3. 25. Chen LY, Willis WD, Eddy EM. Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development. Proceedings of the National Academy of Sciences of the United States of America 2016; 113(7): 1829-34. 26. Phillips BT, Gassei K, Orwig KE. Spermatogonial stem cell regulation and spermatogenesis. Philosophical Transactions of the Royal Society B: Biological Sciences 2010; 365(1546): 1663-78. 27. Kanatsu-Shinohara M, Miki H, Inoue K, Ogonuki N, Toyokuni S, Ogura A, et al. Germline niche transplantation restores fertility in infertile mice. Human Reproduction 2005; 20(9): 2376-82. 28. Kubota H, Avarbock MR, Brinster RL. Culture conditions and single growth factors affect fate determination of mouse spermatogonial stem cells. Biology of Reproduction 2004; 71(3): 722-31.