Anatomy and Cell Biology

Korean Association of Anatomists (대한해부학회)
권호 표지
DOI QR코드

DOI QR Code

Ameliorative effect of vitamin B12 on seminiferous epithelium of cimetidine-treated rats: a histopathological, immunohistochemical and ultrastructural study

  • Elsaed, Wael M. (Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University) ;
  • Bedeer, Raouf Fekry (Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University) ;
  • Eladl, Mohamed Ahmed (Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University)
  • Received : 2017.11.27
  • Accepted : 2018.01.10
  • Published : 2018.03.31
⟨ Previous Next ⟩

Abstract

Cimetidine is an H2 receptor antagonist that has an antiandrogenic effect. It intervenes with the conversion of testosterone into estrogen in the Sertoli cells with accompanying testicular structural changes. In the present study, the microscopic and the ultrastructural changes induced by cimetidine and the effect of vitamin B12 as a protective agent on rat testes were studied. Immunoexpression of estrogen receptor ${\beta}$ ($ER{\beta}$) in testes was evaluated. Twenty-four adult male rats were divided into four groups: control, cimetidine-treated, vitamin B12 treated, and combined cimetidine and vitamin B12 treated. The experimental rats were administered with cimetidine and/or vitamin B12 for 52 days. Group II rats showed marked atrophy of the seminiferous tubules with a significant increase in tubular diameter and decrease in the tubular luminal and epithelial areas. Ultrastructure of this group showed irregular Sertoli cells with basal cytoplasmic vacuolation and significantly thickened basement membrane. $ER{\beta}$ immunoexpression was similar to controls. Group III rats showed near normal seminiferous tubular structures with minimal cellular alterations and the immunoreactivity of the testicular sections was very close to normal. However, group IV rats showed markedly immunopositive detached cells, spermatids, and primary spermatocytes. Cimetidine interferes with the control of spermatogenesis as evidenced by microscopic and ultrastructural studies and affection of $ER{\beta}$ receptors and vitamin B12 has a protective action against this harmful effect.

Keywords

References

  1. Kubecova M, Kolostova K, Pinterova D, Kacprzak G, Bobek V. Cimetidine: an anticancer drug? Eur J Pharm Sci 2011;42:439-44. https://doi.org/10.1016/j.ejps.2011.02.004
  2. Kalra BS, Aggarwal S, Khurana N, Gupta U. Effect of cimetidine on hepatotoxicity induced by isoniazid-rifampicin combination in rabbits. Indian J Gastroenterol 2007;26:18-21.
  3. Beltrame FL, Caneguim BH, Miraglia SM, Cerri PS, Sasso-Cerri E. Vitamin B12 supplement exerts a beneficial effect on the seminiferous epithelium of cimetidine-treated rats. Cells Tissues Organs 2011;193:184-94. https://doi.org/10.1159/000319371
  4. Sasso-Cerri E. Enhanced ERbeta immunoexpression and apoptosis in the germ cells of cimetidine-treated rats. Reprod Biol Endocrinol 2009;7:127. https://doi.org/10.1186/1477-7827-7-127
  5. Genissel C, Levallet J, Carreau S. Regulation of cytochrome P450 aromatase gene expression in adult rat Leydig cells: comparison with estradiol production. J Endocrinol 2001;168:95-105. https://doi.org/10.1677/joe.0.1680095
  6. McCullough LD, Blizzard K, Simpson ER, Oz OK, Hurn PD. Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. J Neurosci 2003;23:8701-5. https://doi.org/10.1523/JNEUROSCI.23-25-08701.2003
  7. Rago V, Maggiolini M, Vivacqua A, Palma A, Carpino A. Differential expression of estrogen receptors (ERalpha/ERbeta) in testis of mature and immature pigs. Anat Rec A Discov Mol Cell Evol Biol 2004;281:1234-9.
  8. Hamid Q, Hamid S, Minhas LA, Gul A. Influence of cimetidine and bromocriptine on prolactin levels in rat fertility. Int J Physiol Pathophysiol Pharmacol 2009;1:33-40.
  9. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003;67:979-86.
  10. Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a protonpump inhibitor. Ann Pharmacother 2002;36:812-6. https://doi.org/10.1345/aph.10325
  11. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 2002;129:1983-93.
  12. Yamada K, Kawata T, Wada M, Mori K, Tamai H, Tanaka N, Tadokoro T, Tobimatsu T, Toraya T, Maekawa A. Testicular injury to rats fed on soybean protein-based vitamin B12-deficient diet can be reduced by methionine supplementation. J Nutr Sci Vitaminol (Tokyo) 2007;53:95-101. https://doi.org/10.3177/jnsv.53.95
  13. Kawata T, Funada U, Wada M, Matsushita M, Sanai T, Yamada H, Kuwamori M, Arai K, Yamamoto Y, Tanaka N, Tadokoro T, Maekawa A. Breeding severely vitamin B12-deficient mice as model animals. Int J Vitam Nutr Res 2004;74:57-63. https://doi.org/10.1024/0300-9831.74.1.57
  14. Oshio S, Ozaki S, Ohkawa I, Tajima T, Kaneko S, Mohri H. Mecobalamin promotes mouse sperm maturation. Andrologia 1989;21:167-73.
  15. Rago V, Siciliano L, Aquila S, Carpino A. Detection of estrogen receptors ER-alpha and ER-beta in human ejaculated immature spermatozoa with excess residual cytoplasm. Reprod Biol Endocrinol 2006;4:36. https://doi.org/10.1186/1477-7827-4-36
  16. Naraghi MA, Abolhasani F, Kashani I, Anarkooli IJ, Hemadi M, Azami A, Barbarestani M, Aitken RJ, Shokri S. The effects of swimming exercise and supraphysiological doses of nandrolone decanoate on the testis in adult male rats: a transmission electron microscope study. Folia Morphol (Warsz) 2010;69:138-46.
  17. Bilinska B, Schmalz-Fraczek B, Kotula M, Carreau S. Photoperiod-dependent capability of androgen aromatization and the role of estrogens in the bank vole testis visualized by means of immunohistochemistry. Mol Cell Endocrinol 2001;178:189-98. https://doi.org/10.1016/S0303-7207(01)00427-0
  18. Beltrame FL, Sasso-Cerri E. Vitamin B12-induced spermatogenesis recovery in cimetidine-treated rats: effect on the spermatogonia number and sperm concentration. Asian J Androl 2017;19:567-72. https://doi.org/10.4103/1008-682X.182397
  19. Sasso-Cerri E, Miraglia SM. In situ demonstration of both TUNEL-labeled germ cell and Sertoli cell in the cimetidine-treated rats. Histol Histopathol 2002;17:411-7.
  20. Sasso-Cerri E, Cerri PS. Morphological evidences indicate that the interference of cimetidine on the peritubular components is responsible for detachment and apoptosis of Sertoli cells. Reprod Biol Endocrinol 2008;6:18. https://doi.org/10.1186/1477-7827-6-18
  21. Hooley RP, Paterson M, Brown P, Kerr K, Saunders PT. Intratesticular injection of adenoviral constructs results in Sertoli cell-specific gene expression and disruption of the seminiferous epithelium. Reproduction 2009;137:361-70. https://doi.org/10.1530/REP-08-0247
  22. Mruk DD, Cheng CY. Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 2004;25:747-806. https://doi.org/10.1210/er.2003-0022
  23. Kianifard D, Sadrkhanlou RA, Hasanzadeh S. The ultrastructural changes of the sertoli and leydig cells following streptozotocin induced diabetes. Iran J Basic Med Sci 2012;15:623-35.
  24. Yamamoto Y, Sofikitis N, Mio Y, Loutradis D, Kaponis A, Miyagawa I. Morphometric and cytogenetic characteristics of testicular germ cells and Sertoli cell secretory function in men with non-mosaic Klinefelter's syndrome. Hum Reprod 2002;17:886-96. https://doi.org/10.1093/humrep/17.4.886
  25. Hutson JC. Altered biochemical responses by rat Sertoli cells and peritubular cells cultured under simulated diabetic conditions. Diabetologia 1984;26:155-8.
  26. Tirado OM, Selva DM, Toran N, Suarez-Quian CA, Jansen M, McDonnell DP, Reventos J, Munell F. Increased expression of estrogen receptor beta in pachytene spermatocytes after shortterm methoxyacetic acid administration. J Androl 2004;25:84-94. https://doi.org/10.1002/j.1939-4640.2004.tb02762.x
  27. Simpkins JW, Yang SH, Sarkar SN, Pearce V. Estrogen actions on mitochondria: physiological and pathological implications. Mol Cell Endocrinol 2008;290:51-9. https://doi.org/10.1016/j.mce.2008.04.013
  28. Gruber HE, Yamaguchi D, Ingram J, Leslie K, Huang W, Miller TA, Hanley EN Jr. Expression and localization of estrogen receptor-beta in annulus cells of the human intervertebral disc and the mitogenic effect of 17-beta-estradiol in vitro. BMC Musculoskelet Disord 2002;3:4. https://doi.org/10.1186/1471-2474-3-4
  29. Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM Jr, Valencia T, Brun-Zinkernagel AM, Prokai L, Will Y, Dykens J, Koulen P, Simpkins JW. Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci U S A 2004;101:4130-5. https://doi.org/10.1073/pnas.0306948101
  30. Solakidi S, Psarra AM, Nikolaropoulos S, Sekeris CE. Estrogen receptors alpha and beta (ERalpha and ERbeta) and androgen receptor (AR) in human sperm: localization of ERbeta and AR in mitochondria of the midpiece. Hum Reprod 2005;20:3481-7. https://doi.org/10.1093/humrep/dei267
  31. Saunders PT, Millar MR, Macpherson S, Irvine DS, Groome NP, Evans LR, Sharpe RM, Scobie GA. ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis. J Clin Endocrinol Metab 2002;87:2706-15.
  32. Selva DM, Tirado OM, Toran N, Suarez-Quian CA, Reventos J, Munell F. Estrogen receptor beta expression and apoptosis of spermatocytes of mice overexpressing a rat androgen-binding protein transgene. Biol Reprod 2004;71:1461-8. https://doi.org/10.1095/biolreprod.103.025619
  33. Agarwal VR, Sinton CM, Liang C, Fisher C, German DC, Simpson ER. Upregulation of estrogen receptors in the forebrain of aromatase knockout (ArKO) mice. Mol Cell Endocrinol 2000;162:9-16. https://doi.org/10.1016/S0303-7207(00)00227-6
  34. de Ronde W, de Jong FH. Aromatase inhibitors in men: effects and therapeutic options. Reprod Biol Endocrinol 2011;9:93. https://doi.org/10.1186/1477-7827-9-93
  35. Sasso-Cerri E, Giovanoni M, Hayashi H, Miraglia SM. Morphological alterations and intratubular lipid inclusions as indicative of spermatogenic damage in cimetidine-treated rats. Arch Androl 2001;46:5-13. https://doi.org/10.1080/01485010150211092
  36. Franca LR, Leal MC, Sasso-Cerri E, Vasconcelos A, Debeljuk L, Russell LD. Cimetidine (Tagamet) is a reproductive toxicant in male rats affecting peritubular cells. Biol Reprod 2000;63:1403-12. https://doi.org/10.1095/biolreprod63.5.1403
  37. Moreau F, Mittre H, Benhaim A, Bois C, Bertherat J, Carreau S, Reznik Y. Aromatase expression in the normal human adult adrenal and in adrenocortical tumors: biochemical, immunohistochemical, and molecular studies. Eur J Endocrinol 2009;160:93-9. https://doi.org/10.1530/EJE-08-0215

Cited by

  1. Effect of Nandrolone decanoate induced-oxidative stress on rat testes, prostate, and seminal vesicle: Biochemical, morphometric and histopathological studies vol.28, pp.1, 2018, https://doi.org/10.1016/j.sjbs.2020.09.039