Volume 15, Issue 4 (6-2017)                   IJRM 2017, 15(4): 217-224 | Back to browse issues page


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Iamsaard S, Sukhorum W, Arun S, Phunchago N, Uabundit N, Boonruangsri P et al . Valproic acid induces histologic changes and decreases androgen receptor levels of testis and epididymis in rats. IJRM 2017; 15 (4) :217-224
URL: http://ijrm.ir/article-1-814-en.html
1- 1.Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 2.Center for Research and Development of Herbal Health Products, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand , sittia@kku.ac.th
2- 1.Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.2.School of Medicine, Mae Fah Luang University, Chiang Rai 57100, Thailand.
3- Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
4- Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Abstract:   (2943 Views)
Background: Valproic acid (VPA), an anti-epileptic drug, can cause male subfertility. However, the degree to which testicular and epididymal histopathologies and androgen receptor (AR) expression are changed under VPA treatment has never been reported.
Objective: To investigate the histopathological changes and AR protein levels of testis and epididymis in VPA-treated rats for every single day.
Materials and Methods: Sixty-four adult male Wistar rats were divided intocontrol and VPA-treated groups (n=8/ each). Treated rats were injected with 500mg/ kgBW, intraperitoneally, VPA for 10 consecutive days. At the end of everyexperimental day, all reproductive parameters including histology by hematoxylinand eosin staining and protein expression of AR by Immuno-Western blot in testisand epididymis were examined.
Results: VPA-treated rats showed dramatically changes in testicular and epididymal histopathologies compared to control group. The multinucleated giant cells and sloughing of germ cells were observed on day 6. The germ cell disintegration and increased intercellular spaces of seminiferous tubular epithelium appeared in days 7-10 of VPA treatment. Additionally, extensive multinucleated giant cells and complete exfoliation were clearly found from days 8-10. Such exfoliated germ cells were clearly seen in its epididymal lumen at day 10. The increasing rate of sperm concentration was approximately 32.31% of that in control group at day 10 (p=0.03). Moreover, the protein expressions of testicular and epididymal AR (% intensity/ 80 μg protein lysate) was decreased in VPA-treated rats compared with control.
Conclusion: VPA treatment induces histologic changes of germ cell epithelium in seminiferous tubules and decreases the expression of testicular and epididymal
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Type of Study: Original Article |

References
1. Gottlicher M. Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol 2004; 83: S91-S92.
2. Berendsen S, Broekman M, Seute T, Snijders T, van Es C, de Vos F, et al. Valproic acid for the treatment of malignant gliomas: a review of the preclinical rationale and published clinical results. Expert Opin Investig Drugs 2012; 21: 1391-1415. [DOI:10.1517/13543784.2012.694425]
3. Glister C, Satchell L, Michael AE, Bicknell AB, Knight PG. The anti-epileptic drug valproic acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro. PLoS One 2012; 7: e49553. [DOI:10.1371/journal.pone.0049553]
4. Bialer M, Yagen B. Valproic acid: second generation. Neurotherapeutics 2007; 4: 130-137. [DOI:10.1016/j.nurt.2006.11.007]
5. Isoja¨rvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms. Seizure 2008; 17: 111-119. [DOI:10.1016/j.seizure.2007.11.007]
6. Taubøll E, Røste LS, Svalheim S, Gjerstad L. Disorders of reproduction in epilepsy: what can we learn from animal studies. Seizure 2008; 17: 120-126. [DOI:10.1016/j.seizure.2007.11.008]
7. RøsteLS,Taubøll E, Mørkrid L, Bjørnenak T, Saetre ER, Mørland T, et al. Antiepileptic drugs alter reproductive endocrine hormones in menwith epilepsy. Eur J Neurol 2005; 12: 118-124. [DOI:10.1111/j.1468-1331.2004.00899.x]
8. Bauer J, Blumenthal S, Reuber M, Stoffel-Wangner B. Epilepsy syndrome, focus location, and treatment choice affect testicular function in men with epilepsy. Neurology 2004; 62: 243-246. [DOI:10.1212/01.WNL.0000091866.48962.79]
9. Krogenaes AK, Taubøll E, Stien A, Oskam IC, Lyche JL, Dahl E, et al Valproate affects reproductive endocrine function, testis diameter and some semen variables in non-epileptic adolescent goat bucks. Theriogenology 2008; 70: 5-26. [DOI:10.1016/j.theriogenology.2008.01.029]
10. Nishimura T, Sakai M, Yonezawa H. Effects of valproic acid on fertility and reproductive organs inmale rats. J Toxicol Sci 2000; 25: 85-93. [DOI:10.2131/jts.25.85]
11. SvebergRøste LS, Taubøll E, Berner A, Berg KA, Aleksandersen M, Gjerstad L. Morphological changes in the testis after long-term valproate treatment in male Wistar rats. Seizure 2001; 10, 559-565. [DOI:10.1053/seiz.2001.0545]
12. Hamza AA, Amin A. Apiumgraveolensmodulates sodium valproate-induced reproductive toxicity in rats. J Exp Zool A Ecol Gen Physiol 2007; 307: 199-206.
13. Bairy L, Paul V, Rao Y. Reproductive toxicity of sodium valproate in male rats. Indian J Pharmacol 2010; 42: 90-94. [DOI:10.4103/0253-7613.64503]
14. Khan S, Ahmad T, Parekh CV, Trivedi PP, Kushwaha S, Jena G. Investigation on sodium valproate induced germ cell damage, oxidative stress and genotoxicity in male Swiss mice. Reprod Toxicol 2011; 32: 385-394. [DOI:10.1016/j.reprotox.2011.09.007]
15. Girish C, Shweta O, Raj V, Balakrishnan S, Varghese RG. Ellagic acid modulates sodium valproate reproductive toxicity in male Wistar rats. Indian J Physiol Pharmacol 2014; 58: 416- 422.
16. Sakr S, ZowailME, Marzouk AM. Effect of saffron (Crocus sativusL.) on sodium valproate induced cytogenetic and testicular alterations in albino rats. Anat Cell Biol 2014; 47: 171-179. [DOI:10.5115/acb.2014.47.3.171]
17. 17. Iamsaard S, Arun S, Burawat J, Sukhorum W, Boonruangsri P, Namking M, et al. PhylanthusemblicaL. branch extract ameliorates testicular damage in valproic acid-induced rats. Int J Morphol 2015; 33: 1016-1022. [DOI:10.4067/S0717-95022015000300033]
18. Sukhorum W, Iamsaard S. Changes in testicular function proteins and sperm acrosome status in rats treated with valproic acid. Reprod Fertil Dev 2016; In press.
19. Wang YC, Peterson SE, Loring JF. Protein posttranslational modifications and regulation of pluripotency in human stem cells. Cell Res 2014; 24: 143-160. [DOI:10.1038/cr.2013.151]
20. Collins LL, Lee HJ, Chen YT, Chang M, Hsu HY, Yeh S, Chang C. The androgen receptor in spermatogenesis. Cytogenet Genome Res 2003; 103: 299-301. [DOI:10.1159/000076816]
21. Arun S, Burawat J, Sukhorum W, Sampannang A, Maneenin C, Iamsaard S. Chronic restraint stress induces sperm acrosome reaction and changes in testicular tyrosine phosphorylated proteins in rats. Int J Reprod Biomed 2016; 14: 443-452.
22. Vijay P, Yeshwanth R, Bairy KL. The effect of sodium valproate on the biochemical parameters of reproductive function in male albino Wistar rats. Indian J Pharmacol 2008; 40: 248-250. [DOI:10.4103/0253-7613.45149]
23. Shum WW, Smith TB, Cortez-Retamozo V, Grigoryeva LS, Roy JW, Hill E, Pittet MJ, Breton S, Da Silva N. Epithelial basal cells are distinct from dendritic cells and macrophages in the mouse epididymis. Biol Reprod 2014; 90: 90. [DOI:10.1095/biolreprod.113.116681]
24. Ramos-Ibeas P, Pericuesta E, Fernández-González R, Ramírez MA, Gutierrez-Adan A. Most regions of mouse epididymis are able to phagocytose immature germ cells. Reproduction 2013; 146: 481-489. [DOI:10.1530/REP-13-0145]
25. Talebi AR, Khorsandi L, Moridian M. The effect of zinc oxide nanoparticles on mouse spermatogenesis. J Assist Reprod Genet 2013; 30: 1203-1209. [DOI:10.1007/s10815-013-0078-y]
26. Mirhoseini M, Mohamadpour M, Khorsandi L. Toxic effects of Carthamustinctorius L. (Safflower) extract on mouse spermatogenesis. J Assist Reprod Genet 2012; 29: 457-461. [DOI:10.1007/s10815-012-9734-x]
27. D'Souza UJ. Tamoxifen induced multinucleated cells (symplasts) and distortion of seminiferous tubules in rat testis. Asian J Androl 2003; 5: 217-220.
28. Bharali MK, Dutta K. Testicular toxicity of para-phenylenediamine after subchronic topical application in rat. Int J Environ Health Res 2012; 22: 270-278. [DOI:10.1080/09603123.2011.634388]
29. Hill CM, Anway MD, Zirkin BR, Brown TR. Intratesticular androgen levels, androgen receptor localization, and androgen receptor expression in adult rat Sertoli cells. Biol Reprod 2004; 71: 1348-1358. [DOI:10.1095/biolreprod.104.029249]
30. Sar M, Lubahn DB, French FS, Wilson EM. Immunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology 1990; 127: 3180-3186. [DOI:10.1210/endo-127-6-3180]
31. Yamashita S. Localization of estrogen and androgen receptors in male reproductive tissues of mice and rats. Anat Rec A Discov Mol Cell Evol Biol 2004; 279: 768-778. [DOI:10.1002/ar.a.20061]
32. O'Hara L, Welsh M, Saunders PT, Smith LB. Androgen receptor expression in the caput epididymal epithelium is essential for development of the initial segment and epididymal spermatozoa transit. Endocrinology 2011; 152: 718-729. [DOI:10.1210/en.2010-0928]
33. Manfo FP, Jubendradass R, Nantia EA, Moundipa PF, Mathur PP. Adverse effects of bisphenol A on male reproductive function. Rev Environ Contam Toxicol 2014; 228: 57-82. [DOI:10.1007/978-3-319-01619-1_3]
34. Qiu LL, Wang X, Zhang XH, Zhang Z, Gu J, Liu L, et al. Decreased androgen receptor expression may contribute to spermatogenesis failure in rats exposed to low concentration of bisphenol A. Toxicol Lett 2013; 219: 116-124. [DOI:10.1016/j.toxlet.2013.03.011]

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