Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Protective effects of vitamin E on cadmium-induced apoptosis in rat testes

  • 86 Accesses

Abstract

Cadmium (Cd) is a toxic metal that is involved in apoptosis. The present study was conducted to investigate the mechanism of Cd-induced apoptosis and the protective effects of vitamin E on rat testes. Thirty-two adult Wistar rats were divided into four groups. The control group was injected with saline and three other groups received Cd, Cd+vitamin E, and vitamin E. Intraperitoneal injection was performed for 28 days. On the 29th day, the rats were slaughtered, their peritoneum was opened, and their left testis removed and weighed. The mRNA expression of apoptosis and mitochondrial dynamics genes were assessed using real-time PCR, and caspase-3/7 activation using the caspase-3/7 Assay. The groups were not significantly different in terms of testicular weight. Compared with the control group, the mRNA expression levels of Bax and caspase-9 genes increased in the rats’ testes receiving Cd, the mRNA expression levels of mitofusin 1 (Mfn1) and mitofusin2 (Mfn2) genes decreased, and those of Bcl-2 remained unchanged. Vitamin E was found to significantly decrease the mRNA expression of Bax and caspase-9 genes and increase the mRNA Mfn1, Mfn2, and Bcl-2 in the rats’ testes receiving Cd. The ratio of Bax/Bcl-2 and caspase-3/7 activity increased in the Cd-exposed rats compared with the control. Vitamin E remarkably attenuated the Cd-induced effects. According to the obtained results, Cd exerts its apoptotic effects through the mitochondrial pathway by increasing the ratio of Bax/Bcl-2 and activating caspases in the rats’ testes, and vitamin E plays a protective role against Cd-induced apoptosis.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Abdelrazek HM, Helmy SA, Elsayed DH, Ebaid HM, Mohamed RM (2016) Ameliorating effects of green tea extract on cadmium induced reproductive injury in male Wistar rats with respect to androgen receptors and caspase-3. Reprod Biol 16(4):300–308

  2. Adamkovicova M, Toman R, Cabaj M, Massanyi P, Martiniakova M, Omelka R, Krajcovicova V, Duranova H (2014) Effects of subchronic exposure to cadmium and diazinon on testis and epididymis in rats. ScientificWorldJournal 2014:632581

  3. Akhtar RS, Ness JM, Roth KA (2004) Bcl-2 family regulation of neuronal development and neurodegeneration. Biochim Biophys Acta 1644(2-3):189–203

  4. Alaei P, Khodarahmi P, Salehipour M (2018) Effect of repeated injection of cadmium on Bax/Bcl-2 mRNA Level in stomach of rats. Int J Med Lab 5(2):133–140

  5. Al-Azemi M, Omu FE, Kehinde EO, Anim JT, Oriowo MA, Omu AE (2010) Lithium protects against toxic effects of cadmium in the rat testes. J Assist Reprod Genet 27(8):469–476

  6. Ali HM (2018) Mitigative role of garlic and vitamin E against cytotoxic, genotoxic, and apoptotic effects of lead acetate and mercury chloride on WI-38 cells. Pharmacol Rep 70(4):804–811

  7. Alian NS, Khodarahmi P, Naseh V (2018) The effect of cadmium on apoptotic genes mRNA expression of Bax and Bcl-2 in small intestine of rats. Iran J Pathol 13(4):408

  8. Alkhedaide A, Alshehri ZS, Sabry A, Abdel-Ghaffar T, Soliman MM, Attia H (2016) Protective effect of grape seed extract against cadmium-induced testicular dysfunction. Mol Med Rep 13(4):3101–3109

  9. Arnoult D, Rismanchi N, Grodet A, Roberts RG, Seeburg DP, Estaquier J, Sheng M, Blackstone C (2005) Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol 15(23):2112–2118

  10. Babaei H, Abshenas J (2013) Zinc therapy improves adverse effects of long term administration of copper on epididymal sperm quality of rats. Iran J Reprod Med 11(7):577–582

  11. Brooks C, Cho S-G, Wang C-Y, Yang T, Dong Z (2010) Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis. Am J Phys Cell Phys 300(3):C447–C455

  12. Chen L, Xu B, Liu L, Luo Y, Zhou H, Chen W, Shen T, Han X, Kontos CD, Huang S (2011) Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Radic Biol Med 50(5):624–632

  13. Dadgar Z, Abdali N, Elyasi Irai A, Salehian Z (2016) The consequence of vitamin E exposure on in vitro cadmium toxicity in rat bone marrow mesenchymal stem cells. Int Biol Biomed J 2(1):21–30

  14. Duan Y, Duan J, Feng Y, Huang X, Fan W, Wang K, Ouyang P, Deng Y, Du Z, Chen D (2018) Hepatoprotective activity of vitamin E and metallothionein in cadmium-induced liver injury in Ctenopharyngodon idellus Oxidative medicine and cellular longevity 2018

  15. Eleawa SM, Alkhateeb MA, Alhashem FH, Bin-Jaliah I, Sakr HF, Elrefaey HM, Elkarib AO, Alessa RM, Haidara MA, Shatoor AS (2014) Resveratrol reverses cadmium chloride-induced testicular damage and subfertility by downregulating p53 and Bax and upregulating gonadotropins and Bcl-2 gene expression. J Reprod Dev 60(2):115–127

  16. Elkhadragy MF, Abdel Moneim AE (2017) Protective effect of Fragaria ananassa methanolic extract on cadmium chloride (CdCl2)-induced hepatotoxicity in rats. Toxicol Mech Methods 27(5):335–345

  17. Elmallah MI, Elkhadragy MF, Al-Olayan EM, Abdel Moneim AE (2017) Protective effect of Fragaria ananassa crude extract on cadmium-induced lipid peroxidation, antioxidant enzymes suppression, and apoptosis in rat testes. Int J Mol Sci 18(5):957

  18. Evenson DP, Wixon R (2005) Environmental toxicants cause sperm DNA fragmentation as detected by the Sperm Chromatin Structure Assay (SCSA®). Toxicol Appl Pharmacol 207(2):532–537

  19. Feng Y, Huang X, Duan Y, Fan W, Duan J, Wang K, Geng Y, Ouyang P, Deng Y, Chen D (2018) The effect of vitamin E and metallothionein on the antioxidant capacities of cadmium-damaged liver in grass carp Ctenopharyngodon idellus. Biomed Res Int

  20. Fouad A, Jresat I (2015) Thymoquinone therapy abrogates toxic effect of cadmium on rat testes. Andrologia 47(4):417–426

  21. Gavazza M, Catalá A (2001) The effect of α-tocopherol on the lipid peroxidation of mitochondria and microsomes obtained from rat liver and testis. Mol Cell Biochem 225(1-2):121–128

  22. Ghooshchian M, Khodarahmi P, Tafvizi F (2017) Apoptosis-mediated neurotoxicity and altered gene expression induced by silver nanoparticles. Toxicol Ind Health 33(10):757–764

  23. Goyer RA, Liu J, Waalkes MP (2004) Cadmium and cancer of prostate and testis. Biometals 17(5):555–558

  24. Gupta RS, Gupta ES, Dhakal BK, Thakur AR, Ahnn J (2004) Vitamin C and vitamin Е protect the rat testes from cadmium-induced reactive oxygen species. Mol Cell 17(1):132–139

  25. Hossain S, Liu H-N, Nguyen M, Shore G, Almazan G (2009) Cadmium exposure induces mitochondria-dependent apoptosis in oligodendrocytes. Neurotoxicology 30(4):544–554

  26. Hu Y, Benedict MA, Ding L, Núñez G (1999) Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J 18(13):3586–3595

  27. Interdonato M, Pizzino G, Bitto A, Galfo F, Irrera N, Mecchio A, Pallio G, Ramistella V, Luca FD, Santamaria A (2015) Cadmium delays puberty onset and testis growth in adolescents. Clin Endocrinol 83(3):357–362

  28. Iyer S, Uren RT, Kluck RM (2019) Probing BAK and BAX activation and pore assembly with cytochrome c release, limited proteolysis, and oxidant-induced linkage. In: BCL-2 Family Proteins. Springer, pp 201–216

  29. Kandeil MA, Hassanin KM, Mohammed ET, Safwat GM, Mohamed DS (2018) Wheat germ and vitamin E decrease BAX/BCL-2 ratio in rat kidney treated with gentamicin. Beni-Suef Univ J Basic Appl Sci 7(3):257–262

  30. Kim K, Lee M, Park H, Kim J-H, Kim S, Chung H, Choi K, Kim I-S, Seong BL, Kwon IC (2006) Cell-permeable and biocompatible polymeric nanoparticles for apoptosis imaging. J Am Chem Soc 128(11):3490–3491

  31. Kondoh M, Araragi S, Sato K, Higashimoto M, Takiguchi M, Sato M (2002) Cadmium induces apoptosis partly via caspase-9 activation in HL-60 cells. Toxicology 170(1-2):111–117

  32. Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 15(6):691–699

  33. Laxman B, Hall DE, Bhojani MS, Hamstra DA, Chenevert TL, Ross BD, Rehemtulla A (2002) Noninvasive real-time imaging of apoptosis. Proc Natl Acad Sci 99(26):16551–16555

  34. Lee B, Jung J-H, Kim H-S (2012) Assessment of red onion on antioxidant activity in rat. Food Chem Toxicol 50(11):3912–3919

  35. Letai AG (2008) Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer 8(2):121

  36. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91(4):479–489

  37. Lin H-Y, Lai R, Lin S, Lin R, Wang M, Lin C, Lee H, Wang F, Chen J (2013) Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission via regulating DRP1 translocation. Cell Death Differ 20(1):139–153

  38. Lindsay J, Degli Esposti M, Gilmore AP (2011) Bcl-2 proteins and mitochondria—specificity in membrane targeting for death. Biochim Biophys Acta 1813(4):532–539

  39. Liu D, Shi J, Ibarra AC, Kakuda Y, Xue SJ (2008) The scavenging capacity and synergistic effects of lycopene, vitamin E, vitamin C, and β-carotene mixtures on the DPPH free radical. LWT-Food Sci Technol 41(7):1344–1349

  40. Liu S, Xu F-p, Yang Z-j, Li M, Min Y-h, Li S (2014) Cadmium-induced injury and the ameliorative effects of selenium on chicken splenic lymphocytes: mechanisms of oxidative stress and apoptosis. Biol Trace Elem Res 160(3):340–351

  41. Liu G, Zou H, Luo T, Long M, Bian J, Liu X, Gu J, Yuan Y, Song R, Wang Y (2016) Caspase-dependent and caspase-independent pathways are involved in cadmium-induced apoptosis in primary rat proximal tubular cell culture. PLoS One 11(11):e0166823

  42. Lopez E, Arce C, Oset-Gasque M, Canadas S, Gonzalez M (2006) Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Radic Biol Med 40(6):940–951

  43. Mahdavi S, Khodarahmi P, Roodbari N (2018) Effects of cadmium on Bcl-2/Bax expression ratio in rat cortex brain and hippocampus. Hum Exp Toxicol 37(3):321–328

  44. Maire M, Rast C, Vasseur P (2005) Di-(2-ethylhexyl) phthalate (DEHP) increases Bcl-2/Bax ratio and modifies c-myc expression in Syrian hamster embryo (SHE) cells. Toxicol Lett 158(3):237–245

  45. Medina MF, Arrieta MC, Villafañe MN, Klyver SMR, Odstrcil IMA, González ME (2017) Early signs of toxicity in testes and sperm of rats exposed to low cadmium doses. Toxicol Ind Health 33(7):576–587

  46. Mehranjani MS, Taefi R (2012) The protective role of vitamin E on the testicular tissue in rats exposed to sodium arsenite during the prenatal stage till sex maturity: a stereological analysis. Iran J Reprod Med 10(6):571

  47. Min Y, Li J, Liu F, Yeow EK, Xing B (2014) Near-infrared light-mediated photoactivation of a platinum antitumor prodrug and simultaneous cellular apoptosis imaging by upconversion-luminescent nanoparticles. Angew Chem Int Ed 53(4):1012–1016

  48. Mohamed D, Saber A, Omar A, Soliman A (2014) Effect of cadmium on the testes of adult albino rats and the ameliorating effect of zinc and vitamin E. Br J Sci 11(1):72–95

  49. Momeni HR, Oryan S, Eskandari N (2012) Effect of vitamin E on sperm number and testis histopathology of sodium arsenite-treated rats. Reprod Biol 12(2):171–181

  50. Oettinghaus B, D’Alonzo D, Barbieri E, Restelli LM, Savoia C, Licci M, Tolnay M, Frank S, Scorrano L (2016) DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress. Biochim Biophys Acta 1857(8):1267–1276

  51. Parmar MS, Syed I, Gray JP, Ray SD (2015) Curcumin, hesperidin, and rutin selectively interfere with apoptosis signaling and attenuate streptozotocin-induced oxidative stress-mediated hyperglycemia. Curr Neurovasc Res 12(4):363–374

  52. Pi H, Xu S, Zhang L, Guo P, Li Y, Xie J, Tian L, He M, Lu Y, Li M, Zhang Y, Zhong M, Xiang Y, Deng L, Zhou Z, Yu Z (2013) Dynamin 1-like-dependent mitochondrial fission initiates overactive mitophagy in the hepatotoxicity of cadmium. Autophagy 9(11):1780–1800

  53. Pizent A, Tariba B, Živković T (2012) Reproductive toxicity of metals in men. Arch Ind Hyg Toxicol 63(Supplement 1):35–46

  54. Pyakurel A, Savoia C, Hess D, Scorrano L (2015) Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis. Mol Cell 58(2):244–254

  55. Ramirez-Bajo MJ, de Atauri P, Ortega F, Westerhoff HV, Gelpi JL, Centelles JJ, Cascante M (2014) Effects of cadmium and mercury on the upper part of skeletal muscle glycolysis in mice. PLoS One 9(1):e80018

  56. Ranade AV, Tripathi Y, Rajalakshmi R, Vinodini N, Soubhagya R, Nayanatara A, Rekha D, Kumari M (2011) Effect of vitamin E administration on histopathological changes in rat testes following torsion and detorsion. Singap Med J 52(10):742–746

  57. Ranganathan P, Rao KA, Sudan JJ, Balasundaram S (2018) Cadmium effects on sperm morphology and semenogelin with relates to increased ROS in infertile smokers: an in vitro and in silico approach. Reprod Biol 18(2):189–197

  58. Rouhani F, Khodarahmi P, Naseh V (2019) NGF, BDNF and Arc mRNA expression in the hippocampus of rats after administration of morphine. Neurochem Res 1–8

  59. Sajjad S, Malik H, Farooq U, Rashid F, Nasim H, Tariq S, Rehman S (2014) Cadmium chloride toxicity revisited: effect on certain andrological, endocrinological and biochemical parameters of adult male rabbits. Physiol Res 63(4):505–512

  60. Shen B, Jeon J, Palner M, Ye D, Shuhendler A, Chin FT, Rao J (2013) Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-triggered nanoaggregation probe. Angew Chem Int Ed 52(40):10511–10514

  61. Siu ER, Mruk DD, Porto CS, Cheng CY (2009) Cadmium-induced testicular injury. Toxicol Appl Pharmacol 238(3):240–249

  62. Sjöström J, Blomqvist C, von Boguslawski K, Bengtsson N-O, Mjaaland I, Malmström P, Ostenstadt B, Wist E, Valvere V, Takayama S (2002) The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer. Clin Cancer Res 8(3):811–816

  63. Sun I-C, Lee S, Koo H, Kwon IC, Choi K, Ahn C-H, Kim K (2010) Caspase sensitive gold nanoparticle for apoptosis imaging in live cells. Bioconjug Chem 21(11):1939–1942

  64. Xu S, Pi H, Chen Y, Zhang N, Guo P, Lu Y, He M, Xie J, Zhong M, Zhang Y, Yu Z, Zhou Z (2013) Cadmium induced Drp1-dependent mitochondrial fragmentation by disturbing calcium homeostasis in its hepatotoxicity. Cell Death Dis 4:e540

  65. Xu Z, Jin X, Pan T, Liu T, Wan N, Li S (2017) Antagonistic effects of selenium on cadmium-induced apoptosis by restoring the mitochondrial dynamic equilibrium and energy metabolism in chicken spleens. Oncotarget 8(32):52629–52641

  66. Yari A, Asadi MH, Bahadoran H, Dashtnavard H, Imani H, Naghii MR (2010) Cadmium toxicity in spermatogenesis and protective effects of L-carnitine in adult male rats. Biol Trace Elem Res 137(2):216–225

  67. Zhang R, Zhu Y, Dong X, Liu B, Zhang N, Wang X, Liu L, Xu C, Huang S, Chen L (2017) Celastrol attenuates cadmium-induced neuronal apoptosis via inhibiting Ca2+-CaMKII-dependent Akt/mTOR pathway. J Cell Physiol 232(8):2145–2157

  68. Zhao L, Gu Q, Xiang L, Dong X, Li H, Ni J, Wan L, Cai G, Chen G (2017) Curcumin inhibits apoptosis by modulating Bax/Bcl-2 expression and alleviates oxidative stress in testes of streptozotocin-induced diabetic rats. Ther Clin Risk Manag 13:1099

Download references

Acknowledgments

The results described in this paper were based on a student thesis.

Author information

PK and MS designed the research. PK and PA conducted the studies. PK analyzed the data. PK interpreted the results. PK and PA wrote the manuscript. All authors read and approved the manuscript.

Correspondence to Parvin Khodarahmi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All protocols for animal experiments were approved by the institutional animal Ethical Committee, Parand branch, Islamic Azad University, Parand, Iran.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Amanpour, P., Khodarahmi, P. & Salehipour, M. Protective effects of vitamin E on cadmium-induced apoptosis in rat testes. Naunyn-Schmiedeberg's Arch Pharmacol 393, 349–358 (2020). https://doi.org/10.1007/s00210-019-01736-w

Download citation

Keywords

  • Cadmium
  • Vitamin E
  • Apoptosis
  • Mitochondrial dynamics
  • Testis