, Volume 28, Issue 2, pp 255–265 | Cite as

Roles of oxidative stress and endoplasmic reticulum stress in selenium deficiency-induced apoptosis in chicken liver



Oxidative stress and endoplasmic reticulum (ER) stress are involved in different types of stress-induced injuries. The aim of the present study was to evaluate the effect of Se deficiency on oxidative stress, ER stress and apoptosis in chicken livers. Chickens (1 day old, n = 180) were randomly divided into two groups: the L group [fed with a Se-deficient (Se 0.033 mg/kg) diet] and the control group [fed with a normal (Se 0.2 mg/kg) diet]. Factor-associated oxidative stress, catalase (CAT) activity, H2O2 production and the inhibition of hydroxyl radicals (·OH) in the chicken liver were determined on days 15, 25, 35, 45, 55 and 65, respectively. In addition, ER stress-related genes (GRP78, GRP94, ATF4, ATF6 and IRE) and apoptosis-related genes (caspase3 and Bcl-2) were examined by fluorescence quantitative PCR or western blot analysis. Apoptosis levels were also measured using ultrastructural observations and the TdT-mediated dUTP nick end labeling assay. The results showed that CAT activity and ·OH inhibition were decreased and that H2O2 production was increased in the low-Se group, which demonstrated that oxidative stress occurred in the chicken liver. The ER stress-related genes (GRP78, GRP94, ATF4, ATF6 and IRE) and the apoptosis-related gene caspase3 were increased (p < 0.05), while Bcl-2 was decreased (p < 0.05) by Se deficiency. In addition, apoptosis and ER lesions were observed by ultrastructural observations of the chicken liver in the low-Se group. The level of apoptosis and the number of apoptotic cells increased with time. These results indicated that the oxidative-ER stress pathway participates in Se deficiency-induced apoptosis in the chicken liver.


Selenium deficiency Oxidative stress Endoplasmic reticulum stress Apoptosis Chicken liver 



This study was supported by the National Natural Science Foundation of China (31272626); the International (Regional) Cooperation and Exchange Projects of the National Natural Science Foundation of China (31320103920) and the Study Abroad Foundation of Heilongjiang Province (LC201031).

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP (2010) Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J Biol Chem 285:6091–6100. doi: 10.1074/jbc.M109.014092 CrossRefPubMedCentralPubMedGoogle Scholar
  2. Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS (2009) Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta 30(Suppl A):S43–S48. doi: 10.1016/j.placenta.2008.11.003 CrossRefPubMedGoogle Scholar
  3. Chen YW et al (2010) Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways. Toxicol Lett 199:333–340. doi: 10.1016/j.toxlet.2010.09.016 CrossRefPubMedGoogle Scholar
  4. Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ, Samali A (2011) Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med 15:2025–2039. doi: 10.1111/j.1582-4934.2011.01374.x CrossRefPubMedGoogle Scholar
  5. Fan TJ, Han LH, Cong RS, Liang J (2005) Caspase family proteases and apoptosis. Acta Biochim Biophys Sin 37:719–727CrossRefPubMedGoogle Scholar
  6. Fischer JL, Lancia JK, Mathur A, Smith ML (2006) Selenium protection from DNA damage involves a Ref1/p53/Brca1 protein complex. Anticancer Res 26:899–904PubMedGoogle Scholar
  7. Gao X, Xing H, Li S, Li J, Ying T, Xu S (2012) Selenium regulates gene expression of selenoprotein W in chicken gastrointestinal tract. Biol Trace Elem Res 145:181–188. doi: 10.1007/s12011-011-9175-x CrossRefPubMedGoogle Scholar
  8. Hammadi M et al (2013) Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78. FASEB J 27:1600–1609. doi: 10.1096/fj.12-218875 CrossRefPubMedGoogle Scholar
  9. Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917. doi: 10.1016/j.cell.2010.02.034 CrossRefPubMedCentralPubMedGoogle Scholar
  10. Irmak MB, Ince G, Ozturk M, Cetin-Atalay R (2003) Acquired tolerance of hepatocellular carcinoma cells to selenium deficiency: a selective survival mechanism? Cancer Res 63:6707–6715PubMedGoogle Scholar
  11. Jergens A et al (2014) Bcl-2/caspase 3 mucosal imbalance favors T cell resistance to apoptosis in dogs with inflammatory bowel disease. Vet Immunol Immunopathol 158:167–174. doi: 10.1016/j.vetimm.2014.01.004 CrossRefPubMedGoogle Scholar
  12. Jiang C et al (2012) The role of the IRE1 pathway in PBDE-47-induced toxicity in human neuroblastoma SH-SY5Y cells in vitro. Toxicol Lett 211:325–333. doi: 10.1016/j.toxlet.2012.04.009 CrossRefPubMedGoogle Scholar
  13. Jimbo A et al (2003) ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. Exp Cell Res 283:156–166CrossRefPubMedGoogle Scholar
  14. Kayanoki Y, Fujii J, Islam KN, Suzuki K, Kawata S, Matsuzawa Y, Taniguchi N (1996) The protective role of glutathione peroxidase in apoptosis induced by reactive oxygen species. J Biochem 119:817–822CrossRefPubMedGoogle Scholar
  15. Kim YS, Jhon DY, Lee KY (2004) Involvement of ROS and JNK1 in selenite-induced apoptosis in Chang liver cells. Exp Mol Med 36:157–164. doi: 10.1038/emm.2004.22 CrossRefPubMedGoogle Scholar
  16. Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030. doi: 10.1038/nrd2755 CrossRefPubMedGoogle Scholar
  17. Kitamura M, Hiramatsu N (2010) The oxidative stress: endoplasmic reticulum stress axis in cadmium toxicity. Biometals 23:941–950. doi: 10.1007/s10534-010-9296-2 CrossRefPubMedGoogle Scholar
  18. Ko WS et al (2005) Blood micronutrient, oxidative stress, and viral load in patients with chronic hepatitis C. World J Gastroenterol 11:4697–4702CrossRefPubMedGoogle Scholar
  19. Lee AS (2001) The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci 26:504–510CrossRefPubMedGoogle Scholar
  20. Lee AS (2005) The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 35:373–381. doi: 10.1016/j.ymeth.2004.10.010 CrossRefPubMedGoogle Scholar
  21. Li HT, Feng L, Jiang WD, Liu Y, Jiang J, Li SH, Zhou XQ (2013) Oxidative stress parameters and anti-apoptotic response to hydroxyl radicals in fish erythrocytes: protective effects of glutamine, alanine, citrulline and proline. Aquat Toxicol 126:169–179. doi: 10.1016/j.aquatox.2012.11.005 CrossRefPubMedGoogle Scholar
  22. Liang X, Xu K, Xu Y, Liu J, Qian X (2011) B1-induced caspase-independent apoptosis in MCF-7 cells is mediated by down-regulation of Bcl-2 via p53 binding to P2 promoter TATA box. Toxicol Appl Pharmacol 256:52–61. doi: 10.1016/j.taap.2011.07.010 CrossRefPubMedGoogle Scholar
  23. Liu XF, Zhang LM, Guan HN, Zhang ZW, Xu SW (2013) Effects of oxidative stress on apoptosis in manganese-induced testicular toxicity in cocks. Food Chem Toxicol 60:168–176. doi: 10.1016/j.fct.2013.07.058 CrossRefPubMedGoogle Scholar
  24. Matsuda A, Kimura M, Itokawa Y (1998) Influence of selenium deficiency on vital functions in rats. Biol Trace Elem Res 61:287–301. doi: 10.1007/BF02789089 CrossRefPubMedGoogle Scholar
  25. Miao K, Zhang L, Yang S, Qian W, Zhang Z (2013) Intervention of selenium on apoptosis and Fas/FasL expressions in the liver of fluoride-exposed rats. Environ Toxicol Pharmacol 36:913–920. doi: 10.1016/j.etap.2013.08.003 CrossRefPubMedGoogle Scholar
  26. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45CrossRefPubMedCentralPubMedGoogle Scholar
  27. Qin P, Liu R (2013) Oxidative stress response of two fluoroquinolones with catalase and erythrocytes: a combined molecular and cellular study. J Hazard Mater 252–253:321–329. doi: 10.1016/j.jhazmat.2013.03.006 CrossRefPubMedGoogle Scholar
  28. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897–907. doi: 10.1038/nrm1496 CrossRefPubMedGoogle Scholar
  29. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529. doi: 10.1038/nrm2199 CrossRefPubMedGoogle Scholar
  30. Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochimica et biophysica acta 1833:3460–3470. doi: 10.1016/j.bbamcr.2013.06.028 CrossRefPubMedGoogle Scholar
  31. Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63. doi: 10.1016/j.mrfmmm.2004.06.056 CrossRefPubMedGoogle Scholar
  32. Seong YA, Shin PG, Kim GD (2013) Anacardic acid induces mitochondrial-mediated apoptosis in the A549 human lung adenocarcinoma cells. Int J Oncol 42:1045–1051. doi: 10.3892/ijo.2013.1763 PubMedGoogle Scholar
  33. Seong YA, Shin PG, Yoon JS, Yadunandam AK, Kim GD (2014) Induction of the endoplasmic reticulum stress and autophagy in human lung carcinoma A549 cells by anacardic acid. Cell Biochem Biophys 68:369–377. doi: 10.1007/s12013-013-9717-2 CrossRefPubMedGoogle Scholar
  34. Sharifi AM, Eslami H, Larijani B, Davoodi J (2009) Involvement of caspase-8, -9, and -3 in high glucose-induced apoptosis in PC12 cells. Neurosci Lett 459:47–51. doi: 10.1016/j.neulet.2009.03.100 CrossRefPubMedGoogle Scholar
  35. Sheng PF, Jiang Y, Zhang ZW, Zhang JL, Li S, Zhang ZQ, Xu SW (2014) The effect of Se-deficient diet on gene expression of inflammatory cytokines in chicken brain. Biometals 27:33–43. doi: 10.1007/s10534-013-9682-7 CrossRefPubMedGoogle Scholar
  36. Srivastava RK et al (2013) Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption. Toxicol Appl Pharmacol 272:879–887. doi: 10.1016/j.taap.2013.08.004 CrossRefPubMedGoogle Scholar
  37. Sun YY, Yin Y, Zhang JF, Yu HX, Wang XR, Wu JC, Xue YQ (2008) Hydroxyl radical generation and oxidative stress in Carassius auratus liver, exposed to pyrene. Ecotoxicol Environ Saf 71:446–453. doi: 10.1016/j.ecoenv.2007.12.016 CrossRefPubMedGoogle Scholar
  38. Sun B, Wang R, Li J, Jiang Z, Xu S (2011) Dietary selenium affects selenoprotein W gene expression in the liver of chicken. Biol Trace Elem Res 143:1516–1523. doi: 10.1007/s12011-011-8995-z CrossRefPubMedGoogle Scholar
  39. Tagawa Y, Hiramatsu N, Kasai A, Hayakawa K, Okamura M, Yao J, Kitamura M (2008) Induction of apoptosis by cigarette smoke via ROS-dependent endoplasmic reticulum stress and CCAAT/enhancer-binding protein-homologous protein (CHOP). Free Radic Biol Med 45:50–59. doi: 10.1016/j.freeradbiomed.2008.03.003 CrossRefPubMedGoogle Scholar
  40. Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Investig 115:2656–2664. doi: 10.1172/JCI26373 CrossRefPubMedCentralPubMedGoogle Scholar
  41. Xu SW, Yao HD, Zhang J, Zhang ZW, Wang JT, Zhang JL, Jiang ZH (2013) The oxidative damage and disbalance of calcium homeostasis in brain of chicken induced by selenium deficiency. Biol Trace Elem Res 151:225–233. doi: 10.1007/s12011-012-9552-0 CrossRefPubMedGoogle Scholar
  42. Yao HD, Wu Q, Zhang ZW, Li S, Wang XL, Lei XG, Xu SW (2013a) Selenoprotein W serves as an antioxidant in chicken myoblasts. Biochim Biophys Acta 1830:3112–3120. doi: 10.1016/j.bbagen.2013.01.007 CrossRefPubMedGoogle Scholar
  43. Yao HD et al (2013b) Gene expression of endoplasmic reticulum resident selenoproteins correlates with apoptosis in various muscles of se-deficient chicks. J Nutr 143:613–619. doi: 10.3945/jn.112.172395 CrossRefPubMedCentralPubMedGoogle Scholar
  44. Yokouchi M et al (2008) Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem 283:4252–4260. doi: 10.1074/jbc.M705951200 CrossRefPubMedGoogle Scholar
  45. Yu D, Li JL, Zhang JL, Gao XJ, Xu S (2011) Effects of dietary selenium on selenoprotein W gene expression in the chicken immune organs. Biol Trace Elem Res 144:678–687. doi: 10.1007/s12011-011-9062-5 CrossRefPubMedGoogle Scholar
  46. Zhang ZW, Zhang JL, Gao YH, Wang QH, Li S, Wang XL, Xu SW (2013) Effect of oxygen free radicals and nitric oxide on apoptosis of immune organ induced by selenium deficiency in chickens. Biometals 26:355–365. doi: 10.1007/s10534-013-9612-8 CrossRefPubMedGoogle Scholar
  47. Zhang P, Sun Q, Zhao C, Ling S, Li Q, Chang YZ, Li Y (2014) HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4. Cell Signal 26:556–563. doi: 10.1016/j.cellsig.2013.11.026 CrossRefPubMedGoogle Scholar
  48. Zhou N, Xiao H, Li TK, Nur EKA, Liu LF (2003) DNA damage-mediated apoptosis induced by selenium compounds. J Biol Chem 278:29532–29537. doi: 10.1074/jbc.M301877200 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Veterinary Medicine, College of Veterinary MedicineNortheast Agricultural UniversityHarbinPeople’s Republic of China

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