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Oxidative Stress and Ca2+ Signals Involved on Cadmium-Induced Apoptosis in Rat Hepatocyte

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Abstract

Cadmium (Cd) is an important industrial and environmental pollutant. In animals, the liver is the major target organ of Cd toxicity. In this study, rat hepatocytes were treated with 2.5∼10 μM Cd for various durations. Studies on nuclear morphology, chromatin condensation, and apoptotic cells demonstrate that Cd concentrations ranging within 2.5∼10 μM induced apoptosis. The early-stage marker of apoptosis, i.e., decreased mitochondrial membrane potential, was observed as early as 1.5 h at 5 μM Cd. Significant (P < 0.01) reactive oxygen species (ROS) production at 5 μM Cd and 0.75 h occurred prior to the decrease of the mitochondrial membrane potential, suggesting the involvement of ROS in mitochondrial membrane damage. Glutathione (GSH) level significantly decreased after cell treatment with 5 and 10 μM Cd after 12 h (P < 0.01). Meanwhile, the intracellular free Ca2+ concentration ([Ca2+] i ) of Cd-exposed cells significantly increased (P < 0.01) at 1.5 h, and pretreatment with the calcium chelator Bapta-AM partially blocked Cd-induced apoptosis. This finding indicated that the elevation of [Ca2+] i may play an important role in apoptosis. Overall, these results showed that oxidative stress and Ca2+ signaling were critical mediators of the Cd-induced apoptosis of rat hepatocytes.

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References

  1. Ye J, Mao W, Wu A et al (2007) Cadmium-induced apoptosis in human normal liver L-02 cells by acting on mitochondria and regulating Ca2+ signals. Environ Toxicol Pharmacol 24:45–54

    Article  PubMed  Google Scholar 

  2. Savolainen H (1995) Cadmium-associated renal disease. Ren Fail 17:483–487

    Article  PubMed  CAS  Google Scholar 

  3. Lecoeur S, Huynh-Delerme C, Blais A et al (2002) Implication of distinct proteins in cadmium uptake and transport by intestinal cells HT-29. Cell Biol Toxicol 18:409–423

    Article  PubMed  CAS  Google Scholar 

  4. Wang J, Wang Q, Li J et al (2012) Cadmium induces hydrogen peroxide production and initiates hydrogen peroxide-dependent apoptosis in the gill of freshwater crab, Sinopotamon henanense. Comp Biochem Physiol Part C: Toxicol Pharmcol 156:195–201

    CAS  Google Scholar 

  5. Alpsoy S, Kanter M, Aktas C et al. (2014) Protective effects of onion extract on cadmium-induced oxidative stress, histological damage, and apoptosis in rat heart. Biol Trace Elem Res 159:297–303

  6. Hagar H, Al Malki W (2014) Betaine supplementation protects against renal injury induced by cadmium intoxication in rats: role of oxidative stress and caspase-3. Environ Toxicol Pharmacol 37:803–811

    Article  PubMed  CAS  Google Scholar 

  7. Jiang C, Yuan Y, Hu F et al (2014) Cadmium induces PC12 cells apoptosis via an extracellular signal-regulated kinase and c-Jun N-terminal kinase-mediated mitochondrial apoptotic pathway. Biol Trace Elem Res 158:249–258

    Article  PubMed  CAS  Google Scholar 

  8. Chen D, Xu Y, Du J et al (2014) Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB. Biochem Biophys Res Commun 445:95–99

    Article  PubMed  CAS  Google Scholar 

  9. Pham T, Marion M, Denizeau F et al (2006) Cadmium-induced apoptosis in rat hepatocytes does not necessarily involve caspase-dependent pathways. Toxicol in Vitro 20:1331–1342

    Article  PubMed  CAS  Google Scholar 

  10. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    Article  PubMed  CAS  Google Scholar 

  11. Oh S, Lim S (2006) A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation. Toxicol Appl Pharmacol 212:212–223

    Article  PubMed  CAS  Google Scholar 

  12. Nazıroğlu M, Yoldaş N, Uzgur EN et al (2013) Role of contrast media on oxidative stress, Ca(2+) signaling and apoptosis in kidney. J Membrane Biol 246:91–100

    Article  Google Scholar 

  13. Nazıroğlu M (2012) Molecular role of catalase on oxidative stress-induced Ca(2+) signaling and TRP cation channel activation in nervous system. J Receptors Signal Transduct 32:134–141

    Article  Google Scholar 

  14. Pathak N, Khandelwal S (2006) Oxidative stress and apoptotic changes in murine splenocytes exposed to cadmium. Toxicology 220:26–36

    Article  PubMed  CAS  Google Scholar 

  15. Stohs S, Bagchi D, Hassoun E et al (2000) Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol 19:201–214

    PubMed  CAS  Google Scholar 

  16. Wang L, Xu T, W-w L et al (2011) Cadmium-induced oxidative stress and apoptotic changes in the testis of freshwater crab, Sinopotamon henanense. PLoS One 6:e27853

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Ghazizadeh V, Nazıroğlu M (2014) Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats. Metab Brain Dis 5:1–13

    Google Scholar 

  18. Uguz AC, Cig B, Espino J et al (2012) Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells. J Pineal Res 53:91–98

    Article  PubMed  CAS  Google Scholar 

  19. Melendez J, Davies K (1996) Manganese superoxide dismutase modulates interleukin-1alpha levels in HT-1080 fibrosarcoma cells. J Biol Chem 271:18898

    Article  PubMed  CAS  Google Scholar 

  20. Kowaltowski A, Netto L, Vercesi A (1998) The thiol-specific antioxidant enzyme prevents mitochondrial permeability transition. J Biol Chem 273:12766

    Article  PubMed  CAS  Google Scholar 

  21. Lemarié A, Lagadic-Gossmann D, Morzadec C et al (2004) Cadmium induces caspase-independent apoptosis in liver Hep3B cells: role for calcium in signaling oxidative stress-related impairment of mitochondria and relocation of endonuclease G and apoptosis-inducing factor. Free Radic Biol Med 36:1517–1531

    Article  PubMed  Google Scholar 

  22. Jin L, Li C, Li R et al (2014) Corticotropin-releasing hormone receptors mediate apoptosis via cytosolic calcium-dependent phospholipase A2 and migration in prostate cancer cell RM-1. J Mol Endocrinol 52:255–267

    Article  PubMed  CAS  Google Scholar 

  23. Shen H, Dong S, Ong C (2001) Critical role of calcium overloading in cadmium-induced apoptosis in mouse thymocytes. Toxicol Appl Pharmacol 171:12–19

    Article  PubMed  CAS  Google Scholar 

  24. Yuan Y, Jiang C, Xu H et al (2013) Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway. PLoS One 8:e64330

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Baker T, VanVooren H, Smith W et al (2003) Involvement of calcium channels in the sexual dimorphism of cadmium-induced hepatotoxicity. Toxicol Lett 137:185–192

    Article  PubMed  CAS  Google Scholar 

  26. Lin W, Liao Y, Liau M et al (2006) Inhibitory effect of CDA-II, a urinary preparation, on aflatoxin B1-induced oxidative stress and DNA damage in primary cultured rat hepatocytes. Food Chem Toxicol 44:546–551

    Article  PubMed  CAS  Google Scholar 

  27. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  28. Pathak N, Khandelwal S (2006) Influence of cadmium on murine thymocytes: potentiation of apoptosis and oxidative stress. Toxicol Lett 165:121–132

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Bai J, Rodriguez AM, Melendez JA et al (1999) Overexpression of catalase in cytosolic or mitochondrial compartment protects HepG2 cells against oxidative injury. J Biol Chem 274:26217–26224

    Article  PubMed  CAS  Google Scholar 

  31. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  PubMed  CAS  Google Scholar 

  32. Yuan Y, Bian J, Liu X et al (2012) Oxidative stress and apoptotic changes of rat cerebral cortical neurons exposed to cadmium in vitro. Biomed Environ Sci 25:172–181

    CAS  Google Scholar 

  33. Shih C, Ko W, Wu J et al (2004) Mediating of caspase-independent apoptosis by cadmium through the mitochondria-ROS pathway in MRC-5 fibroblasts. J Cell Biochem 91:384–397

    Article  PubMed  CAS  Google Scholar 

  34. Bolduc J-S, Denizeau F, Jumarie C (2004) Cadmium-induced mitochondrial membrane-potential dissipation does not necessarily require cytosolic oxidative stress: studies using rhodamine-123 fluorescence unquenching. Toxicol Sci 77:299–306

    Article  PubMed  CAS  Google Scholar 

  35. Sivaprasad R, Nagaraj M, Varalakshmi P (2002) Lipoic acid in combination with a chelator ameliorates lead-induced peroxidative damages in rat kidney. Arch Toxicol 76:437–441

    Article  PubMed  CAS  Google Scholar 

  36. Sivaprasad R, Nagaraj M, Varalakshmi P (2004) Combined efficacies of lipoic acid and 2, 3-dimercaptosuccinic acid against lead-induced lipid peroxidation in rat liver. J Nutr Biochem 15:18–23

    Article  PubMed  CAS  Google Scholar 

  37. Pulido M, Parrish A (2003) Metal-induced apoptosis: mechanisms. Mutat Res-Fundam Mol Mech Mutagen 533:227–241

    Article  CAS  Google Scholar 

  38. Desagher S, Martinou J-C (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10:369–377

    Article  PubMed  CAS  Google Scholar 

  39. Yang C, Shen H, Shen Y et al (1997) Cadmium-induced oxidative cellular damage in human fetal lung fibroblasts (MRC-5 cells). Environ Health Perspect 105:712–716

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Beyersmann D, Hechtenberg S (1997) Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol 144:247–261

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are thankful to Dr Mao-Zhi Hu for his technical assistance in the flow cytometry analysis.

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Authors and Affiliations

  1. College of Animal Science and Technology, Henan University of Science and Technology, No. 70 Tianjin Road, Luoyang, 471003, People’s Republic of China

    Jicang Wang & Huali Zhu

  2. College of Veterinary Medicine, Yangzhou University, No. 12 East Wenhui Road, Yangzhou, 225009, People’s Republic of China

    Xuezhong Liu & Zongping Liu

Authors
  1. Jicang Wang
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  2. Huali Zhu
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  3. Xuezhong Liu
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  4. Zongping Liu
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Correspondence to Jicang Wang.

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Wang, J., Zhu, H., Liu, X. et al. Oxidative Stress and Ca2+ Signals Involved on Cadmium-Induced Apoptosis in Rat Hepatocyte. Biol Trace Elem Res 161, 180–189 (2014). https://doi.org/10.1007/s12011-014-0105-6

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  • DOI: https://doi.org/10.1007/s12011-014-0105-6

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