Skip to main content
Log in

Apoptotic rate and metallothionein levels in the tissues of cadmium-and copper-exposed rats

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

It is well known that cadmium (Cd) has toxic and carcinogenic effects in rodents and humans, but the effects of Cd on apoptosis are still not clear. Although some studies have shown that Cd has apoptotic potential, other studies have shown that Cd can be antiapoptotic. Parameters such as sensitivity of the exposed organism or cells and the exposure conditions should be important in delineating the effect of Cd on apoptosis. In the present study, we aimed to determine the apoptotic index (AI) of Sprague-Dawley rat tissues that are loaded at a lower Cd concentration than the critical concentration (50 μg/g) for its toxic effects. Metallothionein (MT) levels of tissues were also determined and the experiments repeated with copper (Cu)-exposed rats. We detected decreases in the apoptotic index in liver and lung tissues of Cd-exposed groups accompanied with an increase in MT levels. Also, decreases of AI were detected in the liver tissues of Cu-exposed groups. These findings indicate that Cd can suppress apoptosis in vivo. The possible role of MT expression on the suppression of apoptosis and the importance of free-Cd ion concentration on switching antiapoptotic effects to proapoptotic effects are also discussed.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. P. L. Goering, M. P. Waalkes, and C. D. Klassen, Toxicology of cadmium, in Handbook of Experimental Pharmacology Toxicology of Metals, Biochemical Effects, R. A. Goyer and M. G. Cherian, eds., Springer-Verlag, New York, vol. 115, pp. 189–214 (1994).

    Google Scholar 

  2. H. M. Perry, G. S. Thind, and E. F. Perry, The biology of cadmium, Med. Clin. North Am. 60(4), 759–769 (1976).

    PubMed  CAS  Google Scholar 

  3. R. A. Goyer and M. G. Cherian, Renal effects of metals, in Metal Toxicology, R. A. Goyer, C. D. Klaassen, and M. P. Waalkes, eds., Academic, San Diego, pp. 389–412 (1995).

    Google Scholar 

  4. International Agency for Research on Cancer, Beryllium, Cadmium, Mercury and Exposures in the Glass Industry, IARC, Lyon, 119–238 (1993).

    Google Scholar 

  5. National Toxicology Program, Tenth Report on Carcinogens, Department of Health and Human Services, Research, Triangle Park, NC, pp. III42-III44 (2000).

    Google Scholar 

  6. B. Pesch, J. Haerting, U. Ranft, A. Klimpel, B. Oelschlagel, and W. Schill, MURC Study Group. Occupational risk factors for renal cell carcinoma: agent-specific results from a case-control study in Germany, Int. J. Epidemiol. 29, 1014–1024 (2000).

    Article  PubMed  CAS  Google Scholar 

  7. M. P. Waalkes and R. R. Misra, Cadmium carcinogenicity and genotoxicity, in Toxicology of Metals, L. Chang, ed., CRC, Boca. Raton, FL, pp. 231–244 (1996).

    Google Scholar 

  8. M. P. Waalkes, Cadmium carcinogenesis, Mutat. Res. 533, 107–120 (2003).

    PubMed  CAS  Google Scholar 

  9. G. G. Schwartz and I. M. Reis, Is cadmium a cause of human pancreatic cancer, Cancer Epidemiol. Biomarkers Prev. 9, 139–145 (2000).

    PubMed  CAS  Google Scholar 

  10. World Health Organization, Guidelines for Drinking-Water Quality, 2nd ed. Addendum to Vol. 2, Health Criteria and Other Supporting Information. WHO, Geneva, pp. 31–46 (1998).

    Google Scholar 

  11. K. Schumann, H. G. Classen, H. H. Dieter, et al., Hohenheim consensus workshop: copper, Eur. J. Clin. Nutr. 56(6), 469–483 (2002).

    Article  PubMed  CAS  Google Scholar 

  12. M. C. Linder and M. Hazegh-Azam, Copper biochemistry and molecular biology, Am. J. Clin. Nutr. 63(5), 797S-811S (1996).

    PubMed  CAS  Google Scholar 

  13. B. Desoize, Metals and metal compounds in carcinogenesis, In Vivo 17(6), 529–539 (2003).

    PubMed  CAS  Google Scholar 

  14. T. Theophanides and J. Anastassopoulou, Copper and carcinogenesis, Crit. Rev. Oncol. Hematol. 42(1), 57–64 (2002).

    Article  PubMed  CAS  Google Scholar 

  15. D. H. Hamer, Metallothionein, Annu. Rev. Biochem. 55, 913–951 (1986).

    PubMed  CAS  Google Scholar 

  16. D. Curtis, J. L. Klaassen, and C. Supratim, Metallothionein: an intracellular protein to protect against cadmium toxicity, Annu. Rev. Pharmacol. Toxicol. 39, 267–294 (1999).

    Article  Google Scholar 

  17. K. Kiningham and E. Kasarskis, Antioxidant function of metallothionein, J. Trace Elements Exp. Med. 11, 219–226 (1998).

    Article  CAS  Google Scholar 

  18. L. Cai, M. Satoh, C. Tohyama, and M. G. Cherian, Metallothionein in radiation exposure: its induction and protective role, Toxicology 132(2–3), 85–98 (1999).

    Article  PubMed  CAS  Google Scholar 

  19. R. Shimoda, W. E. Achanzar, W. Qu, et al., Metallothionein is a potential negative regulator of apoptosis, Toxicol. Sci. 73, 294–300 (2003).

    Article  PubMed  CAS  Google Scholar 

  20. W. E. Achanzar, K. B. Achanzar, J. G. Lewis, M. M. Webber, and M. P. Waalkes, Cadmium induces c-myc, p53, and c-jun expression in normal human prostate epithelial cells as a prelude to apoptosis, Toxicol. Appl. Pharmacol. 16, 291–300 (2000).

    Article  CAS  Google Scholar 

  21. S. S. Habeebu, J. Liu, and C. D. Klaassen, Cadmium-induced apoptosis in mouse liver, Toxicol. Appl. Pharmacol. 149(2), 203–209 (1998).

    Article  PubMed  CAS  Google Scholar 

  22. B. A. Hart, C. H. Lee, G. S. Shukla, et al., Characterization of cadmium-induced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress, Toxicology 133, 43–58 (1999).

    Article  PubMed  CAS  Google Scholar 

  23. H. Shimada, Y. H. Shiao, M. Shibata, and M. P. Waalkes, Cadmium suppresses apoptosis induced by chromium, J. Toxicol. Environ. Health A 54, 159–168 (1998).

    Article  PubMed  CAS  Google Scholar 

  24. T. von Zglinicki, C. Edwall, E. Ostlund et al., Very low cadmium concentrations stimulate DNA synthesis and cell growth, J. Cell Sci. 103, 1073–1081 (1992).

    Google Scholar 

  25. C. Yuan, M. Kadiiska, W. E. Achanzar, R. P. Mason, and M. P. Waalkes, Possible role of caspase-3 inhibition in cadmium-induced blockage of apoptosis, Toxicol. Appl. Pharmacol. 164(3), 321–329 (2000).

    Article  PubMed  CAS  Google Scholar 

  26. D. Ozcelik, Y. Eralp, G. Oztekin, S. Dursun, and H. Uzunismail, The impact of penicillamine and zinc in hepatic and brain tissues of copper-overloaded rats, Trace Elements Electrolytes 18(1), 34–38 (2001).

    CAS  Google Scholar 

  27. D. Ozcelik, R. Ozaras, Z. Gurel, H. Uzun, and S. Aydin, Copper-mediated oxidative stress in rat liver, Biol. Trace Element Res. 96, 209–215 (2003).

    Article  CAS  Google Scholar 

  28. L. Cai, S. Iskander, M. G. Cherian, and R. R. Hammond, Zinc- or cadmium-pre-induced metallothionein protects human central nervous system cells and astrocytes from radiation-induced apoptosis, Toxicol. Lett. 146(3), 217–226 (2004).

    Article  PubMed  CAS  Google Scholar 

  29. K. Y. Kwon, J. H. Jang, S. Y. Kwon, C. H. Cho, H. K. Oh, and S. P. Kim, Cadmium induced acute lung injury and TUNEL expression of apoptosis in respiratory cells, J. Korean Med. Sci. 18(5), 655–662 (2003).

    PubMed  CAS  Google Scholar 

  30. R. Shimoda, T. Nagamine, H. Takagi, M. Mori, and M. P. Waalkes, Induction of apoptosis in cells by cadmium: quantitative negative correlation between basal or induced metallothionein concentration and apoptotic rate, Toxicol. Sci. 64(2), 208–215 (2001).

    Article  PubMed  CAS  Google Scholar 

  31. D. X. Deng, S. Chakrabarti, M. P. Waalkes, and M. G. Cherian, Metallothionein and apoptosis in primary human hepatocellular carcinoma and metastatic adenocarcinoma, Histopathology 32, 340–347 (1998).

    Article  PubMed  CAS  Google Scholar 

  32. Y. Kondo, J. M. Rusnak, D. G. Hoyt, C. E. Settineri, B. R. Pitt, and J. S. Lazo, Enhanced apoptosis in metallothionein null cells, Mol. Pharmacol. 52, 195–201 (1997).

    PubMed  CAS  Google Scholar 

  33. A. T. Miles, G. M. Hawksworth, J. H. Beattie, and V. Rodilla, Induction, regulation, degradation, and biological significance of mammalian metallothioneins, Crit. Rev. Biochem. Mol. Biol. 35(1), 35–70 (2000).

    Article  PubMed  CAS  Google Scholar 

  34. M. Hamatake, K. Iguchi, K. Hirano, and R. Ishida, Zinc induces mixed types of cell death, necrosis, and apoptosis in molt-4 cells, J. Biochem. 128, 933–939 (2000).

    PubMed  CAS  Google Scholar 

  35. M. Ishido, S. Homma-Takeda, C. Tohyama, and T. Suzuki, Apoptosis in rat renal proximal tubular cells induced by cadmium, J. Toxicol. Environ. Health 55, 1–12 (1998).

    Article  CAS  Google Scholar 

  36. M. Ishido, C. Tohyama, and T. Suzuki, Cadmium-bound metallothionein induces apoptosis in rat kidneys, but not in cultured kidney LLC-PK1 cells, Life Sci. 64, 797–804 (1999).

    Article  PubMed  CAS  Google Scholar 

  37. C. Erfurt, E. Roussa, and F. Thevenod, Apoptosis by Cd2+ or CdMT in proximal tubule cells: different uptake routes and permissive role of endo/lysosomal CdMT uptake, Am. J. Physiol. Cell Physiol. 285(6), C1367-C1376 (2003).

    PubMed  CAS  Google Scholar 

  38. J. Liu, S. S. Habeebu, Y. Liu, and C. D. Klaassen, Acute CdMT injection is not a good model to study chronic Cd nephropathy: comparison of chronic CdCl2 and CdMT exposure with acute CdMT injection in rats, Toxicol. Appl. Pharmacol. 153, 48–58 (1998).

    Article  PubMed  CAS  Google Scholar 

  39. T. Kjellström, C. G. Elinder, and L. Friberg, Conceptual problems in establishing the critical concentration of cadmium in human kidney cortex, Environ. Res. 33, 284–295 (1984).

    Article  PubMed  Google Scholar 

  40. World Health Organization, Cadmium, in Safety Evaluation of Certain Food Additives and Contaminants, 55th Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), WHO Food Additives Series No. 46, WHO, Geneva, pp. 247–305 (2001).

    Google Scholar 

  41. A. Tanimoto, T. Hamada, and O. Koide, Cell death and regeneration of renal proximal tubular cells in rats with subchronic cadmium intoxication, Toxicol. Pathol. 21(4), 341–352 (1993).

    Article  PubMed  CAS  Google Scholar 

  42. A. Tanimoto, T. Hamada, K. Higashi, and Y. Sasagur, Distribution of cadmium and metallothionein in CdCl2-exposed rat kidney: relationship with apoptosis and regeneration, Pathol. Int. 49, 125–132 (1999).

    Article  PubMed  CAS  Google Scholar 

  43. M. P. Waalkes, Cadmium carcinogenesis in review, J. Inorg. Biochem. 79, 241–244 (2000).

    Article  PubMed  CAS  Google Scholar 

  44. C. Davis and S. Newman, Inadequate dietary copper increases the spontaneous tumorigenesis in the Min mouse, Cancer Lett. 159, 57–62 (2001).

    Article  Google Scholar 

  45. P. Senesse, S. Meance, V. Cottet, J. Faivre, and M. C. Boutron-Ruault, High dietary iron and copper and risk of colorectal cancer: a case-control study in burgundy, Nutr. Cancer 49(1), 66–71 (2004).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gurel, Z., Ozcelik, D. & Dursun, S. Apoptotic rate and metallothionein levels in the tissues of cadmium-and copper-exposed rats. Biol Trace Elem Res 116, 203–217 (2007). https://doi.org/10.1007/BF02685931

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02685931

Index Entries

Navigation