, Volume 28, Issue 1, pp 21–33 | Cite as

Effect of Cr(VI) and Ni(II) metal ions on human adipose derived stem cells

  • R. Indra
  • K. Purna Sai
  • A. Rajaram
  • Rama Rajaram


Environmental exposure of Cr(VI) and Ni(II) due to rapid industrialization causes adverse effects in living tissues. Small quantities of these ions also find their way into tissues when metal alloys are used as implants. Even though considerable research has been done on the effects due to their exposure in animal cells, there are only very few reports on how they can affect stem cells which have been shown to be found in adult tissues as well, albeit in small quantities. Hence this study was aimed at understanding how Cr(VI) and Ni(II) affect human adipose derived stem cells (hADSCs) in a cell culture environment. Our results indicate that both ions induce apoptosis in a concentration and time dependent manner with loss of mitochondrial membrane potential (MMP) and corresponding increase in caspase-3 activity. With regard to Ni(II), apoptosis seems to occur only in a small percentage of cells while necrosis is predominant. It can be inferred that the long term exposure of these metals may cause adverse effects in stem cell proliferation and differentiation.


hADSCs Apoptosis Necrosis Cr(VI) Ni(II) Caspase-3 activity 



The authors thank the Director, CLRI, Chennai, India for providing necessary facilities to carry out our work and CSIR, New Delhi for the financial assistance provided through the CSIR XII-five year plan (NanoShe BSC0112).

Conflict of interest

The authors do not have any conflict of interests.

Supplementary material

10534_2014_9800_MOESM1_ESM.doc (94 kb)
Supplementary material 1 (DOC 93 kb)


  1. Afolaranmi GA, Tettey J, Meek RMD, Grant MH (2008) Release of Chromium from orthopaedic arthroplasties. J Orthop 2:10–18Google Scholar
  2. Agrawal A, Kumar V, Pandey BD (2006) Remediation options for the treatment of electroplating and leather tanning effluent containing chromium—a review. Min Process Extr Met Rev 27:99–1306CrossRefGoogle Scholar
  3. Anto V, Valletta R, Amato M, Schweikl H, Simeone M, Paduano S, Rengo S, Spagnuolo G (2012) Effect of Nickel Chloride on Cell Proliferation. Open Dent J 6:177–181PubMedCentralPubMedCrossRefGoogle Scholar
  4. Cai BZ, Meng FY, Zhu SL, Zhao J, Liu JQ, Liu CJ, Chen N, Ye ML, Li ZY, Ai J, Lu YJ, Yang BF (2010) Arsenic trioxide induces the apoptosis in bone marrow mesenchymal stem cells by intracellular calcium signal and caspase-3 pathways. Toxicol Lett 193:173–178PubMedCrossRefGoogle Scholar
  5. Case CP, Langkamer VG, James C, Palmer MR, Kemp AJ, Heap PF, Solomon L (1994) Widespread dissemination of metal debries from implants. J Bone Joint Surg Br 76:701–712PubMedGoogle Scholar
  6. Chen L, Ovesen JL, Puga A, Xia Y (2009) Distinct contributions of JNK and p38 to Chromium cytotoxicity and inhibition of murine embryonic stem cell differentiation. Environ Health Perspect 117:1124–1130PubMedCentralPubMedCrossRefGoogle Scholar
  7. Chen CY, Lin TK, Chang YC, Wang YF, Shyu HW, Lin KH, Chou MC (2010) Nickel(II)-induced oxidative stress, apoptosis, G2/M arrest, and genotoxicity in normal rat kidney cells. J Toxicol Environ Health 73:529–539CrossRefGoogle Scholar
  8. Ciubar R, Mitran V, Cimpean A, Ioedachescu D (2006) In vitro effects of nickel on human embrionary lung fibroblast. Rev Roum Chim 51:199–203Google Scholar
  9. Codd R, Dillon CT, Levina A, Lay PA (2001) Studies on the genotoxicity of chromium: from the test tube to the cell. Coord Chem Rev 216:537–582CrossRefGoogle Scholar
  10. Disegil JA and Eschbachz L (2000) Stainless steel in bone surgery. Injury Int I Care Injured 31:S-D24Google Scholar
  11. Engeland MV, Nieland LJW, Ramaekers FCS, Schutte B, Reutelingsperger CPM (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31:1–9PubMedCrossRefGoogle Scholar
  12. Gafni Y, Turgeman G, Liebergal M, Pelled G, Gazit Z, Gazit D (2004) Stem cells as vehicles for orthopedic gene therapy. Gene Ther 11:417–426PubMedCrossRefGoogle Scholar
  13. Garbuz DS, Tanzer M, Greidanus NV, Masri BA, Duncan CP (2010) Metal-on-metal hip resurfacing versus large-diameter head metal-on-metal total hip arthroplasty. Clin Orthop Relat Res 468:318–325PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gawkrodger DJ (1993) Nickel sensitivity and the implantation of orthopedic prostheses. Contact Dermatitis 28:257–259PubMedCrossRefGoogle Scholar
  15. Gioacchino MD, Petrarca C, Perrone A, Farina M, Sabbioni THE, Martino S, Esposito DL, Lottie LV, Costantini RM (2008) Autophagy as an ultrastructural marker of heavy metal toxicity in human cord blood hematopoietic stem cells. Sci Total Environ 392:50–58PubMedCrossRefGoogle Scholar
  16. Habijan T, Bremm O, Esenwein SA, Muhr G, Koller M (2007) Influence of nickel ions on human multipotent mesenchymal stromal cells (hMSCs). Mater Werkst 38:969–974CrossRefGoogle Scholar
  17. Hallab NJ, Anderson NJ, Stafford T, Glant T, Jacobs JJ (2005) Lymphocyte responses in patients with total hip arthroplasty. J Orthop Res 23:384–391PubMedCrossRefGoogle Scholar
  18. He MD, Xu SC, Lu YH, Li L, Zhong M, Zhang YW, Wang Y, Yang MLJ, Zhang GB, Yu ZP, Zhou Z (2011) L-carnitine protects against nickel-induced neurotoxicity by maintaining mitochondrial function in Neuro-2a cells. Toxicol Appl Pharmacol 253:38–44PubMedCrossRefGoogle Scholar
  19. Hill R, Leidal AM, Madureira PA, Gillis LD, Cochrane HK, Waisman DM, Chiu A, Lee PWK (2008) Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p2−/− HCT116 colon cancer cells. DNA Repair 7:239–252PubMedCrossRefGoogle Scholar
  20. Jantzen C, Jorgensen HL, Duus BR, Sporring SL, Lauritzen JB (2013) Chromium and cobalt ion concentrations in blood and serum following various types of metal-on-metal hip arthroplasties. Acta Orthop 84:229–236PubMedCentralPubMedCrossRefGoogle Scholar
  21. Johnson AJ, Duff MJL, Yoon JP, Hamad MA, Amstutz HC (2013) Metal ion levels in total hip arthroplasty versus hip resurfacing. J Arthroplasty 28:1235–1237PubMedCrossRefGoogle Scholar
  22. Kanerva L, Forstrom L (2001) Allergic nickel and chromate hand dermatitis induced by orthopaedic metal implant. Contact Dermatitis 44(103):104Google Scholar
  23. Kasprzak KS, Sunderman FW, Salnikowa K (2003) Nickel carcinogenesis. Mutat Res 533:67–97PubMedCrossRefGoogle Scholar
  24. Keegan GM, Learmonth ID, Case CP (2007) Orthopaedic metals and their potential toxicity in the arthroplasty patient. J Bone Joint Surg Br 89:567–573PubMedCrossRefGoogle Scholar
  25. Levina A, Lay PA (2008) Chemical properties and toxicity of Chromium (III) nutritional supplements. Chem Res Toxicol 21:563–571PubMedCrossRefGoogle Scholar
  26. Levina A, Zhang L, Lay PA (2010) Formation and reactivity of Chromium(V)-Thiolato complexes: a modelfor the intracellular reactions of carcinogenic Chromium(VI) with biological thiols. J Am Chem Soc 132:8720–8731PubMedCrossRefGoogle Scholar
  27. Li Q, Suen TC, Sun H, Arita A, Costa M (2009) Nickel compounds induce apoptosis in human bronchial epithelial Beas-2B cells by activation of c-Myc through ERK pathway. Toxicol Appl Pharmacol 235:191–198PubMedCentralPubMedCrossRefGoogle Scholar
  28. Lu Y, Xu D, Zhou J, Ma Y, Jiang Y, Zeng W, Dai W (2013) Differential responses to genotoxic agents between induced pluripotent stem cells and tumor cell lines. J Hematol Oncol 6:1–11CrossRefGoogle Scholar
  29. Meka PM, Lemieux N, Chakrabarti SK (2006) Role of oxidative stress, mitochondrial membrane potential, and calcium homeostasis in human lymphocyte death induced by nickel carbonate hydroxide in vitro. Arch Toxicol 80:405–420CrossRefGoogle Scholar
  30. Ries MW, Kampmann C, Rupprecht HJ, Hintereder G, Hafner G, Meyer J (2003) Nickel release after implantation of the Amplatzer occluder. Am Heart J 145:737–741PubMedCrossRefGoogle Scholar
  31. Rio JD, Beguiristain J, Duart J (2007) Metal levels in corrosion of spinal implants. Eur Spine J 16:1055–1061PubMedCentralPubMedCrossRefGoogle Scholar
  32. Seilkopa SK, Oller AR (2003) Respiratory cancer risks associated with low-level nickel exposure: an integrated assessment based on animal, epidemiological and mechanistic data. Regul Toxicol Pharmacol 37:173–190CrossRefGoogle Scholar
  33. Sharma V, Sachdeva MV, Sakhuja N, Arora D (2011) Impact of heavy metals (Chromium and Nickel) on the health of residents of Jagadhri city due to intake of contaminated underground water. Arch Appl Sci Res 3:207–212Google Scholar
  34. Son YO, Hitron JA, Wang X, Chang Q, Pan J, Zhang Z, Liu J, Lee JC, Wang S, Shi X (2010) Cr(VI) induces mitochondrial-mediated and caspase-dependent apoptosis through reactive oxygen species-mediated p53 activation in JB6 Cl41 cells. Toxicol Appl Pharmacol 245:226–235PubMedCrossRefGoogle Scholar
  35. Teramoto S, Tomita T, Matsui H, Ohga E, Matsuse T, Ouchi Y (1999) Hydrogen peroxide-induced apoptosis and necrosis in human lung fibroblasts: protective roles of glutathione. Jpn J Pharmacol 79:33–40PubMedCrossRefGoogle Scholar
  36. Vasant C, Rajaram R, Ramasami T (2003) Apoptosis of lymphocytes by chromium (VI/V) is through ROS-mediated activation of Src––family kinase and caspase-3. Free Radic Biol Med 35:1082–1100PubMedCrossRefGoogle Scholar
  37. Wang YF, Shyu HW, Chang YC, Tseng WC, Huang YL, Lin KH, Liu HL, Chou MC, Chen CY (2012) Nickel (II)-induced cytotoxicity and apoptosis in human proximal tubule cells through a ROS and mitochondria-mediated pathway. Toxicol Appl Pharmacol 259:177–186PubMedCrossRefGoogle Scholar
  38. Wu HC, Yang CY, Hung DZ, Su CC, Chen KL, Yen CC, Ho TJ, Su YC, Huang CF, Chen CH, Tsai LM, Chen YW (2011) Nickel(II) induced JNK activation-regulated mitochondria-dependent apoptotic pathway leading to cultured rat pancreatic-cell death. Toxicology 289:103–111PubMedCrossRefGoogle Scholar
  39. Xiao F, Feng X, Zeng M, Guan L, Hu Q, Zhong C (2012) Hexavalent chromium induces energy metabolism disturbance and p53-dependent cell cycle arrest via reactive oxygen species in L-02 hepatocytes. Mol Cell Biochem 371:65–76PubMedCrossRefGoogle Scholar
  40. Yadav S, Shi Y, Wang F, Wang H (2010) Arsenite induces apoptosis in human mesenchymal stem cells by altering Bcl-2 family proteins and by activating intrinsic pathway. Toxicol Appl Pharmacol 244:263–272PubMedCrossRefGoogle Scholar
  41. Zeng Y, Feng W (2013) Metal allergy in patients with total hip replacement: a review. J Int Med Res 41:247–252PubMedCrossRefGoogle Scholar
  42. Zuk PA, Zhu M, Ashjian P, Ugarte DAD, Jerry HM, Huang I, Alfonso ZC, Fraser JK, Hedrick MH, Benhaim P (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • R. Indra
    • 1
  • K. Purna Sai
    • 2
  • A. Rajaram
    • 3
  • Rama Rajaram
    • 1
  1. 1.Department of BiochemistryCentral Leather Research InstituteChennaiIndia
  2. 2.Department of BiomaterialsCentral Leather Research InstituteChennaiIndia
  3. 3.Department of BiophysicsCentral Leather Research InstituteChennaiIndia

Personalised recommendations