Cardiovascular Toxicology

, Volume 13, Issue 4, pp 323–337

Pulmonary Cerium Dioxide Nanoparticle Exposure Differentially Impairs Coronary and Mesenteric Arteriolar Reactivity

  • Valerie C. Minarchick
  • Phoebe A. Stapleton
  • Dale W. Porter
  • Michael G. Wolfarth
  • Engin Çiftyürek
  • Mark Barger
  • Edward M. Sabolsky
  • Timothy R. Nurkiewicz


Cerium dioxide nanoparticles (CeO2 NPs) are an engineered nanomaterial (ENM) that possesses unique catalytic, oxidative, and reductive properties. Currently, CeO2 NPs are being used as a fuel catalyst but these properties are also utilized in the development of potential drug treatments for radiation and stroke protection. These uses of CeO2 NPs present a risk for human exposure; however, to date, no studies have investigated the effects of CeO2 NPs on the microcirculation following pulmonary exposure. Previous studies in our laboratory with other nanomaterials have shown impairments in normal microvascular function after pulmonary exposures. Therefore, we predicted that CeO2 NP exposure would cause microvascular dysfunction that is dependent on the tissue bed and dose. Twenty-four-hour post-exposure to CeO2 NPs (0–400 μg), mesenteric, and coronary arterioles was isolated and microvascular function was assessed. Our results provided evidence that pulmonary CeO2 NP exposure impairs endothelium-dependent and endothelium-independent arteriolar dilation in a dose-dependent manner. The CeO2 NP exposure dose which causes a 50 % impairment in arteriolar function (EC50) was calculated and ranged from 15 to 100 μg depending on the chemical agonist and microvascular bed. Microvascular assessments with acetylcholine revealed a 33–75 % reduction in function following exposure. Additionally, there was a greater sensitivity to CeO2 NP exposure in the mesenteric microvasculature due to the 40 % decrease in the calculated EC50 compared to the coronary microvasculature EC50. CeO2 NP exposure increased mean arterial pressure in some groups. Taken together, these observed microvascular changes may likely have detrimental effects on local blood flow regulation and contribute to cardiovascular dysfunction associated with particle exposure.


Cerium dioxide Mesentery Coronary Arteriole Microcirculation Engineered nanomaterial 


  1. 1.
    Borm, P. J., Robbins, D., Haubold, S., Kuhlbusch, T., Fissan, H., Donaldson, K., et al. (2006). The potential risks of nanomaterials: A review carried out for ECETOC. Particle and Fibre Toxicology, 3, 11.PubMedCrossRefGoogle Scholar
  2. 2.
    Hanson, N., Harris, J., Joseph, L. A., Ramakrishnan, K., & Thompson, T. EPA Needs to Manage Nanomaterial Risks More Effectively. 2011. Report No.: 12-P-0162.Google Scholar
  3. 3.
    Borm, P. J., & Muller-Schulte, D. (2006). Nanoparticles in drug delivery and environmental exposure: Same size, same risks? Nanomedicine (Lond), 1(2), 235–249.CrossRefGoogle Scholar
  4. 4.
    Aitken, R. J., Chaudhry, M. Q., Boxall, A. B., & Hull, M. (2006). Manufacture and use of nanomaterials: Current status in the UK and global trends. Occupational Medicine (Lond), 56(5), 300–306.CrossRefGoogle Scholar
  5. 5.
    Cassee, F. R., van Balen, E. C., Singh, C., Green, D., Muijser, H., Weinstein, J., et al. (2011). Exposure, health and ecological effects review of engineered nanoscale cerium and cerium oxide associated with its use as a fuel additive. Critical Reviews in Toxicology, 41(3), 213–229.PubMedCrossRefGoogle Scholar
  6. 6.
    Cassee, F. R., Campbell, A., Boere, A. J., McLean, S. G., Duffin, R., Krystek, P., et al. (2012). The biological effects of subacute inhalation of diesel exhaust following addition of cerium oxide nanoparticles in atherosclerosis-prone mice. Environmental Research, 115, 1–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Preisler, E. J., Marsh, O. J., Beach, R. A., & McGill, T. C. (2001). Stability of cerium oxide on silicon studied by X-ray photoelectron spectroscopy. Journal of Vacuum Science and Technology B, 19(4), 1611–1618.CrossRefGoogle Scholar
  8. 8.
    Geraets, L., Oomen, A. G., Schroeter, J. D., Coleman, V. A., & Cassee, F. R. (2012). Tissue distribution of inhaled micro- and nano-sized cerium oxide particles in rats: Results from a 28-day exposure study. Toxicology Science, 127(2), 463–473.CrossRefGoogle Scholar
  9. 9.
    Yokel, R. A., Au, T. C., Macphail, R., Hardas, S. S., Butterfield, D. A., Sultana, R., et al. (2012). Distribution, elimination, and biopersistence to 90 days of a systemically introduced 30 nm ceria-engineered nanomaterial in rats. Toxicology Science, 127(1), 256–268.CrossRefGoogle Scholar
  10. 10.
    Pairon, J. C., Roos, F., Sebastien, P., Chamak, B., Bd-Alsamad, I., Bernaudin, J. F., et al. (1995). Biopersistence of cerium in the human respiratory tract and ultrastructural findings. American Journal of Industrial Medicine, 27(3), 349–358.PubMedCrossRefGoogle Scholar
  11. 11.
    Celardo, I., Traversa, E., & Ghibelli, L. (2011). Cerium oxide nanoparticles: A promise for applications in therapy. Journal of experimental therapeutics & oncology, 9(1), 47–51.Google Scholar
  12. 12.
    Heckert, E. G., Karakoti, A. S., Seal, S., & Self, W. T. (2008). The role of cerium redox state in the SOD mimetic activity of nanoceria. Biomaterials, 29(18), 2705–2709.PubMedCrossRefGoogle Scholar
  13. 13.
    Colon, J., Herrera, L., Smith, J., Patil, S., Komanski, C., Kupelian, P., et al. (2009). Protection from radiation-induced pneumonitis using cerium oxide nanoparticles. Nanomedicine, 5(2), 225–231.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim, C. K., Kim, T., Choi, I. Y., Soh, M., Kim, D., Kim, Y. J., et al. (2012). Ceria nanoparticles that can protect against ischemic stroke. Angewandte Chemie (International ed. in English), 51(44), 11039–11043.CrossRefGoogle Scholar
  15. 15.
    Stapleton, P. A., Minarchick, V. C., McCawley, M., Knuckles, T. L., & Nurkiewicz, T. R. (2012). Xenobiotic particle exposure and microvascular endpoints: A call to arms. Microcirculation, 19(2), 126–142.PubMedCrossRefGoogle Scholar
  16. 16.
    Ma, J. Y., Zhao, H., Mercer, R. R., Barger, M., Rao, M., Meighan, T., et al. (2011). Cerium oxide nanoparticle-induced pulmonary inflammation and alveolar macrophage functional change in rats. Nanotoxicology, 5(3), 312–325.PubMedCrossRefGoogle Scholar
  17. 17.
    Toya, T., Takata, A., Otaki, N., Takaya, M., Serita, F., Yoshida, K., et al. (2010). Pulmonary toxicity induced by intratracheal instillation of coarse and fine particles of cerium dioxide in male rats. Industrial Health, 48(1), 3–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Schwartzkopff, B., Mundhenke, M., & Strauer, B. E. (1998). Alterations of the architecture of subendocardial arterioles in patients with hypertrophic cardiomyopathy and impaired coronary vasodilator reserve: A possible cause for myocardial ischemia. Journal of the American College of Cardiology, 31(5), 1089–1096.PubMedCrossRefGoogle Scholar
  19. 19.
    Prewitt, R. L., Rice, D. C., & Dobrian, A. D. (2002). Adaptation of resistance arteries to increases in pressure. Microcirculation, 9(4), 295–304.PubMedGoogle Scholar
  20. 20.
    Zweifach, B. W. (1984). Pressure-flow relations in blood and lymph microcirculation. In E. M. Renkin & C. C. Michel (Eds.), Handbook of physiology (pp. 251–308). Bethesda, MD: American Physiological Society.Google Scholar
  21. 21.
    Renkin, E. M. (1984). Control of microcirculation and blood-tissue exchange. In E. M. Renkin & C. C. Michel (Eds.), Handbook of physiology (pp. 627–687). Bethesda, MD: American Physiology Society.Google Scholar
  22. 22.
    Wingard, C. J., Walters, D. M., Cathey, B. L., Hilderbrand, S. C., Katwa, P., Lin, S., et al. (2011). Mast cells contribute to altered vascular reactivity and ischemia-reperfusion injury following cerium oxide nanoparticle instillation. Nanotoxicology, 5(4), 531–545.PubMedCrossRefGoogle Scholar
  23. 23.
    Nalabotu, S. K., Kolli, M. B., Triest, W. E., Ma, J. Y., Manne, N. D., Katta, A., et al. (2011). Intratracheal instillation of cerium oxide nanoparticles induces hepatic toxicity in male Sprague-Dawley rats. International Journal of Nanomedicine, 6, 2327–2335.PubMedCrossRefGoogle Scholar
  24. 24.
    LeBlanc, A. J., Cumpston, J. L., Chen, B. T., Frazer, D., Castranova, V., & Nurkiewicz, T. R. (2009). Nanoparticle inhalation impairs endothelium-dependent vasodilation in subepicardial arterioles. Journal of toxicology and environmental health. Part A, 72(24), 1576–1584.PubMedCrossRefGoogle Scholar
  25. 25.
    Nurkiewicz, T. R., Porter, D. W., Barger, M., Millecchia, L., Rao, K. M., Marvar, P. J., et al. (2006). Systemic microvascular dysfunction and inflammation after pulmonary particulate matter exposure. Environmental Health Perspectives, 114(3), 412–419.PubMedCrossRefGoogle Scholar
  26. 26.
    Tok, A. I. Y., Du, S. W., Boey, F. Y. C., & Chong, W. K. (2013). Hydrothermal synthesis and characterization of rare earth doped ceria nanoparticles. Materials science & engineering, 466, 223–229.CrossRefGoogle Scholar
  27. 27.
    Nurkiewicz, T. R., Porter, D. W., Barger, M., Castranova, V., & Boegehold, M. A. (2004). Particulate matter exposure impairs systemic microvascular endothelium-dependent dilation. Environmental Health Perspectives, 112(13), 1299–1306.PubMedCrossRefGoogle Scholar
  28. 28.
    Porter, D. W., Barger, M., Robinson, V. A., Leonard, S. S., Landsittel, D., & Castranova, V. (2002). Comparison of low doses of aged and freshly fractured silica on pulmonary inflammation and damage in the rat. Toxicology, 175(1–3), 63–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Sun, D., Messina, E. J., Kaley, G., & Koller, A. (1992). Characteristics and origin of myogenic response in isolated mesenteric arterioles. American Journal of Physiology, 263(5 Pt 2), H1486–H1491.PubMedGoogle Scholar
  30. 30.
    Chilian, W. M., Eastham, C. L., & Marcus, M. L. (1986). Microvascular distribution of coronary vascular resistance in beating left ventricle. American Journal of Physiology, 251(4 Pt 2), H779–H788.PubMedGoogle Scholar
  31. 31.
    Kotani, A., Jo, T., & Parlebas, J. C. (2013). Many-body effects in core-level spectroscopy of rare-earth compounds. Advances in Physics, 37, 8952–8961.Google Scholar
  32. 32.
    Burroughs, P., Hamnett, A., Orchard, A. F., & Thomton, G. (2013). Satellite structure in the X-ray photoelectron spectra of some binary and mixed oxides of lanthanum and cerium. Journal of the Chemical Society, Dalton Transactions, 17, 1686–1698.Google Scholar
  33. 33.
    Kumar, S., Butcher, K. S. A., & Tansley, T. L. (2013). X-ray photoelectron spectroscopy characterization of radio frequency reactively sputtered carbon nitride thin films. Journal of Vacuum Science and Technology A, 14(5), 2687–2692.CrossRefGoogle Scholar
  34. 34.
    Grossi, L., & D’Angelo, S. (2005). Sodium nitroprusside: Mechanism of NO release mediated by sulfhydryl-containing molecules. Journal of Medicinal Chemistry, 48(7), 2622–2626.PubMedCrossRefGoogle Scholar
  35. 35.
    Stone, K. C., Mercer, R. R., Gehr, P., Stockstill, B., & Crapo, J. D. (1992). Allometric relationships of cell numbers and size in the mammalian lung. American Journal of Respiratory Cell and Molecular Biology, 6(2), 235–243.PubMedCrossRefGoogle Scholar
  36. 36.
    Galer, D. M., Leung, H. W., Sussman, R. G., & Trzos, R. J. (1992). Scientific and practical considerations for the development of occupational exposure limits (OELs) for chemical substances. Regulatory Toxicology and Pharmacology, 15(3), 291–306.PubMedCrossRefGoogle Scholar
  37. 37.
    Phalen, R. F. (1984). Basic morphology and physiology of the respiratory tract, in inhalation studies: Foundations and techniques. Boca Raton: CRC Press.Google Scholar
  38. 38.
    Nurkiewicz, T. R., Porter, D. W., Hubbs, A. F., Stone, S., Moseley, A. M., Cumpston, J. L., et al. (2011). Pulmonary particulate matter and systemic microvascular dysfunction. Research Report/Health Effects Institute, 164, 3–48.Google Scholar
  39. 39.
    Menache, M. G., Miller, F. J., & Raabe, O. G. (1995). Particle inhalability curves for humans and small laboratory animals. Annals of Occupational Hygiene, 39(3), 317–328.PubMedGoogle Scholar
  40. 40.
    LeBlanc, A. J., Moseley, A. M., Chen, B. T., Frazer, D., Castranova, V., & Nurkiewicz, T. R. (2010). Nanoparticle inhalation impairs coronary microvascular reactivity via a local reactive oxygen species-dependent mechanism. Cardiovascular Toxicology, 10(1), 27–36.PubMedCrossRefGoogle Scholar
  41. 41.
    Stapleton, P. A., Minarchick, V. C., Cumpston, A. M., McKinney, W., Chen, B. T., Sager, T. M., et al. (2012). Impairment of coronary arteriolar endothelium-dependent dilation after multi-walled carbon nanotube inhalation: A time-course study. International Journal of Molecular Sciences, 13(11), 13781–13803.PubMedCrossRefGoogle Scholar
  42. 42.
    Courtois, A., Andujar, P., Ladeiro, Y., Baudrimont, I., Delannoy, E., Leblais, V., et al. (2008). Impairment of NO-dependent relaxation in intralobar pulmonary arteries: Comparison of urban particulate matter and manufactured nanoparticles. Environmental Health Perspectives, 116(10), 1294–1299.PubMedCrossRefGoogle Scholar
  43. 43.
    Straub, A. C., Lohman, A. W., Billaud, M., Johnstone, S. R., Dwyer, S. T., Lee, M. Y., et al. (2012). Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling. Nature, 491(7424), 473–477.PubMedCrossRefGoogle Scholar
  44. 44.
    Park, E. J., Choi, J., Park, Y. K., & Park, K. (2008). Oxidative stress induced by cerium oxide nanoparticles in cultured BEAS-2B cells. Toxicology, 245(1–2), 90–100.PubMedCrossRefGoogle Scholar
  45. 45.
    Driscoll, K. E., Costa, D. L., Hatch, G., Henderson, R., Oberdorster, G., Salem, H., et al. (2000). Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: Uses and limitations. Toxicological Sciences, 55(1), 24–35.PubMedCrossRefGoogle Scholar
  46. 46.
    He, X., Zhang, H., Ma, Y., Bai, W., Zhang, Z., Lu, K., et al. (2010). Lung deposition and extrapulmonary translocation of nano-ceria after intratracheal instillation. Nanotechnology, 21(28), 285103.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Valerie C. Minarchick
    • 1
    • 2
  • Phoebe A. Stapleton
    • 1
    • 2
  • Dale W. Porter
    • 2
    • 3
  • Michael G. Wolfarth
    • 3
  • Engin Çiftyürek
    • 4
  • Mark Barger
    • 3
  • Edward M. Sabolsky
    • 4
  • Timothy R. Nurkiewicz
    • 1
    • 2
    • 3
  1. 1.Center for Cardiovascular and Respiratory Sciences, Robert C. Byrd Health Sciences CenterWest Virginia University School of MedicineMorgantownUSA
  2. 2.Department of Physiology and PharmacologyWest Virginia University School of MedicineMorgantownUSA
  3. 3.Pathology and Physiology Research Branch, Health Effects Laboratory DivisionNational Institute for Occupational Safety and HealthMorgantownUSA
  4. 4.Department of Mechanical and Aerospace EngineeringWest Virginia UniversityMorgantownUSA

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