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

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Abstract

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.

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References

  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.

    Article  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  19. Prewitt, R. L., Rice, D. C., & Dobrian, A. D. (2002). Adaptation of resistance arteries to increases in pressure. Microcirculation, 9(4), 295–304.

    PubMed  Google Scholar 

  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. 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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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. 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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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. 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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Carroll McBride and Kimberly Wix for their expert technical assistance in this study. The authors would also like to thank Katarzyna Sabolsky for assistance with the TEM characterization of the CeO2 nanoparticles. This work is supported by the National Institutes of Health RO1-ES015022, RC1-ES018274 (TRN), F32-ES023435 (PAS) and the National Science Foundation Cooperative Agreement-1003907 (TRN and VCM).

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Authors and Affiliations

  1. Center for Cardiovascular and Respiratory Sciences, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, 1 Medical Center Drive, PO Box 9105, Morgantown, WV, 26506-9105, USA

    Valerie C. Minarchick, Phoebe A. Stapleton & Timothy R. Nurkiewicz

  2. Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, 26506, USA

    Valerie C. Minarchick, Phoebe A. Stapleton, Dale W. Porter & Timothy R. Nurkiewicz

  3. Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA

    Dale W. Porter, Michael G. Wolfarth, Mark Barger & Timothy R. Nurkiewicz

  4. Department of Mechanical and Aerospace Engineering, West Virginia University, Morgantown, WV, 26506, USA

    Engin Çiftyürek & Edward M. Sabolsky

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  1. Valerie C. Minarchick
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  2. Phoebe A. Stapleton
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Correspondence to Timothy R. Nurkiewicz.

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Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.

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Minarchick, V.C., Stapleton, P.A., Porter, D.W. et al. Pulmonary Cerium Dioxide Nanoparticle Exposure Differentially Impairs Coronary and Mesenteric Arteriolar Reactivity. Cardiovasc Toxicol 13, 323–337 (2013). https://doi.org/10.1007/s12012-013-9213-3

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