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Biokinetically-Based In Vitro Cardiotoxicity of Residual Oil Fly Ash: Hazard Identification and Mechanisms of Injury

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Abstract

Epidemiological studies have associated air pollution particulate matter (PM) exposure with adverse cardiovascular effects. Identification of causal PM sources is critically needed to support regulatory decisions to protect public health. This research examines the in vitro cardiotoxicity of bioavailable constituents of residual oil fly ash (ROFA) employing in vivo, biokinetically-based, concentrations determined from their pulmonary deposition. Pulmonary deposition of ROFA led to a rapid increase in plasma vanadium (V) levels that were prolonged in hypertensive animals without systemic inflammation. ROFA cardiotoxicity was evaluated using neonatal rat cardiomyocyte (RCM) cultures exposed to particle-free leachates of ROFA (ROFA-L) at levels present in exposed rat plasma. Cardiotoxicity was observed at low levels (3.13 μg/mL) of ROFA-L 24 h post-exposure. Dimethylthiourea (28 mM) inhibited ROFA-L-induced cytotoxicity at high (25–12.5 μg/mL) doses, suggesting that oxidative stress is responsible at high ROFA-L doses. Cardiotoxicity could not be reproduced using a V + Ni + Fe mixture or a ROFA-L depleted of these metals, suggesting that ROFA-L cardiotoxicity requires the full complement of bioavailable constituents. Susceptibility of RCMs to ROFA-L-induced cytotoxicity was increased following tyrosine phosphorylation inhibition, suggesting that phosphotyrosine signaling pathways play a critical role in regulating ROFA-L-induced cardiotoxicity. These data demonstrate that bioavailable constituents of ROFA are capable of direct adverse cardiac effects.

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  1. Travis L. Knuckles

    Present address: Robert C. Byrd-Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506, USA

Authors and Affiliations

  1. College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27606, USA

    Travis L. Knuckles

  2. National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Mail Drop B105-02, 109 TW Alexander Drive, Research Triangle Park, NC, 27711, USA

    Richard Jaskot, Judy H. Richards, Allen Ledbetter, John McGee & Kevin L. Dreher

  3. National Risk Management Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, 27711, USA

    C. Andrew Miller & William P. Linak

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Correspondence to Kevin L. Dreher.

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Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use.

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Knuckles, T.L., Jaskot, R., Richards, J.H. et al. Biokinetically-Based In Vitro Cardiotoxicity of Residual Oil Fly Ash: Hazard Identification and Mechanisms of Injury. Cardiovasc Toxicol 13, 426–437 (2013). https://doi.org/10.1007/s12012-013-9225-z

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