Biokinetically-based in vitro cardiotoxicity of residual oil fly ash: hazard identification and mechanisms of injury.
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.
College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27606, USA, tknuckles@hsc.wvu.edu.
Travis L
TL
Knuckles
Richard
R
Jaskot
Judy H
JH
Richards
C Andrew
CA
Miller
Allen
A
Ledbetter
John
J
McGee
William P
WP
Linak
Kevin L
KL
Dreher
D000818:Animals; D000831:Animals, Newborn; D054715:Cardiotoxins / Q000633:toxicity*; D002478:Cells, Cultured; D060729:Coal Ash / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D054715:Cardiotoxins; D060729:Coal Ash