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IN VITRO CARDIOTOXICITY OF AIR POLLUTION PARTICLES: ROLE OF BIOAVAILABLE CONSTITUENTS, OXIDATIVE STRESS AND TYROSINE PHOSPHORYLATION
Knuckles, T., K L. Dreher, R. H. Jaskot, AND J. E. Richards. IN VITRO CARDIOTOXICITY OF AIR POLLUTION PARTICLES: ROLE OF BIOAVAILABLE CONSTITUENTS, OXIDATIVE STRESS AND TYROSINE PHOSPHORYLATION. Presented at College of Veterinary Medicine Annual Research Forum, Raleigh, N. C, April 4, 2003.
IN VITRO CARDIOTOXICITY OF AIR POLLUTION PARTICLES: ROLE OF BIOAVAILABLE CONSTITUENTS, OXIDATIVE STRESS AND TYROSINE PHOSPHORYLATION.
T. L. Knuckles1 R. Jaskot2, J. Richards2, and K.Dreher2.
1Department of Molecular and Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, 2 US Environmental Protection Agency, Research Triangle Park, North Carolina.
Epidemiological studies have shown that exposure to particulate air pollution increases cardiac morbidity and mortality in sensitive populations. Residual oil fly ash (ROFA) represents a 2.05mm fine particle collected from a smoke stack at a utility power plant and therefore contributes to particulate air pollution. ROFA contains a high concentration of first row transition metals (V, Fe, and Ni) most of which are bioavailable. In order to assess the cardiotoxicity of ROFA constituents, rat neonatal cardiomyocyte (RNCM) cultures were exposed to particle free leachates of ROFA (ROFA-L). A significant level of cardiotoxicity was induced at ROFA-L concentrations of 25ug/mL to 1.56ug/mL at 24 h post-exposure. Significant reductions in cell numbers were also observed during these exposures. Concurrent exposure to dimethylthiourea (DMTU 30mM) and ROFA-L in RNCM cultures attenuated the cytotoxic response for both 25ug/mL and 12.5ug/mL doses. However, cardiotoxicity was not affected by DMTU at the 6.25ug/mL and 3.125ug/mL ROFA-L doses. These data suggest that at high doses of ROFA-L cytotoxicity is dependent on oxidative stress. However, at lower doses cytotoxicity is not mediated by an oxidative stress dependent mechanism. Single metal solutions of V, Fe and Ni as well as V, Fe and Ni metal mixtures equivalent to 12.5ug/mL ROFA-L had no cytotoxic effect on the RNCM at 24 h post-exposure. In addition removal of the major transition metals (V, Fe and Ni) from the ROFA-L was found to abolish its cytotoxic effect on RNCMs. Inhibition of tyrosine phosphorylation by genistein (25uM) greatly increased the cytotoxicity of ROFA-L at all exposure doses. These findings suggest that ROFA-L induced cardiotoxicity is not due to the major first row transition metals present within ROFA-L but maybe due to an as yet unidentified metal(s). Also, the tyrosine phosphorylation state of RNCMs plays a critical role in the susceptibility of these cells to the cytotoxicity of ROFA-L. (This abstract does not necessarily reflect USEPA policy)
Supported by the USEPA and the NCSU/EPA cooperative agreement #CT826512010.