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PARADOXICAL ROLE OF ZINC IN CARDIAC INJURY: A POTENTIAL LINK TO ENVIRONMENTAL ZINC EXPOSURE AND CARDIOVASCULAR MORBIDITY
Kodavanti, U P., M. Schladweiler, P. S. Gilmour, J K. McGee, W P. Watkinson, R. H. Jaskot, J H. Richards, A. D. Ledbetter, D L. Costa, D. Graff, W. E. Cascio, W. H. Rowan, AND A. Nyska. PARADOXICAL ROLE OF ZINC IN CARDIAC INJURY: A POTENTIAL LINK TO ENVIRONMENTAL ZINC EXPOSURE AND CARDIOVASCULAR MORBIDITY. Presented at Amer. Heart Associa. Mtg, New Orleans, LA, Nov. 6-10, 2004.
Zinc (Zn) is consistently detected in respirable air particulate matter (PM). We recently demonstrated that inhalation of environmental combustion PM containing Zn produces myocardial lesions in rats, supporting epidemiological associations of cardiac morbidity and mortality with air pollution. Therefore, we studied potential mechanisms responsible for Zn-induced cardiac injury. The first study (long-term) involved multiple pulmonary intratracheal (IT) exposures in Wistar-Kyoto rats (once per wk x 8 or16 wks) to either (1) saline (control), (2) combustion PM suspension containing 14.5 microgram/mg Zn, (3) the aqueous fraction of this suspension, (4) PM having no soluble Zn, or (5) Zn sulfate. Zn concentrations were identical in all Zn groups. The second study (acute) investigated the systemic distribution, the time-course of the development of cardiac lesions, coagulation abnormalities, and gene expression patterns following a single IT exposure to Zn sulfate (0 or 2 micromol/kg) in rats. Long-term exposure to PM with or without soluble Zn, or Zn sulfate caused distinct myocardial lesions characterized by subepicardial and randomly distributed myocardial inflammation, degeneration, and fibrosis. The lesion severity was higher in those groups receiving Zn PM or Zn sulfate. Acute exposure to Zn resulted in the redistribution of Zn, copper, and selenium in plasma and tissues, and induction of metallothionein as well as Zn transporter protein in the heart. Pulmonary exposure to Zn also resulted in increased cardiac plasminogen activator inhibitor-1, tissue factor, and thrombomodulin mRNA expression. Microarray (Affymetrix) analysis indicated disturbances in Ca2+ and K+ channel expression and mitochondrial function, suggesting potential conductance abnormalities and altered mitochondrial respiration. Our studies demonstrate that pulmonary exposure to Zn or Zn-containing ambient PM may cause cardiac injury via direct effects on the heart and/or via activation of blood coagulation cascade. (Does not reflect US EPA policy).
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
EXPERIMENTAL TOXICOLOGY DIVISION
PULMONARY TOXICOLOGY BRANCH