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SYSTEMIC IMBALANCE OF ESSENTIAL METALS AND CARDIAC GENE EXPRESSION IN RATS FOLLOWING ACUTE PULMONARY ZINC EXPOSURE
GILMOUR, P., M. SCHLADWEILER, A. NYSKA, J. K. MCGEE, R. THOMAS, R. H. JASKOT, JUDY E. SCHMID, AND U. P. KODAVANTI. SYSTEMIC IMBALANCE OF ESSENTIAL METALS AND CARDIAC GENE EXPRESSION IN RATS FOLLOWING ACUTE PULMONARY ZINC EXPOSURE. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH - PART A: CURRENT ISSUES. Taylor & Francis, Inc., Philadelphia, PA, 69(22):2011-2032, (2006).
To investigate whether pulmonary zinc exposure causes systemic metal imbalance and direct cardiac effects
We have recently demonstrated that PM containing water-soluble zinc may cause cardiac injury following pulmonary exposure. To investigate if pulmonary zinc exposure causes systemic metal imbalance and direct cardiac effects, we intratracheally (IT) instilled male Wistar Kyoto (WKY) rats (12-13 weeks age) with saline or 2 µmol/kg zinc sulfate, and performed temporal analysis for systemic levels of essential metals, i.e. zinc, copper and selenium, and induction of zinc transporter-2 (ZT-2) and metallothionein-1 (MT-1) mRNA in the lung, heart, and liver. Additionally, cardiac gene expression profile was evaluated using Affymetrix gene chips-rat 230-A arrays to identify zinc-specific effects. Pulmonary zinc instillation caused an increase in plasma zinc to ~20% at 1 and 4 h postexposure with concomitant decline in the lung levels. At 24 and 48 h post exposure, zinc levels increased remarkably (~35%) in the liver. At these time points, plasma, and liver levels of copper and selenium also increased significantly, suggesting systemic disturbance in essential metals at 24 and 48 h post exposure. Zinc exposure was associated with marked induction of MT-1 and ZT-2 mRNA in lung, heart and liver suggesting systemic metal sequestration response. Given the functional role of zinc in thousands of proteins, the gene expression profiles revealed changes that are consistent with its physiological role. Zinc exposure caused an increase in expression of kinases and inhibition of phosphatases; up or down regulation of genes involved in mitochondrial function; changes in calcium regulatory proteins suggestive of increased intracellular free calcium and increases in sulfotransferases; upregulation of potassium channel genes; and changes in free radical sensitive proteins. Some of these expression changes are consistent with direct effect of zinc on myocardium following pulmonary exposure which may result in impaired mitochondrial respiration, stimulated cell signaling, altered Ca2+ homeostasis, and increased activity of sulfotransferases involved in regulation of free cellular essential metals. Cardiotoxicity may be an outcome of acute zinc toxicosis and occupational exposures to metal fumes. Systemic metal homeostasis imbalance from selective pulmonary zinc exposure may underlie the cause of extra-pulmonary effects.