Toxicological Sciences 74, 228-229 (2003)
Copyright © 2003 by the Society of Toxicology
Reply*
1 Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 2 Pathology Associates, Inc., Raleigh, NC 27606 3 Harvard School of Public Health, Boston, MA 02115 4 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
To the Editor:
The Letter to the Editor regarding our recent article, "Inhaled Environmental Combustion Particles Cause Myocardial Injury in the Wistar Kyoto Rat," suggests a potential mechanism by which cardiac pathology may occur after long-term inhalation of particulate matter containing bioavailable zinc. Our paper is the first to demonstrate pathological myocardial lesions in Wistar-Kyoto rats following inhalation exposure to combustion emission particles rich in bioavailable zinc (Kodavanti et al., 2003
). Since the mechanism(s) of cardiac pathology was not addressed in the paper, we have begun follow-up studies to investigate likely mechanisms. In our initial study, we exposed animals to soluble zinc to examine the role of pulmonary-delivered zinc in cardiac pathology. The results from this study (unpublished) indicate the presence of focal myocardial necrosis in the zinc-exposed rats, suggesting its possible role in the induction of cardiac damage. The evidence that nutritional supplementation of zinc or accidental exposure can result in copper deficiency represents an intriguing hypothesis (Breitschwerdt et al., 1986; Klevay, 2000) because, as stated in the letter, nutritional copper deficiency has long been associated with cardiac disease in animals and humans. Similarly, a role for metals, such as zinc, in nutritional selenium deficiency and associated cardiac disease has been proposed in pigs (Hulland, 1989). Zinc was also suggested to induce functional disturbances in the human heart (Silve-Mamy and Plancade, 1969). Both copper and zinc have been shown to exchange or compete for protein binding sites (Powell et al., 1994, 1999; Santon et al., 2002). How the relatively small amount of zinc inhaled can analogously lead to cardiac damage remains a challenge to investigate. We intend to address these issues in with our zinc exposure study. The proposed experimental guidelines in the letter will be of great value in determining the role of copper, as well as zinc-induced copper deficiency, in heart and vascular disease in Wistar-Kyoto rats.
While zinc has been shown to bind with thousands of proteins, the dynamics of zinc binding and release from proteins are not well understood (Maret, 2000). The regulation of cellular zinc by metallothionein/thionein recycling has been demonstrated in the maintenance of zinc homeostasis (Maret, 2000, 2001). In contrast to copper and iron, zinc is redox inert, and thus, an increase of zinc in cells can lead to interference in metal-dependent processes (Maret, 2000). In some instances, zinc has been shown to be protective of the heart through its induction of metallothionein via their antioxidant function (Brever et al., 2000; Kang, 1999). In the isolated perfused rat heart, zinc has been shown to be protective against ischemia; the proposed mechanism points to the release of redox active copper from its protein binding sites (Powell et al., 1999). The experimental design and the longevity of zinc exposure will be critical in determining the effect of metal imbalance on the development of cardiac disease. In addition to the potential for zinc to replace copper from functionally critical protein sites, zinc has been shown to be transported to the mitochondria, via its binding to metallothionein, where it may depress respiration (Maret et al., 2001; Ye et al., 2001). Zinc in cell culture systems has also been shown to (1) activate EGF receptors through Src-dependent phosphorylation and (2) activate MAP kinases involved in inflammatory processes (Wu et al., 2002). Increased zinc levels are also associated with increases in cytosolic free Ca2+ (Maret, 2001; Maret et al., 2001). In pursuit of the mechanism by which inhaled zinc may promote cardiac damage, we hope to address several potential hypotheses, including the one suggested in the letter. Unlike dietary zinc, inhaled zinc may be delivered to cardiac tissues prior to its processing in the liver; thus, the induction of liver metallothionein (with potential difference in zinc bioavailability to cardiac cells) and the issue of likely differences in the order of zinc presentation to the cardiac cell—for example, with or without prior processing by the liver—will be important considerations in our follow-up studies. We thank Dr. Klevay for her interest in our work and insight into the mechanism.
NOTES
* This letter does not reflect USEPA policy. 
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