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CARDIOVASCULAR TOXICITY OF PM: SOLUBLE COMPONENTS OR SOLID PARTICLES?
Citation:
KODAVANTI, U. P. CARDIOVASCULAR TOXICITY OF PM: SOLUBLE COMPONENTS OR SOLID PARTICLES? Presented at U.S. EPA Mechanisms and Health Risks of Exposure to Ambient Particulate Matter Research Meeting, Research Triangle Park, NC, April 18 - 19, 2006.
Description:
Since strong suggestion of cardiac-related deaths has arisen from epidemiological studies of ambient PM, a major effort is required to identify PM components and mechanisms responsible for observed cardiac impairments. Unfortunately, it has been difficult to elucidate causality with animal experiments. The first problem is that the ambient PM contains diverse potentially causative constituents and without having knowledge of constituent-specific cardiac effects, it has been difficult to define appropriate PM samples to serve as models with which to study cardiovascular effects. A second important factor is the insensitivity of clinical markers of cardiovascular disease to subtle cardiac injury caused by PM. My research program focuses on identification of causative components and mechanisms of cardiac injury using source-specific and ambient PM samples as well as healthy and susceptible rat models.
Based on our first demonstration in 2003 of cardiac injury from inhalation of ambient-like PM containing water-soluble zinc, our primary hypothesis is that water soluble metals or metals that leached-off from PM are absorbed in the circulation, and cause cardiac oxidative stress, ion channel dysfunction, and mitochondrial impairment. Since zinc is one of the major metal components of near-road PM, and is largely water-soluble relative to other metals such as iron and aluminum, our initial research focus is to identify the role of zinc as a potential causative component of cardiac effects. However, recently we have also conducted studies using diesel and ultrafine carbon particles because organic diesel and nano PM have also been linked to increased oxidative stress and mitochondrial impairments in vitro. Our approach includes exposure of rats via inhalation or intratracheal instillation of PM and determination of metal components in multiple organs, analysis of a variety of biomarkers in the heart, including pathological evaluation, electron microscopy, markers of oxidative stress in myocardium and mitochondria, mitochondrial DNA damage, and gene expression changes.
As a follow-up to the demonstration of cardiac injury from zinc-containing particles, we first asked if pulmonary-deposited zinc, by itself, can induce cardiac injury and if so, is the toxicity associated with increased circulating zinc. Our results support the role of acute high-concentration zinc exposure in causing cardiac injury as evidenced by acute inflammation, increased blood coagulation markers, and changes in gene expression pattern suggestive of mitochondrial impairment of respiration, ion channel activation, perturbed calcium homeostasis, and cell signaling consistent with known zinc-induced changes in vitro. Further, this study demonstrated increases in plasma zinc concentration immediately following exposure with subsequent sequestration of zinc, copper and selenium in liver and kidney, possibly altering systemic metal homeostasis. To study homeostatic changes in essential metals, we plan to evaluate the pharmacokinetics of tracer zinc and other PM-associated non-essential metal indicators to understand the role of metals in multi organ impairments. The temporality of changes in essential metals and marked increases in metallothionein and zinc transporter in lung, heart and liver suggest a direct role of zinc in cardiac injury. However, because a on-time high zinc concentration was used and marked pulmonary injury occurred in these studies, the subsequent question was, if small periodic intratracheal instillations of zinc, zinc containing particles, or particles without any soluble metals cause cardiac injury, and if the gene expression pattern would demonstrate the differences in the mechanism of cardiac effects induced by soluble zinc or solid particles.
The study comparing cardiac toxicity of solid particles devoid of any soluble metals and zinc or zinc-containing particles demonstrated cardiac pathological lesions in animals exposed to zinc and also in those exposed to solid particles without soluble metals. Marked pulmonary inflammation was also noted with both solid and soluble components. Thus, we concluded that cardiac injury could also occur from chronic pulmonary inflammation caused by soluble or solid components. The cardiac gene expression pattern, however, demonstrated significant differences between rats exposed to solid particles and soluble zinc. Analysis of mitochondrial DNA damage indicated no effect of solid particles but significant effect of zinc, further supporting the role of PM-associated zinc in cardiac mitochondrial injury. Recent studies demonstrate inhibition of cardiac mitochondrial aconitase, a sensitive marker of mitochondrial oxidative stress from exposure to zinc and copper individually and in combination. Future studies are designed to evaluate cardiac effects of long-term zinc sulfate inhalation at environmentally relevant concentrations to establish causality.
Inhibition of cardiac mitochondrial aconitase has also been noted in our recent studies involving four-week exposure to diesel but not carbon ultrafines. However, diesel-induced inhibition of aconitase is not accompanied by ultrastructural changes in mitochondria. Further analysis of novel cardiac markers is being performed in house and in collaboration with NIEHS. Since mitochondria and oxidative stress are central in cardiovascular impairments in disease and senescence, we plan to identify additional causative components and address mechanisms of susceptibility using animal models of mitochondrial impairments, oxidative stress and cardiovascular diseases. These research areas are in parallel with EPA identified high priority issues for PM health effects.