Respirable ambient particulate matter (PM) exposure has been associated with an increased risk of cardiovascular disease. Direct translocation of PM-associated metals from the lungs into systemic circulation may be partly responsible. We measured elemental content of lungs, plasma, heart, and liver of healthy male WKY rats (12-15 weeks old) 4 or 24 h following a single intratracheal (IT) instillation of saline or 8.33 mg/kg of oil combustion PM (HP-12) containing a variety of transition metals with differing water and acid solubility. Tissues were digested with a combination of quaternary acid, amine, and nitric acid and analyzed using inductively coupled plasma-atomic emission spectroscopy. Lung levels of metals were lower at 24 h than at 4 h. Metals with high water solubility and relatively high concentration in HP-12 were increased in extrapulmonary organs. Water-soluble nonessential metals, like vanadium and nickel, were increased in plasma, hearts, and livers of exposed animals at both time points. Exposure-related small increases in essential metals, like zinc and manganese, were also noted in extrapulmonary tissues at both time points. Lead, with low water solubility but high acid solubility, was detected in liver only at 24-h postinstillation. Elements with low water or acid solubility, like silicon and aluminum, were not detected in extrapulmonary tissues despite decreased levels in the lung suggesting mucociliary clearance. We have shown that HP-12-associated metals translocate to systemic circulation and extrapulmonary organs following IT exposure. This translocation is dependent upon their relative levels and water solubility. Thus, following inhalation, PM-associated metals deposited in the lung may be released into systemic circulation at different rates depending on their water/acid solubility, thereby providing a means by which metals may elicit direct extrapulmonary effects.

BackgroundMechanisms of cardiovascular injuries from exposure to gas and particulate air pollutants are unknown.ObjectiveWe sought to determine whether episodic exposure of rats to ozone or diesel exhaust particles (DEP) causes differential cardiovascular impairments that are exacerbated by ozone plus DEP.Methods and resultsMale Wistar Kyoto rats (10–12 weeks of age) were exposed to air, ozone (0.4 ppm), DEP (2.1 mg/m3), or ozone (0.38 ppm) + DEP (2.2 mg/m3) for 5 hr/day, 1 day/week for 16 weeks, or to air, ozone (0.51 or 1.0 ppm), or DEP (1.9 mg/m3) for 5 hr/day for 2 days. At the end of each exposure period, we examined pulmonary and cardiovascular biomarkers of injury. In the 16-week study, we observed mild pulmonary pathology in the ozone, DEP, and ozone + DEP exposure groups, a slight decrease in circulating lymphocytes in the ozone and DEP groups, and decreased platelets in the DEP group. After 16 weeks of exposure, mRNA biomarkers of oxidative stress (hemeoxygenase-1), thrombosis (tissue factor, plasminogen activator inhibitor-1, tissue plasminogen activator, and von Willebrand factor), vasoconstriction (endothelin-1, endothelin receptors A and B, endothelial NO synthase) and proteolysis [matrix metalloprotease (MMP)-2, MMP-3, and tissue inhibitor of matrix metalloprotease-2] were increased by DEP and/or ozone in the aorta, but not in the heart. Aortic LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) mRNA and protein increased after ozone exposure, and LOX-1 protein increased after exposure to ozone + DEP. RAGE (receptor for advanced glycation end products) mRNA increased in the ozone + DEP group. Exposure to ozone or DEP depleted cardiac mitochondrial phospholipid fatty acids (DEP > ozone). The combined effect of ozone and DEP exposure was less pronounced than exposure to either pollutant alone. Exposure to ozone or DEP for 2 days (acute) caused mild changes in the aorta.ConclusionsIn animals exposed to ozone or DEP alone for 16 weeks, we observed elevated biomarkers of vascular impairments in the aorta, with the loss of phospholipid fatty acids in myocardial mitochondria. We conclude that there is a possible role of oxidized lipids and protein through LOX-1 and/or RAGE signaling.

BackgroundExposure to diesel exhaust (DE) is linked to vasoconstriction, endothelial dysfunction, and myocardial ischemia in compromised individuals.ObjectiveWe hypothesized that DE inhalation would cause greater inflammation, hematologic alterations, and cardiac molecular impairment in spontaneously hypertensive (SH) rats than in healthy Wistar Kyoto (WKY) rats.Methods and resultsMale rats (12–14 weeks of age) were exposed to air or DE from a 30-kW Deutz engine at 500 or 2,000 μg/m3, 4 hr/day, 5 days/week for 4 weeks. Neutrophilic influx was noted in the lung lavage fluid of both strains, but injury markers were minimally changed. Particle-laden macrophages were apparent histologically in DE-exposed rats. Lower baseline cardiac anti-oxidant enzyme activities were present in SH than in WKY rats; however, no DE effects were noted. Cardiac mitochondrial aconitase activity decreased after DE exposure in both strains. Electron microscopy indicated abnormalities in cardiac mitochondria of control SH but no DE effects. Gene expression profiling demonstrated alterations in 377 genes by DE in WKY but none in SH rats. The direction of DE-induced changes in WKY mimicked expression pattern of control SH rats without DE. Most genes affected by DE were down-regulated in WKY. The same genes were down-regulated in SH without DE producing a hypertensive-like expression pattern. The down-regulated genes included those that regulate compensatory response, matrix metabolism, mitochondrial function, and oxidative stress response. No up-regulation of inflammatory genes was noted.ConclusionsWe provide the evidence that DE inhalation produces a hypertensive-like cardiac gene expression pattern associated with mitochondrial oxidative stress in healthy rats.

BackgroundExposure to particulate matter (PM) has been associated with increased cardiovascular morbidity; however, causative components are unknown. Zinc is a major element detected at high levels in urban air.ObjectiveWe investigated the role of PM-associated zinc in cardiac injury.MethodsWe repeatedly exposed 12- to 14-week-old male Wistar Kyoto rats intratracheally (1×/week for 8 or16 weeks) to a) saline (control); b) PM having no soluble zinc (Mount St. Helens ash, MSH); or c) whole-combustion PM suspension containing 14.5 μg/mg of water-soluble zinc at high dose (PM-HD) and d ) low dose (PM-LD), e) the aqueous fraction of this suspension (14.5 μg/mg of soluble zinc) (PM-L), or f ) zinc sulfate (rats exposed for 8 weeks received double the concentration of all PM components of rats exposed for 16 weeks).ResultsPulmonary inflammation was apparent in all exposure groups when compared with saline (8 weeks > 16 weeks). PM with or without zinc, or with zinc alone caused small increases in focal subepicardial inflammation, degeneration, and fibrosis. Lesions were not detected in controls at 8 weeks but were noted at 16 weeks. We analyzed mitochondrial DNA damage using quantitative polymerase chain reaction and found that all groups except MSH caused varying degrees of damage relative to control. Total cardiac aconitase activity was inhibited in rats receiving soluble zinc. Expression array analysis of heart tissue revealed modest changes in mRNA for genes involved in signaling, ion channels function, oxidative stress, mitochondrial fatty acid metabolism, and cell cycle regulation in zinc but not in MSH-exposed rats.ConclusionThese results suggest that water-soluble PM-associated zinc may be one of the causal components involved in PM cardiac effects.

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