Effects of Subchronic Exposures to Concentrated Ambient Particles (CAPs) in Mice: IV. Characterization of Acute and Chronic Effects of Ambient Air Fine Particulate Matter Exposures on Heart-Rate Variability

Abstract

Long-term exposure to fine particulate air pollution (PM_2.5) has been associated with increased risk of death from cardiopulmonary diseases. Cardiac function parameters have also been affected by ambient particulate matter (PM) exposure, including heart-rate variability (HRV), a measure of autonomic function that has been recognized as a well-defined, quantitative indicator of autonomic dysfunction. However, the role of HRV in ambient PM-induced cardiovascular effects is not fully understood. In an accompanying article, we report significant decreasing patterns of heart rate (HR), body temperature, and physical activity for mice lacking apoliproprotein (ApoE^?/?) over 5 mo of exposure to concentrated ambient PM (CAPs), with smaller and nonsignificant changes for C57 mice. In this article, we report the effects of subchronic CAPs exposure on HRV parameters that are sensitive to cardiac sympathetic and parasympathetic nerve activity. The standard deviation of normal to normal beat intervals (SDNN) and the square root of the mean squared differences of successive RR intervals (RMSSD) in the late afternoon and overnight for the ApoE^?/? mice showed a gradual increase for the first 6 wk, a decline for about 12 more wk, and a slight turn upward at the end of the study period. For C57 mice, there were no chronic effect changes of SDNN or RMSSD in the late afternoon, and a slight increase after 6 wk for the overnight period. The response patterns of ApoE^?/? mice indicated a perturbation of the homeostatic function in the cardiovascular system (initial enhancement and later depression of the HRV parameters). Our results complement the findings in human panel and controlled CAPs exposure studies in demonstrating that increased levels of particle pollution are able to perturb cardiac autonomic function, which may lead to adverse cardiovascular outcomes.     

Effects of subchronic exposures to concentrated ambient particles in mice. IX. Integral assessment and human health implications of subchronic exposures of mice to CAPs

In order to examine the biologic plausibility of adverse chronic cardiopulmonary effects in humans associated with ambient particulate matter (PM) exposure, we exposed groups of normal mice (C57) and knockout mice that develop atherosclerotic plaque (ApoE-/- and ApoE-/- LDLr-/-) for 6 h/day, 5 days/wk for 5 or 6 mo during the spring/summer of 2003 to either filtered air or 10-fold concentrated ambient particles (CAPs) in Tuxedo, NY (average PM2.5 concentration during exposure = 110 microg/m3). Some of the mice had implanted electrocardiographic monitors. We demonstrated that: (1) this complex interdisciplinary study was technically feasible in terms of daily exposure, collection of air quality monitoring data, the collection, analysis, and interpretation of continuous data on cardiac function, and the collection and analyses of tissues of the animals sacrificed at the end of the study; (2) the daily variations in CAPs were significantly associated, in ApoE-/- mice, with daily variations in cardiac functions; (3) there were significant differences between CAPs and sham-exposed ApoE-/- mice in terms of cardiac function after the end of exposure period, as well as small differences in atherosclerotic plaque density, coronary artery disease, and cell density in the substantia nigra in the brain in the ApoE-/- mice; (4) there are suggestive indications of gene expression changes for genes associated with the control of circadian rhythm in the ApoE-/- LDLr-/- double knockout (DK) mice. These various CAPs-related effects on cardiac function and the development of histological evidence of increased risk of clinically significant disease at the end of exposures in animal models of atherosclerosis provide biological plausibility for the premature mortality associated with PM2.5 exposure in human subjects and provide suggestive evidence for neurogenic disease as well.     

Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. V. CAPs exacerbate aortic plaque development in hyperlipidemic mice

Recent epidemiological studies suggest that long-term exposure to particulate matter (PM) causes chronic effects on the cardiovascular system that result in cumulative increases cardiovascular morbidity and mortality. Since atherosclerosis is a progressive irreversible condition and an underlying cause of many cardiovascular diseases, we hypothesized that long-term exposure to PM causes adverse cardiovascular effects by exacerbating atherosclerosis. In this study, we exposed C57- and ApoE-deficient (ApoE-/-) and ApoE, LDLr (DK)-deficient mice to concentrated ambient PM2.5 for 6 h/5 days/wk, for up to 5 mo. The overall mean exposure concentration for these groups of animals was 110 microg/m3. The cross-sectional area of the aorta root of DK mice was examined morphologically using confocal microscopy for the severity of lesion, extent of cellularity, and lipid contents. Aortas from the arch to the iliac bifurcations were also sectioned longitudinally and lesion areas were stained with Sudan IV. All DK mice regardless of exposure had developed extensive lesions in the aortic sinus regions, with lesion areas that covered more than 79% of the total area. In male DK mice, the lesion areas in the aortic sinus regions appeared to be enhanced by concentrated ambient particles (CAPs), with changes approaching statistical significance (p = .06). In addition, plaque cellularity was increased by 28% (p = .014, combined), whereas there were no CAPs-associated changes in the lipid content in these mice. When examining the entire aorta opened longitudinally, both the ApoE-/- and DK mice had prominent areas of severe atherosclerosis covering 40% or more of the lumenal surface. Visual examination of all images suggested that plaques tend to form in clusters concentrating near the aortic arch and and the iliac bifurcations. Quantitative measurements showed that CAPs exposure increased the percentage of aortic intimal surface covered by grossly discernible atherosclerotic lesion by 57% in the ApoE-/- mice (p = .03). Changes produced by CAPs in male (10% increase) or female DK mice (8% increase) were not statistically significant. In this study, we have demonstrated that subchronic exposure to CAPs in mice prone to develop atherosclerotic lesions had a significant impact on the size, severity, and composition of aortic plaque.     

Ultrafine carbon black disturbs heart rate variability in mice

Previous epidemiological and toxicological studies have reported the associations between ambient particulate matter (PM) exposure and changes in heart rate variability (HRV), a marker of cardiac autonomic nervous system (ANS) function. However, both the responsible components in PM and their mechanisms affecting HRV remain uncertain. We propose that carbon black (CB), one of the main components in PM, may affect HRV through mechanisms independent of cardio-pulmonary and systemic inflammation and/or injury. Male C57BL/6 mice were exposed by intra-tracheal instillation to ultrafine CB (once every two days for three times) at doses of 0, 0.05, 0.15 and 0.6 mg/kg. HRV indices, standard deviation of all normal R-R intervals (SDNN) and the square root of mean of sum of squares of differences between adjacent normal R-R intervals (RMSSD), showed significant decreases in 0.15 and 0.6 mg/kg CB exposed groups. Slight pulmonary inflammation and myocardial injury were only observed in 0.6 mg/kg CB exposed group. We conclude that CB can disturb cardiac ANS function in mice, indicated by the withdrawal of parasympathetic modulation, through mechanisms independent of apparent myocardial and pulmonary injury.     

Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. III. Acute and chronic effects of CAPs on heart rate, heart-rate fluctuation, and body temperature

Normal mice (C57) and mice prone to develop atherosclerosis (ApoE-/-) were implanted with electrocardiograph (EKG), core body temperature, and motion transmitters were exposed daily for 6 h to Tuxedo, NY, concentrated ambient particles (CAPs) for 5 day/wk during the spring and summer of 2003. The series of 5-min EKG monitoring and body-temperature measurements were obtained for each animal in the CAPs and filtered air sham exposure groups. Our hypothesis was that chronic exposure could cause cumulative health effects. We used our recently developed nonparametric method to estimate the daily time periods that mean heart rates (HR), body temperature, and physical activity differed significantly between the CAPs and sham exposed group. CAPs exposure most affected heart rate between 1:30 a.m. and 4:30 a.m. With the response variables being the average heart rate, body temperature, and physical activity, we adopted a two-stage modeling approach to obtain the estimates of chronic and acute effects on the changes of these three response variables. In the first stage, a time-varying model estimated daily crude effects. In the second stage, the true means of the estimated crude effects were modeled with a polynominal function of time for chronic effects, a linear term of daily CAPs exposure concentrations for acute effects, and a random component for unknown noise. A Bayesian framework combined these two stages. There were significant decreasing patterns of HR, body temperature, and physical activity for the ApoE-/- mice over the 5 mo of CAPs exposure, with smaller and nonsignificant changes for the C57 mice. The chronic effect changes of the three response variables for ApoE-/- mice were maximal in the last few weeks. There was also a significant relationship between CAPs exposure concentration and short-term changes of heart rate in ApoE-/- mice during exposure. Response variables were also defined for examining fluctuations of 5-min heart rates within long (i.e., 3-6 h) and short time periods (i.e., approximately 15 min). The results for the ApoE-/- mice showed that heart-rate fluctuation within the longer periods increased to 1.35-fold by the end of exposure experiment, while the heart-rate fluctuation within 15 min decreased to 0.7-fold.     

Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. I. Introduction, objectives, and experimental plan

This subchronic (6-mo) inhalation study of the effects of concentrated ambient air fine particulate matter (PM2.5) in normal mice (C57) and a murine model of humans with an advanced level of aortic plaque (ApoE-/- or ApoE-/- LDLr-/-) was designed to determine the presence and extent of a variety of health-related responses. The animals were exposed for 6 h/day, 5 day/wk during the spring and summer of 2003 to concentrations that were elevated 10-fold in Tuxedo, NY, a regional background site that is upwind and approximately 50 km west-northwest of New York City. The average PM2.5 concentration during exposure was 110 microgram/m3, and the long-term average was 19.7 microg/m3. There were substantial daily variations in concentration, and we sought evidence both for the influence of peak exposures on acute responses and for the cumulative effects of the prolonged series of exposures. Acute responses were characterized in terms of: (1) short-term electrocardiographic (EKG), core body temperature, and physical activity differences between PM and sham-exposed mice; and (2) in vitro toxicity of a simultaneously collected PM2.5 sample to lung epithelial cells. Cumulative responses to PM2.5 were characterized in terms of changes in heart rate, heart-rate variability, heart-rate variance, aortic plaque density, genetic marker expression, and brain cell distributions. There were no significant changes in the normal mice. The nature and extent of the exposure-related responses that were seen in the ApoE-/- as well as ApoE-/- LDLr-/- mice are described in the articles that follow in this special issue of Inhalation Toxicology.     

Time course of heart rate variability decline following particulate matter exposures in an occupational cohort

Although research suggests that particles influence cardiac autonomic response as evidenced by decreases in heart rate variability (HRV), the time course of the response remains unclear. Using a crossover panel study, we monitored 36 male boilermaker welders, occupationally exposed to metal-rich particulate matter (PM) to investigate the temporal trend of hourly HRV subsequent to PM exposure. Ambulatory electrocardiograms were collected over work (exposure) and non-work (control) periods and the mean of the standard deviations of all normal-to-normal intervals for all 5-min segments (SDNN(i)) was calculated hourly for up to 14-hrs post-work. The exposure-response relationship was examined with linear mixed effects regression models to account for participants monitored over multiple occasions. Models were adjusted for non-work HRV to control for diurnal fluctuations and individual predictors of HRV. The mean (SD) work PM(2. 5) concentration was 1.12 (0.76) mg/m(3). Hourly SDNN(i) was consistently lower post-work as compared to the same time period on a non-work day. HRV was inversely associated with work PM(2. 5) exposures in each of the 14-hrs post-work. The hourly associations suggested an early and later phase response, with the largest regression coefficients observed 2-3 hrs (beta = -6.86 (95% CI: -11.91, -1.81) msec/1 mg/m(3) at 3-hrs), and then 9-13 hrs (beta = -8.60 (95% CI: -17.45, 0.24) msec/1 mg/m(3) at 11-hrs), after adjusting for non-work HRV, smoking status, and age. This investigation demonstrates declines in HRV for up to 14 hours following PM exposure and a multiphase cardiovascular autonomic response with immediate (2 hrs) and delayed (9-13 hrs) responses.     

Heart-rate variability in the apolipoprotein E knockout transgenic mouse following exposure to Seattle particulate matter

Epidemiological studies show that the elderly and/or people with preexisting cardiovascular disease (CVD) are more susceptible to the adverse effects of ambient air pollution. Heart-rate variability (HRV) measured through electrocardiogram (ECG) is a sensitive and effective tool for monitoring the adverse effects of particulate matter (PM). Common HRV parameters used include the standard deviation of the interval between normal beats (SDNN), square root of the mean of the squared differences between normal beats (rMSSD), and distinct high, low, and very low components of frequency. Aged apolipoprotein E knockout transgenic mice, a model of CVD, were implanted with miniaturized ECG telemetry devices and intranasally exposed to saline, 50 microg Seattle PM(2.5) (PM having a mean aerodynamic diameter of < or = 2.5 microm), or silica. They were monitored for a 1-d baseline prior to and for 4 d following exposure. After an initial increase in both heart rate and activity in all groups, there was delayed bradycardia with no change in activity of the animals in the PM- and silica-exposed groups. In addition, with PM and silica exposure there was a decrease in HRV parameters, suggesting a decrease in parasympathetic tone, which may lead to cardiac arrhythmia and mortality. Seattle PM is a toxic species that modulates the autonomic nervous system in a mouse model of CVD.     

Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. VIII. Source-related daily variations in in vitro responses to CAPs

The NYU PM Center subchronic animal inhalation study addressed the issues of composition and sources of ambient fine particulate matter (PM2.5), as well as the relationship of these PM2.5 characteristics to the cellular response of human bronchial epithelial cells. In this simultaneous study, we used an in vitro exposure technique to compare the daily variations of the responses of cells to fine concentrated ambient particles (CAPs) collected from a rural area upwind of New York City for the period of 9 a.m. to 3 p.m. on weekdays only, March-September, 2003. Chemical composition data for CAPs were modeled using factor analysis with varimax orthogonal rotation to determine four particle source categories contributing significant amount of mass to CAPs at Sterling Forest (Tuxedo, NY). These source categories are: (1) regional secondary sulfate characterized by high S, Si, and organic carbon (OC); (2) resuspended soil characterized by high concentrations of Ca, Fe, Al, and Si; (3) oil-fired power plants emissions of the eastern United States identified by presence of V, Ni, and Se; and (4) unknown other sources. To estimate the mass contributions of each individual source category, the CAPs mass concentration was regressed against the factor scores. Regional sulfate was the largest contributor to mass (65%), followed by soil (20%), residual oil combustion (2%), and the other sources contributing 13%. Based on an evaluation of the cellular responses to CAPs and a detailed chemical characterization of the ambient PM2.5, we investigated the sources and individual components of ambient PM2.5 that are responsible for the induced cellular response. Nuclear Factor kappa B (NF-kappa B) was selected as a monitor of cellular stress response that followed after the exposure to CAPs. The results of the NF-kappa B assay were found to be most highly correlated with Ni and V among the individual components, and with the residual oil combustion source category.     

PM2.5-induced changes in cardiac function of hypertensive rats depend on wind direction and specific sources in Steubenville, Ohio

BACKGROUND: Increases in particulate matter less than 2.5 μm (PM(2.5)) in ambient air is linked to acute cardiovascular morbidity and mortality. Specific components and potential emission sources of PM(2.5) responsible for adverse health effects of cardiovascular function are unclear. Methods: Spontaneously hypertensive rats were implemented with radiotelemeters to record ECG responses during inhalation exposure to concentrated ambient particles (CAPs) for 13 consecutive days in Steubenville, OH. Changes in heart rate (HR) and its variability (HRV) were compared to PM(2.5) trace elements in 30-min time frames to capture acute physiological responses with real-time fluctuations in PM(2.5) composition. Using positive matrix factorization, six major source factors were identified: (i) coal/secondary, (ii) mobile sources, (iii) metal coating/processing, (iv) iron/steel manufacturing, (v) lead and (vi) incineration. Results: Exposure-related changes in HR and HRV were dependant on winds predominately from either the northeast (NE) or southwest (SW). During SW winds, the metal processing factor was associated with increased HR, whereas factors of incineration, lead and iron/steel with NE winds were associated with decreased HR. Decreased SDNN was dominated during NE winds by the incinerator factor, and with SW winds by the metal factor. Metals and mobile source factors also had minor impacts on decreased SDNN with NE winds. Individual elemental components loaded onto these factors generally showed significant associations, although there were some discrepancies. Conclusions: Acute cardiovascular changes in response to ambient PM(2.5) exposure can be attributed to specific PM constituents and sources linked with incineration, metal processing, and iron/steel production.     

Synergistic effects of exposure to concentrated ambient fine pollution particles and nitrogen dioxide in humans

Context: Exposure to single pollutants e.g. particulate matter (PM) is associated with adverse health effects, but it does not represent a real world scenario that usually involves multiple pollutants.

Objectives: Determine if simultaneous exposure to PM and NO₂ results in synergistic interactions.

Materials and methods: Healthy young volunteers were exposed to clean air, nitrogen dioxide (NO₂, 0.5 ppm), concentrated fine particles from Chapel Hill air (PM_2.5CAPs, 89.5?±?10.7 µg/m³), or NO₂+PM_2.5CAPs for 2?h. Each subject performed intermittent exercise during the exposure. Parameters of heart rate variability (HRV), changes in repolarization, peripheral blood endpoints and lung function were measured before and 1 and 18?h after exposure. Bronchoalveolar lavage (BAL) was performed 18?h after exposure.

Results: NO₂ exposure alone increased cholesterol and HDL 18?h after exposure, decreased high frequency component of HRV one and 18?h after exposure, decreased QT variability index 1?h after exposure, and increased LDH in BAL fluid. The only significant change with PM_2.5CAPs was an increase in HDL 1?h after exposure, likely due to the low concentrations of PM_2.5CAPs in the exposure chamber. Exposure to both NO₂ and PM_2.5CAPs increased BAL α1-antitrypsin, mean t wave amplitude, the low frequency components of HRV and the LF/HF ratio. These changes were not observed following exposure to NO₂ or PM_2.5CAPs alone, suggesting possible interactions between the two pollutants.

Discussion and conclusions: NO₂ exposure may produce and enhance acute cardiovascular effects of PM_2.5CAPs. Assessment of health effects by ambient PM should consider its interactions with gaseous copollutants.     

Health effects of concentrated ambient air particulate matter (CAPs) and its components

We review literature that provides insights on health-related effects observed in laboratory-based inhalation studies in humans and laboratory animals using concentrated ambient air particulate matter (CAPs) in the fine, thoracic coarse, and ultrafine size ranges. The CAPs studies are highly informative on the health effects of ambient air particulate matter (PM) because they represent realistic PM exposure mixtures. When PM components are also analyzed and regressed against the effects, they can sometimes be used to identify influential individual components or source-related mixtures responsible for the effects. Such CAPs inhalation studies are analogous to epidemiological studies of human populations for which both health-related effects were observed and PM composition data were available for multi-pollutant regression analyses or source apportionment. Various acute and chronic health-related effects have occurred in short- and long-term CAPs inhalation studies in the cardiovascular, nervous, hepatic, and pulmonary systems, as well as changes in markers of the metabolic syndrome, and many correspond to effects associated with ambient air PM exposures in epidemiological studies. In addition, many CAPs studies have been conducted in coordination with in vitro studies that have identified biomarkers indicative of the underlying biological mechanisms that account for the responses.     

Effects of concentrated fine ambient particles on rat plasma levels of asymmetric dimethylarginine

The health effects of ambient fine particulate matter (PM(2.5)) and its potential impact on vascular endothelial function have not been thoroughly investigated. As endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis and its complications, we examined the effects of concentrated fine ambient particles (CAPs) on the plasma level of asymmetric dimethylarginine (ADMA) in a pilot study. ADMA is a circulating endogenous inhibitor of nitric oxide synthase (NOS) that is associated with impaired vascular function and increased risk for cardiovascular events. A mobile air research laboratory (AirCARE 1) was used to provide "real-world" CAPs exposures for this study conducted in Detroit, MI. Fourteen Brown Norway rats were exposed to filtered air (FA) (n = 7) or CAPs (0.1-2.5 microm) (n = 7) for 3 consecutive days (8 h/day) in July 2002. Rats were exposed during these periods to average particle mass concentrations of 354 microg/m(3). Rat plasma samples were collected 24 h postexposure. Plasma concentrations of ADMA were significantly elevated in rats exposed to CAPs versus those exposed to FA (mean +/- standard deviation = 1.49 +/- 0.18 vs. 1.29 +/- 0.26 microM, p =.05 by one-tailed t-test). Analyses of meteorological data and CAPs trace element composition suggest that local particle emission sources contributed largely to overall mass of CAPs. Results of this pilot study suggest that exposure to PM(2.5) at high concentrations may trigger an acute increase in circulating ADMA level. This finding has implications for the regulation of vasomotor tone by particulate pollutants and the propensity for adverse cardiovascular events.     

Inhalation of concentrated ambient particulate matter near a heavily trafficked road stimulates antigen-induced airway responses in mice

Motor vehicle exhaust emissions are known to exacerbate asthma and other respiratory diseases. Several studies have demonstrated significant associations between living near highly trafficked roadways and increased incidence of asthma and increased severity of asthma-related symptoms, medication usage, and physician visits. This study tested the hypotheses that (1) exposure to particulate matter (PM) near a heavily trafficked Los Angeles freeway would enhance inflammatory and allergic responses in ovalbumin (OVA)-sensitized BALB/c mice compared to sensitized, clean air controls, and (2) there would be differences in response at two distances downwind of heavily traveled freeways because of greater toxicity of PM closest to the freeway. An ambient particle concentrator was used to expose ovalbumin (OVA)-treated BALB/c mice to purified air, to concentrated fine ambient particles, and to concentrated ultrafine airborne particles (CAPs) at 2 distances, 50 m and 150 m, downwind of a roadway that is impacted by emissions from both heavy-duty diesel and light duty gasoline vehicles. Tissues and biological fluids from the mice were analyzed after exposures for 5 days/wk in 2 consecutive weeks. The biomarkers of allergic or inflammatory responses that were assessed included cytokines released by Type 2 T-helper cells (interleukin [IL]-5 and IL-13), OVA-specific immunoglobulin E (IgE), OVA-specific immunoglobulin G1 (IgG1), and pulmonary infiltration of polymorphonuclear leukocytes and eosinophils. IL-5 and IgG1 were significantly increased in mice exposed to CAPs 50 m downwind of the road, compared to responses in mice exposed to purified air, providing evidence of allergic response. No significant increases in allergy-related responses were observed in mice exposed to CAPs 150 m downwind of the road. The biological responses at the 50-m site were significantly associated with organic and elemental carbon components of fine and ultrafine particles (p < or = .05). The primary source of these contaminants at the roadway sites was motor vehicle emissions, suggesting that particulate matter from motor vehicle fuel combustion could exert adjuvant effects and promote the development of allergic airway diseases.     

Seasonal influences on CAPs exposures: differential responses in platelet activation, serum cytokines and xenobiotic gene expression

Increasing evidence suggests a role for a systemic pro-coagulant state in the pathogenesis of cardiac dysfunction subsequent to inhalation of airborne particulate matter (PM). We evaluated platelet activation, systemic cytokines and pulmonary gene expression in mice exposed to concentrated ambient particulate matter (CAPs) in the summer of 2008 (S08) and winter of 2009 (W09) from the San Joaquin Valley of California, a region with severe PM pollution episodes. Additionally, we characterized the PM from both exposures including organic compounds, metals, and polycyclic aromatic hydrocarbons. Mice were exposed to an average of 39.01 μg/m(3) of CAPs in the winter and 21.7 μg/m3 CAPs in the summer, in a size range less than 2.5 μm for 6 h/day for 5 days per week for 2 weeks. Platelets were analyzed by flow cytometry for relative size, shape, CD41, P-selectin and lysosomal associated membrane protein-1 (LAMP-1) expression. Platelets from W09 CAPs-exposed animals had a greater response to thrombin stimulation than platelets from S08 CAPs-exposed animals. Serum cytokines were analyzed by bead based immunologic assays. W09 CAPs-exposed mice had elevations in IL-2, MIP-1α, and TNFα. Laser capture microdissection (LCM) of pulmonary vasculature, parenchyma and airways all showed increases in CYP1a1 gene expression. Pulmonary vasculature showed increased expression of ICAM-1 and Nox-2. Our findings demonstrate that W09 CAPs exposure generated a greater systemic pro-inflammatory and pro-coagulant response to inhalation of environmentally derived fine and ultrafine PM. Changes in platelet responsiveness to agonists, seen in both exposures, strongly suggests a role for platelet activation in the cardiovascular and respiratory effects of particulate air pollution.     

Seasonal influences on CAPs exposures: differential responses in platelet activation,serum cytokines and xenobiotic gene expression

Increasing evidence suggests a role for a systemic pro-coagulant state in the pathogenesis of cardiac dysfunction subsequent to inhalation of airborne particulate matter (PM). We evaluated platelet activation, systemic cytokines and pulmonary gene expression in mice exposed to concentrated ambient particulate matter (CAPs) in the summer of 2008 (S08) and winter of 2009 (W09) from the San Joaquin Valley of California, a region with severe PM pollution episodes. Additionally, we characterized the PM from both exposures including organic compounds, metals, and polycyclic aromatic hydrocarbons. Mice were exposed to an average of 39.01 μg/m³ of CAPs in the winter and 21.7 μg/m3 CAPs in the summer, in a size range less than 2.5 μm for 6?h/day for 5 days per week for 2 weeks. Platelets were analyzed by flow cytometry for relative size, shape, CD41, P-selectin and lysosomal associated membrane protein-1 (LAMP-1) expression. Platelets from W09 CAPs-exposed animals had a greater response to thrombin stimulation than platelets from S08 CAPs-exposed animals. Serum cytokines were analyzed by bead based immunologic assays. W09 CAPs-exposed mice had elevations in IL-2, MIP-1α, and TNFα. Laser capture microdissection (LCM) of pulmonary vasculature, parenchyma and airways all showed increases in CYP1a1 gene expression. Pulmonary vasculature showed increased expression of ICAM-1 and Nox-2. Our findings demonstrate that W09 CAPs exposure generated a greater systemic pro-inflammatory and pro-coagulant response to inhalation of environmentally derived fine and ultrafine PM. Changes in platelet responsiveness to agonists, seen in both exposures, strongly suggests a role for platelet activation in the cardiovascular and respiratory effects of particulate air pollution.     

Effects of metals within ambient air particulate matter (PM) on human health

We review literature providing insights on health-related effects caused by inhalation of ambient air particulate matter (PM) containing metals, emphasizing effects associated with in vivo exposures at or near contemporary atmospheric concentrations. Inhalation of much higher concentrations, and high-level exposures via intratracheal (IT) instillation that inform mechanistic processes, are also reviewed. The most informative studies of effects at realistic exposure levels, in terms of identifying influential individual PM components or source-related mixtures, have been based on (1) human and laboratory animal exposures to concentrated ambient particles (CAPs), and (2) human population studies for which both health-related effects were observed and PM composition data were available for multipollutant regression analyses or source apportionment. Such studies have implicated residual oil fly ash (ROFA) as the most toxic source-related mixture, and Ni and V, which are characteristic tracers of ROFA, as particularly influential components in terms of acute cardiac function changes and excess short-term mortality. There is evidence that other metals within ambient air PM, such as Pb and Zn, also affect human health. Most evidence now available is based on the use of ambient air PM components concentration data, rather than actual exposures, to determine significant associations and/or effects coefficients. Therefore, considerable uncertainties about causality are associated with exposure misclassification and measurement errors. As more PM speciation data and more refined modeling techniques become available, and as more CAPs studies involving PM component analyses are performed, the roles of specific metals and other components within PM will become clearer.     

The relationship between air pollutants and heart-rate variability among community residents in Korea

Air pollution, both particulate and gaseous, is known to cause adverse health effects and is associated with increased cardiovascular mortality and morbidity. With a growing recognition in the importance of the autonomic nervous system in air pollution, we examined the effects of air pollutants, namely, particulate matter (PM10), sulfur dioxide (SO2), and nitric dioxide (NO2), on cardiac autonomic function by measuring heart-rate variability (HRV) among community residents. This study was conducted at Taein Island, located off the southern coast of South Korea; 1349 subjects (596 males and 753 females) were included in this analysis. Subjects responded to the interview about general characteristics and an HRV examination was conducted. Exposure data were collected from the Environmental Management Corporation during the same period of HRV measurement. Linear regression analyses were carried out to evaluate the association over 72 h, and the parameters of HRV indices were presented as the percentage change. The exposures to PM(10), SO(2), and NO2 were associated with reduced HRV indices, and significant decreases in the standard deviation of the normal to normal interval (SDNN) and low frequency (LF) domain effect, and the effect was largely continued until 12 h. Our results suggest that air pollutants stimulate the autonomic nervous system and provoke an imbalance in cardiac autonomic control. Thus, these subclinical effects may lead to pathological consequences, particularly in high-risk patients and susceptible subjects.