Peat smoke inhalation alters blood pressure, baroreflex sensitivity, and cardiac arrhythmia risk in rats.

Wildland fires (WF) are linked to adverse health impacts related to poor air quality. The cardiovascular impacts of emissions from specific biomass sources are however unknown. The purpose of this study was to assess the cardiovascular impacts of a single exposure to peat smoke, a key regional WF air pollution source, and relate these to baroreceptor sensitivity and inflammation. Three-month-old male Wistar-Kyoto rats, implanted with radiotelemeters for continuous monitoring of heart rate (HR), blood pressure (BP), and spontaneous baroreflex sensitivity (BRS), were exposed once, for 1-hr, to filtered air or low (0.38 mg/m3 PM) or high (4.04 mg/m3) concentrations of peat smoke. Systemic markers of inflammation and sensitivity to aconitine-induced cardiac arrhythmias, a measure of latent myocardial vulnerability, were assessed in separate cohorts of rats 24 hr after exposure. PM size (low peat = 0.4-0.5 microns vs. high peat = 0.8-1.2 microns) and proportion of organic carbon (low peat = 77% vs. high peat = 65%) varied with exposure level. Exposure to high peat and to a lesser extent low peat increased systolic and diastolic BP relative to filtered air. In contrast, only exposure to low peat elevated BRS and aconitine-induced arrhythmogenesis relative to filtered air and increased circulating levels of low-density lipoprotein cholesterol, complement components C3 and C4, angiotensin-converting enzyme (ACE), and white blood cells. Taken together, exposure to peat smoke produced overt and latent cardiovascular consequences that were likely influenced by physicochemical characteristics of the smoke and associated adaptive homeostatic mechanisms.

A single exposure to eucalyptus smoke sensitizes rats to the postprandial cardiovascular effects of a high carbohydrate oral load.

OBJECTIVE: Previous studies have shown that air pollution exposure primes the body to heightened responses to everyday stressors of the cardiovascular system. The purpose of this study was to examine the utility of postprandial responses to a high carbohydrate oral load, a cardiometabolic stressor long used to predict cardiovascular risk, in assessing the impacts of exposure to eucalyptus smoke (ES), a contributor to wildland fire air pollution in the Western coast of the United States. MATERIALS AND METHODS: Three-month-old male Sprague Dawley rats were exposed once (1 h) to filtered air (FA) or ES (700 µg/m3 fine particulate matter), generated by burning eucalyptus in a tube furnace. Rats were then fasted for six hours the following morning, and subsequently administered an oral gavage of either water or a HC suspension (70 kcal% from carbohydrate), mimicking a HC meal. Two hours post gavage, cardiovascular ultrasound, cardiac pressure-volume (PV), and baroreceptor sensitivity assessments were made, and pulmonary and systemic markers assessed. RESULTS: ES inhalation alone increased serum interleukin (IL)-4 and nasal airway levels of gamma glutamyl transferase. HC gavage alone increased blood glucose, blood pressure, and serum IL-6 and IL-13 compared to water vehicle. By contrast, only ES-exposed and HC-challenged animals had increased PV loop measures of cardiac output, ejection fraction %, dP/dtmax, dP/dtmin, and stroke work compared to ES exposure alone and/or HC challenge alone. DISCUSSION AND CONCLUSIONS: Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.

Early-Life Persistent Vitamin D Deficiency Alters Cardiopulmonary Responses to Particulate Matter-Enhanced Atmospheric Smog in Adult Mice.

Early life nutritional deficiencies can lead to increased cardiovascular susceptibility to environmental exposures. Thus, the purpose of this study was to examine the effect of early life persistent vitamin D deficiency (VDD) on the cardiopulmonary response to a particulate matter-enhanced photochemical smog. Mice were fed a VDD or normal diet (ND) after weaning. At 17 weeks of age, mice were implanted with radiotelemeters to monitor electrocardiogram, heart rate (HR), and heart rate variability (HRV). Ventilatory function was measured throughout the diet before and after smog exposure using whole-body plethysmography. VDD mice had lower HR, increased HRV, and decreased tidal volume compared with ND. Regardless of diet, HR decreased during air exposure; this response was blunted by smog in ND mice and to a lesser degree in VDD. When compared with ND, VDD increased HRV during air exposure and more so with smog. However, smog only increased cardiac arrhythmias in ND mice. This study demonstrates that VDD alters the cardiopulmonary response to smog, highlighting the possible influence of nutritional factors in determining responses to air pollution. The mechanism of how VDD induces these effects is currently unknown, but modifiable factors should be considered when performing risk assessment of complex air pollution atmospheres.

Morning NO2 exposure sensitizes hypertensive rats to the cardiovascular effects of same day O3 exposure in the afternoon.

CONTEXT: Within urban air sheds, specific ambient air pollutants typically peak at predictable times throughout the day. For example, in environments dominated by mobile sources, peak nitrogen dioxide (NO2) levels coincide with morning and afternoon rush hours, while peak levels of ozone (O3), occur in the afternoon. OBJECTIVE: Given that exposure to a single pollutant might sensitize the cardiopulmonary system to the effects of a subsequent exposure to a second pollutant, we hypothesized that a morning exposure to NO2 will exaggerate the cardiovascular effects of an afternoon O3 exposure in rats. MATERIALS AND METHODS: Rats were divided into four groups that were each exposed for 3 h in the morning (m) and 3 h in the afternoon (a) on the same day: (1) m-Air/a-Air, (2) m-Air/a-O3 (0.3 ppm), (3) m-NO2 (0.5 ppm)/a-Air and (4) m-NO2/a-O3. Implanted telemetry devices recorded blood pressure and electrocardiographic data. Sensitivity to the arrhythmogenic agent aconitine was measured in a separate cohort. RESULTS: Only m-NO2/a-O3-exposed rats had significant changes in electrophysiological, mechanical and autonomic parameters. These included decreased heart rate and increased PR and QTc intervals and increased heart rate variability, suggesting increased parasympathetic tone. In addition, only m-NO2/a-O3 exposure decreased systolic and diastolic blood pressures and increased pulse pressure and QA interval, suggesting decreased cardiac contractility. DISCUSSION AND CONCLUSION: The findings indicate that initial exposure to NO2 sensitized rats to the cardiovascular effects of O3 and may provide insight into the epidemiological data linking adverse cardiovascular outcomes with exposures to low concentrations of O3.

Systematic proteomic approach to characterize the impacts of chemical interactions on protein and cytotoxicity responses to metal mixture exposures.

Chemical interactions have posed a big challenge in toxicity characterization and human health risk assessment of environmental mixtures. To characterize the impacts of chemical interactions on protein and cytotoxicity responses to environmental mixtures, we established a systems biology approach integrating proteomics, bioinformatics, statistics, and computational toxicology to measure expression or phosphorylation levels of 21 critical toxicity pathway regulators and 445 downstream proteins in human BEAS-2B cells treated with 4 concentrations of nickel, 2 concentrations each of cadmium and chromium, as well as 12 defined binary and 8 defined ternary mixtures of these metals in vitro. Multivariate statistical analysis and mathematical modeling of the metal-mediated proteomic response patterns showed a high correlation between changes in protein expression or phosphorylation and cellular toxic responses to both individual metals and metal mixtures. Of the identified correlated proteins, only a small set of proteins including HIF-1α is likely to be responsible for selective cytotoxic responses to different metals and metals mixtures. Furthermore, support vector machine learning was utilized to computationally predict protein responses to uncharacterized metal mixtures using experimentally generated protein response profiles corresponding to known metal mixtures. This study provides a novel proteomic approach for characterization and prediction of toxicities of metal and other chemical mixtures.

Cardiac effects of seasonal ambient particulate matter and ozone co-exposure in rats.

BACKGROUND: The potential for seasonal differences in the physicochemical characteristics of ambient particulate matter (PM) to modify interactive effects with gaseous pollutants has not been thoroughly examined. The purpose of this study was to compare cardiac responses in conscious hypertensive rats co-exposed to concentrated ambient particulates (CAPs) and ozone (O3) in Durham, NC during the summer and winter, and to analyze responses based on particle mass and chemistry. METHODS: Rats were exposed once for 4 hrs by whole-body inhalation to fine CAPs alone (target concentration: 150 µg/m3), O3 (0.2 ppm) alone, CAPs plus O3, or filtered air during summer 2011 and winter 2012. Telemetered electrocardiographic (ECG) data from implanted biosensors were analyzed for heart rate (HR), ECG parameters, heart rate variability (HRV), and spontaneous arrhythmia. The sensitivity to triggering of arrhythmia was measured in a separate cohort one day after exposure using intravenously administered aconitine. PM elemental composition and organic and elemental carbon fractions were analyzed by high-resolution inductively coupled plasma-mass spectrometry and thermo-optical pyrolytic vaporization, respectively. Particulate sources were inferred from elemental analysis using a chemical mass balance model. RESULTS: Seasonal differences in CAPs composition were most evident in particle mass concentrations (summer, 171 µg/m3; winter, 85 µg/m3), size (summer, 324 nm; winter, 125 nm), organic:elemental carbon ratios (summer, 16.6; winter, 9.7), and sulfate levels (summer, 49.1 µg/m3; winter, 16.8 µg/m3). Enrichment of metals in winter PM resulted in equivalent summer and winter metal exposure concentrations. Source apportionment analysis showed enrichment for anthropogenic and marine salt sources during winter exposures compared to summer exposures, although only 4% of the total PM mass was attributed to marine salt sources. Single pollutant cardiovascular effects with CAPs and O3 were present during both summer and winter exposures, with evidence for unique effects of co-exposures and associated changes in autonomic tone. CONCLUSIONS: These findings provide evidence for a pronounced effect of season on PM mass, size, composition, and contributing sources, and exposure-induced cardiovascular responses. Although there was inconsistency in biological responses, some cardiovascular responses were evident only in the co-exposure group during both seasons despite variability in PM physicochemical composition. These findings suggest that a single ambient PM metric alone is not sufficient to predict potential for interactive health effects with other air pollutants.

The effects of B0, B20, and B100 soy biodiesel exhaust on aconitine-induced cardiac arrhythmia in spontaneously hypertensive rats.

CONTEXT: Diesel exhaust (DE) has been shown to increase the risk of cardiac arrhythmias. Although biodiesel has been proposed as a "safer" alternative to diesel, it is still uncertain whether it actually poses less threat. OBJECTIVE: We hypothesized that exposure to pure or 20% soy biodiesel exhaust (BDE) would cause less sensitivity to aconitine-induced arrhythmia than DE in rats. METHODS: Spontaneously hypertensive (SH) rats implanted with radiotelemeters were exposed once or for 5 d (4 h) to either 50 mg/m(3) (low), 150 mg/m(3) (medium), or 500 mg/m(3) (high) of DE (B0), 20% (B20) or 100% (B100) soy biodiesel exhaust. Arrhythmogenesis was assessed 24 h later by continuous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR), and electrocardiogram (ECG) were monitored. RESULTS: Rats exposed once or for 5 d to low, medium, or high B0 developed arrhythmia at significantly lower doses of aconitine than controls, whereas rats exposed to B20 were only consistently sensitive after 5 d of the high concentration. B100 caused mild arrhythmia sensitivity at the low concentration, only after 5 d of exposure at the medium concentration and after either a single or 5 d at the high concentration. DISCUSSION AND CONCLUSIONS: These data demonstrate that exposure to B20 causes less sensitivity to arrhythmia than B0 and B100. This diminished effect may be due to lower irritant components such as acrolein and nitrogen oxides. Thus, in terms of cardiac health, B20 may be a safer option than both of the pure forms.

Cardiomyopathy confers susceptibility to particulate matter-induced oxidative stress, vagal dominance, arrhythmia and pulmonary inflammation in heart failure-prone rats.

Acute exposure to ambient fine particulate matter (PM2.5) is tied to cardiovascular morbidity and mortality, especially among those with prior cardiac injury. The mechanisms and pathophysiological events precipitating these outcomes remain poorly understood but may involve inflammation, oxidative stress, arrhythmia and autonomic nervous system imbalance. Cardiomyopathy results from cardiac injury, is the leading cause of heart failure, and can be induced in heart failure-prone rats through sub-chronic infusion of isoproterenol (ISO). To test whether cardiomyopathy confers susceptibility to inhaled PM2.5 and can elucidate potential mechanisms, we investigated the cardiophysiologic, ventilatory, inflammatory and oxidative effects of a single nose-only inhalation of a metal-rich PM2.5 (580 µg/m(3), 4 h) in ISO-pretreated (35 days × 1.0 mg/kg/day sc) rats. During the 5 days post-treatment, ISO-treated rats had decreased HR and BP and increased pre-ejection period (PEP, an inverse correlate of contractility) relative to saline-treated rats. Before inhalation exposure, ISO-pretreated rats had increased PR and ventricular repolarization time (QT) and heterogeneity (Tp-Te). Relative to clean air, PM2.5 further prolonged PR-interval and decreased systolic BP during inhalation exposure; increased tidal volume, expiratory time, heart rate variability (HRV) parameters of parasympathetic tone and atrioventricular block arrhythmias over the hours post-exposure; increased pulmonary neutrophils, macrophages and total antioxidant status one day post-exposure; and decreased pulmonary glutathione peroxidase 8 weeks after exposure, with all effects occurring exclusively in ISO-pretreated rats but not saline-pretreated rats. Ultimately, our findings indicate that cardiomyopathy confers susceptibility to the oxidative, inflammatory, ventilatory, autonomic and arrhythmogenic effects of acute PM2.5 inhalation.

Acrolein inhalation alters arterial blood gases and triggers carotid body-mediated cardiovascular responses in hypertensive rats.

CONTEXT: Air pollution exposure affects autonomic function, heart rate, blood pressure and left ventricular function. While the mechanism for these effects is uncertain, several studies have reported that air pollution exposure modifies activity of the carotid body, the major organ that senses changes in arterial oxygen and carbon dioxide levels, and elicits downstream changes in autonomic control and cardiac function. OBJECTIVE: We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke and diesel exhaust, would activate the carotid body chemoreceptor response and lead to secondary cardiovascular responses in rats. MATERIALS AND METHODS: Spontaneously hypertensive (SH) rats were exposed once for 3 h to 3 ppm acrolein gas or filtered air in whole body plethysmograph chambers. To determine if the carotid body mediated acrolein-induced cardiovascular responses, rats were pretreated with an inhibitor of cystathionine γ-lyase (CSE), an enzyme essential for carotid body signal transduction. RESULTS: Acrolein exposure induced several cardiovascular effects. Systolic, diastolic and mean arterial blood pressure increased during exposure, while cardiac contractility decreased 1 day after exposure. The cardiovascular effects were associated with decreases in pO2, breathing frequency and expiratory time, and increases in sympathetic tone during exposure followed by parasympathetic dominance after exposure. The CSE inhibitor prevented the cardiovascular effects of acrolein exposure. DISCUSSION AND CONCLUSION: Pretreatment with the CSE inhibitor prevented the cardiovascular effects of acrolein, suggesting that the cardiovascular responses with acrolein may be mediated by carotid body-triggered changes in autonomic tone. (This abstract does not reflect EPA policy.).

ST depression, arrhythmia, vagal dominance, and reduced cardiac micro-RNA in particulate-exposed rats.

Recently, investigators demonstrated associations between fine particulate matter (PM)-associated metals and adverse health effects. Residual oil fly ash (ROFA), a waste product of fossil fuel combustion from boilers, is rich in the transition metals Fe, Ni, and V, and when released as a fugitive particle, is an important contributor to ambient fine particulate air pollution. We hypothesized that a single-inhalation exposure to transition metal-rich PM will cause concentration-dependent cardiovascular toxicity in spontaneously hypertensive (SH) rats. Rats implanted with telemeters to monitor heart rate and electrocardiogram were exposed once by nose-only inhalation for 4 hours to 3.5 mg/m(3), 1.0 mg/m(3), or 0.45 mg/m(3) of a synthetic PM (dried salt solution), similar in composition to a well-studied ROFA sample consisting of Fe, Ni, and V. Exposure to the highest concentration of PM decreased T-wave amplitude and area, caused ST depression, reduced heart rate (HR), and increased nonconducted P-wave arrhythmias. These changes were accompanied by increased pulmonary inflammation, lung resistance, and vagal tone, as indicated by changes in markers of HR variability (increased root of the mean of squared differences of adjacent RR intervals [RMSSD], low frequency [LF], high frequency [HF], and decreased LF/HF), and attenuated myocardial micro-RNA (RNA segments that suppress translation by targeting messenger RNA) expression. The low and intermediate concentrations of PM had less effect on the inflammatory, HR variability, and micro-RNA endpoints, but still caused significant reductions in HR. In addition, the intermediate concentration caused ST depression and increased QRS area, whereas the low concentration increased the T-wave parameters. Thus, PM-induced cardiac dysfunction is mediated by multiple mechanisms that may be dependent on PM concentration and myocardial vulnerability (this abstract does not reflect the policy of the United States Environmental Protection Agency).

Dietary salt exacerbates isoproterenol-induced cardiomyopathy in rats.

Spontaneously hypertensive heart failure rats (SHHFs) take longer to develop compensated heart failure (HF) and congestive decompensation than common surgical models of HF. Isoproterenol (ISO) infusion can accelerate cardiomyopathy in young SHHFs, while dietary salt loading in hypertensive rats induces cardiac fibrosis, hypertrophy, and--in a minority-congestive HF. By combining ISO with dietary salt loading in young SHHFs, the authors sought a nonsurgical model that is more time--and resource-efficient than any of these factors alone. The authors hypothesized that salt loading would enhance ISO-accelerated cardiomyopathy, promoting fibrosis, hypertrophy, and biochemical characteristics of HF. SHHFs (lean male, 90d) were infused for 4 wk with ISO (2.5 mg/kg/day) or saline. After 2 wk of infusion, a 6-wk high-salt diet (4%, 6%, or 8% NaCl) was initiated. Eight percent salt increased heart weight, HF markers (plasma B-type natriuretic peptide, IL-6), lung lymphocytes, and indicators of lung injury and edema (albumin and protein) relative to control diet, while increasing urine pro-atrial natriuretic peptide relative to ISO-only. High salt also exacerbated ISO-cardiomyopathy and fibrosis. Thus, combining ISO infusion with dietary salt loading in SHHFs holds promise for a new rat HF model that may help researchers to elucidate HF mechanisms and unearth effective treatments.

Early-life persistent vitamin D deficiency-induced cardiovascular dysfunction in mice is mediated by transient receptor potential C channels.

BACKGROUND: Studies indicate that chronic vitamin D deficiency (VDD) may predispose to hypertension, yet, there is very little data characterizing its direct cardiac effects. Vitamin D modulates the function of transient receptor potential C cation channels (TRPC), which is a mechanosensitive cation channel that plays a role in cardiac slow-force responses to hemodynamic changes. The purpose of this study was to determine the cardiac effects of VDD and the potential role of TRPC. METHODS: Three-week old mice were placed on a VDD or normal diet (ND) for 19 weeks. Mice were then implanted with radiotelemeters for the measurement of heart rate (HR) and heart rate variability (HRV), while a separate group was anesthetized to measure blood pressure (BP) and left ventricular function using an intraventricular probe. Animals were treated with a TRPC antagonist or vehicle after which they were challenged with dobutamine to measure cardiac responses. RESULTS: VDD mice had significantly increased BP (72 ± 3 mmHg vs. 62 ± 2 mmHg) and left ventricular pressure (LVP) (84.6 ± 0.8 mmHg vs. 78.2 ± 2.0 mmHg), and decreased cardiac contractility (-3 % vs. + 11 %) and HR response (+8 % vs. + 13 %) to dobutamine when compared to ND. These responses were blocked by the TRPC antagonist. HRV decreased with increasing dobutamine doses in ND but not VDD mice, however, the antagonist had no effect. CONCLUSION: VDD increases BP and alters cardiac mechanical function in mice, the latter appears to be mediated by TRPC, in particular TRPC6. Although the cardiac effects might be due to increased BP, it is likely that VDD also affects the function of the heart directly. This is the first study to demonstrate the potentially deleterious effects of VDD on cardiac function and the role of TRPC6 in this response.

Particulate matter inhalation exacerbates cardiopulmonary injury in a rat model of isoproterenol-induced cardiomyopathy.

Ambient particulate matter (PM) exposure is linked to cardiovascular events and death, especially among individuals with heart disease. A model of toxic cardiomyopathy was developed in Spontaneously Hypertensive Heart Failure (SHHF) rats to explore potential mechanisms. Rats were infused with isoproterenol (ISO; 2.5 mg/kg/day subcutaneous [sc]), a beta-adrenergic agonist, for 28 days and subsequently exposed to PM by inhalation. ISO induced tachycardia and hypotension throughout treatment followed by postinfusion decrements in heart rate, contractility, and blood pressures (systolic, diastolic, pulse), and fibrotic cardiomyopathy. Changes in heart rate and heart rate variability (HRV) 17 days after ISO cessation indicated parasympathetic dominance with concomitantly altered ventilation. Rats were subsequently exposed to filtered air or Harvard Particle 12 (HP12) (12 mg/m(3))--a metal-rich oil combustion-derived PM--at 18 and 19 days (4 h/day) after ISO infusion via nose-only inhalation to determine if cardio-impaired rats were more responsive to the effects of PM exposure. Inhalation of PM among ISO-pretreated rats significantly increased pulmonary lactate dehydrogenase, serum high-density lipoprotein (HDL) cholesterol, and heart-to-body mass ratio. PM exposure increased the number of ISO-pretreated rats that experienced bradyarrhythmic events, which occurred concomitantly with acute alterations of HRV. PM, however, did not significantly affect mean HRV in the ISO- or saline-pretreated groups. In summary, subchronic ISO treatment elicited some pathophysiologic and histopathological features of heart failure, including cardiomyopathy. The enhanced sensitivity to PM exposure in SHHF rats with ISO-accelerated cardiomyopathy suggests that this model may be useful for elucidating the mechanisms by which PM exposure exacerbates heart disease.

Endothelial effects of emission source particles: acute toxic response gene expression profiles.

Air pollution epidemiology has established a strong association between exposure to ambient particulate matter (PM) and cardiovascular outcomes. Experimental studies in both humans and laboratory animals support varied biological mechanisms including endothelial dysfunction as potentially a central step to the elicitation of cardiovascular events. We therefore hypothesized that relevant early molecular alterations on endothelial cells should be assessable in vitro upon acute exposure to PM components previously shown to be involved in health outcomes. Using a model emission PM, residual oil fly ash and one of its predominant constituents (vanadium-V), we focused on the development of gene expression profiles to fingerprint that particle and its constituents to explore potential biomarkers for PM-induced endothelial dysfunction. Here we present differential gene expression and transcription factor activation profiles in human vascular endothelial cells exposed to a non-cytotoxic dose of fly ash or V following semi-global gene expression profiling of approximately 8000 genes. Both fly ash and it's prime constituent, V, induced alterations in genes involved in passive and active transport of solutes across the membrane; voltage-dependent ion pumps; induction of extracellular matrix proteins and adhesion molecules; and activation of numerous kinases involved in signal transduction pathways. These preliminary data suggest that cardiovascular effects associated with exposure to PM may be mediated by perturbations in endothelial cell permeability, membrane integrity; and ultimately endothelial dysfunction.

Early Proteome Shift and Serum Bioactivity Precede Diesel Exhaust-induced Impairment of Cardiovascular Recovery in Spontaneously Hypertensive Rats.

Single circulating factors are often investigated to explain air pollution-induced cardiovascular dysfunction, yet broader examinations of the identity and bioactivity of the entire circulating milieu remain understudied. The purpose of this study was to determine if exposure-induced cardiovascular dysfunction can be coupled with alterations in both serum bioactivity and the circulating proteome. Two cohorts of Spontaneously Hypertensive Rats (SHRs) were exposed to 150 or 500 µg/m3 diesel exhaust (DE) or filtered air (FA). In Cohort 1, we collected serum 1 hour after exposure for proteomics analysis and bioactivity measurements in rat aortic endothelial cells (RAECs). In Cohort 2, we assessed left ventricular pressure (LVP) during stimulation and recovery from the sympathomimetic dobutamine HCl, one day after exposure. Serum from DE-exposed rats had significant changes in 66 serum proteins and caused decreased NOS activity and increased VCAM-1 expression in RAECs. While rats exposed to DE demonstrated increased heart rate at the start of LVP assessments, heart rate, systolic pressure, and double product fell below baseline in DE-exposed rats compared to FA during recovery from dobutamine, indicating dysregulation of post-exertional cardiovascular function. Taken together, a complex and bioactive circulating milieu may underlie air pollution-induced cardiovascular dysfunction.

Ambient Particulate Matter and Acrolein Co-Exposure Increases Myocardial Dyssynchrony in Mice via TRPA1.

Air pollution is a complex mixture of particulate matter and gases linked to adverse clinical outcomes. As such, studying responses to individual pollutants does not account for the potential biological responses resulting from the interaction of various constituents within an ambient air shed. We previously reported that exposure to high levels of the gaseous pollutant acrolein perturbs myocardial synchrony. Here, we examined the effects of repeated, intermittent co-exposure to low levels of concentrated ambient particulates (CAPs) and acrolein on myocardial synchrony and the role of transient receptor potential cation channel A1 (TRPA1), which we previously linked to air pollution-induced sensitization to triggered cardiac arrhythmia. Female B6129 and Trpa1-/- mice (n = 6/group) were exposed to filtered air (FA), CAPs (46 µg/m3 of PM2.5), Acrolein (0.42 ppm), or CAPs+Acrolein for 3 h/day, 2 days/week for 4 weeks. Cardiac ultrasound was conducted to assess cardiac synchronicity and function before and after the first exposure and after the final exposure. Heart rate variability (HRV), an indicator of autonomic tone, was assessed after the final exposure. Strain delay (time between peak strain in adjacent cardiac wall segments), an index of myocardial dyssynchrony, increased by 5-fold after the final CAPs+Acrolein exposure in B6129 mice compared with FA, CAPs, or Acrolein-exposed B6129 mice, and CAPs+Acrolein-exposed Trpa1-/- mice. Only exposure to acrolein alone increased the HRV high frequency domain (5-fold) in B6129 mice, but not in Trpa1-/- mice. Thus, repeated inhalation of pollutant mixtures may increase risk for cardiac responses compared with single or multiple exposures to individual pollutants through TRPA1 activation.

Potentiation of pulmonary reflex response to capsaicin 24h following whole-body acrolein exposure is mediated by TRPV1.

Pulmonary C-fibers are stimulated by irritant air pollutants producing apnea, bronchospasm, and decrease in HR. Chemoreflex responses resulting from C-fiber activation are sometimes mediated by TRPV1 and release of substance P. While acrolein has been shown to stimulate C-fibers, the persistence of acrolein effects and the role of C-fibers in these responses are unknown. These experiments were designed to determine the effects of whole-body acrolein exposure and pulmonary chemoreflex response post-acrolein. Rats were exposed to either air or 3 ppm acrolein for 3 h while ventilatory function and HR were measured; 1-day later response to capsaicin challenge was measured in anesthetized rats. Rats experienced apnea and decrease in HR upon exposure to acrolein, which was not affected by either TRPV1 antagonist or NK(1)R antagonist pretreatment. Twenty-four hours later, capsaicin caused apnea and bronchoconstriction in control rats, which was potentiated in rats exposed to acrolein. Pretreatment with TRPV1 antagonist or NK(1)R antagonist prevented potentiation of apneic response and bronchoconstriction 24h post-exposure. These data suggest that although potentiation of pulmonary chemoreflex response 24h post-acrolein is mediated by TRPV1 and release of substance P, cardiopulmonary inhibition during whole-body acrolein exposure is mediated through other mechanisms.

Acute peat smoke inhalation sensitizes rats to the postprandial cardiometabolic effects of a high fat oral load.

Wildland fire emissions cause adverse cardiopulmonary outcomes, yet controlled exposure studies to characterize health impacts of specific biomass sources have been complicated by the often latent effects of air pollution. The aim of this study was to determine if postprandial responses after a high fat challenge, long used clinically to predict cardiovascular risk, would unmask latent cardiometabolic responses in rats exposed to peat smoke, a key wildland fire air pollution source. Male Wistar Kyoto rats were exposed once (1 h) to filtered air (FA), or low (0.36 mg/m3 particulate matter) or high concentrations (3.30 mg/m3) of peat smoke, generated by burning peat from an Irish bog. Rats were then fasted overnight, and then administered an oral gavage of a HF suspension (60 kcal% from fat), mimicking a HF meal, 24 h post-exposure. In one cohort, cardiac and superior mesenteric artery function were assessed using high frequency ultrasound 2 h post gavage. In a second cohort, circulating lipids and hormones, pulmonary and systemic inflammatory markers, and circulating monocyte phenotype using flow cytometry were assessed before or 2 or 6 h after gavage. HF gavage alone elicited increases in circulating lipids characteristic of postprandial responses to a HF meal. Few effects were evident after peat exposure in un-gavaged rats. By contrast, exposure to low or high peat caused several changes relative to FA-exposed rats 2 and 6 h post HF gavage including increased heart isovolumic relaxation time, decreased serum glucose and insulin, increased CD11 b/c-expressing blood monocytes, increased serum total cholesterol, alpha-1 acid glycoprotein, and alpha-2 macroglobulin (p = 0.063), decreased serum corticosterone, and increased lung gamma-glutamyl transferase. In summary, these findings demonstrate that a HF challenge reveals effects of air pollution that may otherwise be imperceptible, particularly at low exposure levels, and suggest exposure may sensitize the body to mild inflammatory triggers.

Th2 Cytokines in Skin Draining Lymph Nodes and Serum IgE Do Not Predict Airway Hypersensitivity to Intranasal Isocyanate Exposure in Mice.

Isocyanate exposure in the workplace has been linked to asthma and allergic rhinitis. Recently, investigators have proposed that Th2 cytokine responses in lymph nodes draining the site of dermal application of chemicals including isocyanates may be used to identify sensitizers that cause asthma-like responses. The purpose of this study was to determine if the cytokine profile induced after dermal sensitization with isocyanates and serum IgE predict immediate (IHS) and methacholine-induced late (LHS) respiratory hypersensitivity responses after intranasal challenge. Dermal application of hexylmethane diisocyanate (HMDI), toluene diisocyanate (TDI), or methylene diisocyanate (MDI) significantly increased interleukin-4 (IL-4), IL-5, and IL-13 secretion in parotid lymph node cells. Isophorone diisocyanate (IPDI) increased IL-4 and IL-13, but not IL-5. Tolyl(mono)isocyanate (TMI), tetramethylene xylene diisocyanate (TMXDI), or the contact sensitizer dinitrochlorobenzene (DNCB), only induced minor increases in some of the Th2 cytokines. HMDI, TDI, MDI, and IPDI elicited greater increases in total serum IgE than DNCB, TMI, and TMXDI. All chemicals except TMXDI caused IHS after intranasal challenge of sensitized female BALB/c mice. Only HMDI-, TMI-, or TMXDI-sensitized and challenged mice had increases in LHS. All chemicals elicited epithelial cytotoxicity indicative of nasal airway irritation. The discordance between dermal cytokine profiles and respiratory responses suggests that dermal responses do not necessarily predict respiratory responses. Serum IgE also was not predictive of the respiratory responses to the isocyanates, suggesting that other unknown mechanisms may be involved.

Acrolein Inhalation Alters Myocardial Synchrony and Performance at and Below Exposure Concentrations that Cause Ventilatory Responses.

Acrolein is an irritating aldehyde generated during combustion of organic compounds. Altered autonomic activity has been documented following acrolein inhalation, possibly impacting myocardial synchrony and function. Given the ubiquitous nature of acrolein in the environment, we sought to better define the immediate and delayed functional cardiac effects of acrolein inhalation in vivo. We hypothesized that acrolein inhalation would increase markers of cardiac mechanical dysfunction, i.e., myocardial dyssynchrony and performance index in mice. Male C57Bl/6J mice were exposed to filtered air (FA) or acrolein (0.3 or 3.0 ppm) for 3 h in whole-body plethysmography chambers (n = 6). Echocardiographic analyses were performed 1 day before exposure and at 1 and 24 h post-exposure. Speckle tracking echocardiography revealed that circumferential strain delay (i.e., dyssynchrony) was increased at 1 and 24 h following exposure to 3.0 ppm, but not 0.3 ppm, when compared to pre-exposure and/or FA exposure. Pulsed wave Doppler of transmitral blood flow revealed that acrolein exposure at 0.3 ppm, but not 3.0 ppm, increased the Tei index of myocardial performance (i.e., decreased global heart performance) at 1 and 24 h post-exposure compared to pre-exposure and/or FA exposure. We conclude that short-term inhalation of acrolein can acutely modify cardiac function in vivo and that echocardiographic evaluation of myocardial synchrony and performance following exposure to other inhaled pollutants could provide broader insight into the health effects of air pollution.