Search

Combustion of mixed materials during open air burning of refuse or structural fires in the wildland urban interface produces emissions that worsen air quality, contaminate rivers and streams, and cause poor health outcomes including developmental effects. The zebrafish, a freshwater fish, is a useful model for quickly screening the toxicological and developmental effects of agents in such species and elicits biological responses that are often analogous and predictive of responses in mammals. The purpose of this study was to compare the developmental toxicity of smoke derived from the burning of 5 different burn pit-related material types (plywood, cardboard, plastic, a mixture of the three, and the mixture plus diesel fuel as an accelerant) in zebrafish larvae. Larvae were exposed to organic extracts of increasing concentrations of each smoke 6-to-8-hr post fertilization and assessed for morphological and behavioral toxicity at 5 days post fertilization. To examine chemical and biological determinants of toxicity, responses were related to emissions concentrations of polycyclic hydrocarbons (PAH). Emissions from plastic and the mixture containing plastic caused the most pronounced developmental effects, including mortality, impaired swim bladder inflation, pericardial edema, spinal curvature, tail kinks, and/or craniofacial deformities, although all extracts caused concentration-dependent effects. Plywood, by contrast, altered locomotor responsiveness to light changes to the greatest extent. Some morphological and behavioral responses correlated strongly with smoke extract levels of PAHs including 9-fluorenone. Overall, the findings suggest that material type and emissions chemistry impact the severity of zebrafish developmental toxicity responses to burn pit-related smoke., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Photochemical smog is a complex mixture of primary and secondary air pollutants including secondary organic aerosols (SOA), ozone and reactive aldehydes which has been linked to increased risk of adverse cardiovascular and pulmonary responses. The components and related health effects of smog are thought to be determined both by the precursor chemicals and reaction conditions. Here we examined the difference between isoprene- (IS-) and toluene- (TS) generated smog in causing cardiopulmonary effects in rats. Wistar-Kyoto rats were exposed to either filtered air (FA) or smog for 4 hours. IS-smog contained 660ppb NO 2 , 335ppb O 3 , and 178μg/m 3 SOA while TS-smog had 380ppb NO 2 , 250ppb O 3 , and 1,250μg/m 3 SOA. Whole-body plethysmography was performed at baseline and after each exposure and left ventricular function was measured using a Millar probe and arrhythmic sensitivity to aconitine. Tidal volume decreased only after IS-smog while inspiratory time and nasal injury increased following both smog atmospheres. Only TL-smog caused an increase in PenH, which is an indicator of airway irritation. On the other hand, only IS-smog caused left ventricular pressure to decrease, while only TL-smog increased sensitivity to cardiac arrhythmia. These data indicate that the source of smog atmosphere plays a large role in the types of responses it elicits and that its relative SOA and gaseous composition determine the extent of cardiovascular versus respiratory effects.

Introduction: As a lifestyle factor, poor sleep status is associated with increased cardiovascular morbidity and mortality and may be influenced by environmental stressors, including air pollution., Methods: To determine whether exposure to air pollution modified cardiovascular effects of sleep disruption, we evaluated the effects of single or repeated (twice/wk for 4 wks) inhalation exposure to eucalyptus wood smoke (ES; 964 μg/m 3 for 1 h), a key wildland fire air pollution source, on mild sleep loss in the form of gentle handling in rats. Blood pressure (BP) radiotelemetry and echocardiography were evaluated along with assessments of lung and systemic inflammation, cardiac and hypothalamic gene expression, and heart rate variability (HRV), a measure of cardiac autonomic tone., Results and Discussion: GH alone disrupted sleep, as evidenced by active period-like locomotor activity, and increases in BP, heart rate (HR), and hypothalamic expression of the circadian gene Per2 . A single bout of sleep disruption and ES, but neither alone, increased HR and BP as rats transitioned into their active period, a period aligned with a critical early morning window for stroke risk in humans. These responses were immediately preceded by reduced HRV, indicating increased cardiac sympathetic tone. In addition, only sleep disrupted rats exposed to ES had increased HR and BP during the final sleep disruption period. These rats also had increased cardiac output and cardiac expression of genes related to adrenergic function, and regulation of vasoconstriction and systemic blood pressure one day after final ES exposure. There was little evidence of lung or systemic inflammation, except for increases in serum LDL cholesterol and alanine aminotransferase. These results suggest that inhaled air pollution increases sleep perturbation-related cardiovascular risk, potentially in part by increased sympathetic activity., Competing Interests: Conflict of interest The authors MSH, TWJ and CNM declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones., Objectives: We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones., Methods: First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and 0.8  ppm ) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists., Results: Ozone ( 0.8  ppm ) was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4-6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists., Discussion: We demonstrated the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model. Stress hormones assessment with real-time glucose monitoring may be useful in identifying interactions among irritant pollutants and stress-related illnesses. https://doi.org/10.1289/EHP11088.

Background: Exposure to air pollution and high levels of noise have both been independently associated with the development of adverse pregnancy outcomes including low birth weight. However, exposure to such environmental stressors rarely occurs in isolation and is often co-localized, especially in large urban areas., Methods: The purpose of this study was to compare the effects of combined exposure to noise (N) or ozone (O 3 ), compared to either exposure alone. Long-Evans dams were exposed to air or 0.4 ppm ozone for 4 h on gestation day (GD) 5 and 6, coinciding with implantation receptivity. A subset of dams from each exposure group was further exposed to intermittent white noise (~ 85 dB) throughout the dark cycle following each inhalation exposure (n = 14 - 16/group). Uterine artery ultrasound was performed on GD 15 and 21. Fetal growth characteristics and indicators of placental nutrient status were measured at GD 21., Results: Exposure to ozone + quiet (O 3 + Q) conditions reduced uterine arterial resistance at GD 15 compared to air + quiet (A + Q) exposure, with no further reduction by GD 21. By contrast, exposure to air + noise (A + N) significantly increased uterine arterial resistance at both GD 15 and 21. Notably, while peri-implantation exposure to O 3 + Q conditions reduced male fetal weight at GD 21, this effect was not observed in the air + noise (A + N) or the ozone + noise (O 3 + N) exposure groups. Fetal weight in female offspring was not reduced by ozone exposure alone (O 3 + Q), nor was it affected by air + noise (A + N) or by combined ozone + noise (O 3 + N) exposure., Conclusions: These data indicate that exposure to ozone and noise differentially impact uterine blood flow, particularly at mid-gestation, with only ozone exposure being associated with sex-dependent fetal growth retardation in male offspring.

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/m 3 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.

Heart rate assays in wild-type zebrafish embryos have been limited to analysis of one embryo per video/imaging field. Here we present for the first time a platform for high-throughput derivation of heart rate from multiple zebrafish (Danio rerio) embryos per imaging field, which is capable of quickly processing thousands of videos and ideal for multi-well platforms with multiple fish/well. This approach relies on use of 2-day post fertilization wild-type embryos, and uses only bright-field imaging, circumventing requirement for anesthesia or restraint, costly software/hardware, or fluorescently-labeled animals. Our original scripts (1) locate the heart and record pixel intensity fluctuations generated by each cardiac cycle using a robust image processing routine, and (2) process intensity data to derive heart rate. To demonstrate assay utility, we exposed embryos to the drugs epinephrine and clonidine, which increased or decreased heart rate, respectively. Exposure to organic extracts of air pollution-derived particulate matter, including diesel or biodiesel exhausts, or wood smoke, all complex environmental mixtures, decreased heart rate to varying degrees. Comparison against an established lower-throughput method indicated robust assay fidelity. As all code and executable files are publicly available, this approach may expedite cardiotoxicity screening of compounds as diverse as small molecule drugs and complex chemical mixtures.

Background: Epidemiological studies suggest that increased ozone exposure during gestation may compromise fetal growth. In particular, the implantation stage of pregnancy is considered a key window of susceptibility for this outcome., Objectives: The main goals of this study were to investigate the effects of short-term ozone inhalation during implantation on fetal growth outcomes and to explore the potential for alterations in uterine arterial flow as a contributing mechanism., Methods: Pregnant Long-Evans rats were exposed to filtered air, 0.4 ppm ozone, or 0.8 ppm ozone for 4 h/d during implantation, on gestation days (GD) 5 and 6. Tail cuff blood pressure and uterine artery Doppler ultrasound were measured on GD 15, 19, and 21. To assess whether peri-implantation ozone exposure resulted in sustained pulmonary or systemic health effects, bronchoalveolar lavage fluid, serum metabolic and inflammatory end points, and kidney histopathology were evaluated in dams at GD 21. Growth parameters assessed in GD 21 offspring included fetal weight, length, and body composition., Results: Measures of maternal uterine arterial flow, including resistance index and mean velocity, indicated that resistance increased between GD 15 and GD 21 in 0.8 ppm dams but decreased in controls, although absolute values were similar in both groups on GD 21. Ozone-exposed dams also had lower serum glucose and higher free fatty acid concentrations than controls on GD 21. On GD 21, both male and female offspring had lower body weight than controls, and pooled subsets of 3 male and 3 female fetuses from litters exposed to 0.8 ppm ozone had lower lean mass and fat mass than pooled control offspring., Conclusions: Findings from our experimental model suggest that the offspring of dams exposed to ozone during implantation had reduced growth compared with controls, possibly as a consequence of ozone-induced vascular dysfunction. https://doi.org/10.1289/EHP2019.

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.

Background —Smoking is associated with arrhythmia and sudden cardiac death, but the biological mechanisms remain unclear. In electrocardiogram (ECG) recordings abnormal durations of ventricular repolarization (QT interval), atrial depolarization (P wave), and atrioventricular depolarization (PR interval and segment), predict cardiac arrhythmia and mortality. Previous analyses of the National Health and Nutrition Examination Survey (NHANES) database for associations between smoking and ECG abnormalities were incomplete. To elucidate how smoking affects cardiac excitation, we assessed in a nationally representative sample (NHANES III) the association between serum cotinine and P duration, PR interval, PR segment, rate-corrected QT (QTc), QRS duration, and JT interval. Methods and Results—We analyzed data from 5,653 adults using survey-weighted multinomial logistic regression to estimate associations between tobacco use (> 15 ng/ml serum cotinine) and short (< 5th percentile) or long (> 95th percentile) ECG intervals, relative to reference (5–95th percentile). After adjustment for demographics, risk factors, and conduction-altering medications, smoking was associated with a higher odds of short PR interval, PR segment, and QRS, and long JT. Broader effects of smoking on ECG were also assessed by survey-weighted linear regression of continuous cotinine and ECG, which revealed cotinine inversely associated with PR segment and QTc. Over a 22-year follow-up, many ECG abnormalities predicted cardiovascular mortality in smokers, including long JT, QRS, and QTc, and short QRS, whereas only short JT predicted mortality in nonsmokers. Conclusions —Smoking increases likelihood for rapid atrioventricular and ventricular depolarization and slow ventricular repolarization, which may promote cardiac arrhythmia and mortality. [ABSTRACT FROM AUTHOR]

Background: Studies have shown a relationship between air pollution and increased risk of cardiovascular morbidity and mortality. Due to the complexity of ambient air pollution composition, recent studies have examined the effects of co-exposure, particularly particulate matter (PM) and gas, to determine whether pollutant interactions alter (e.g. synergistically, antagonistically) the health response. This study examines the independent effects of fine (FCAPs) and ultrafine (UFCAPs) concentrated ambient particles on cardiac function, and determine the impact of ozone (O₃) co-exposure on the response. We hypothesized that UFCAPs would cause greater decrement in mechanical function and electrical dysfunction than FCAPs, and that O₃ co-exposure would enhance the effects of both particle-types., Methods: Conscious/unrestrained radiotelemetered mice were exposed once whole-body to either 190 μg/m³ FCAPs or 140 μg/m³ UFCAPs with/without 0.3 ppm O₃; separate groups were exposed to either filtered air (FA) or O₃ alone. Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure, and cardiac mechanical function was assessed using a Langendorff perfusion preparation 24 hrs post-exposure., Results: FCAPs alone caused a significant decrease in baseline left ventricular developed pressure (LVDP) and contractility, whereas UFCAPs did not; neither FCAPs nor UFCAPs alone caused any ECG changes. O₃ co-exposure with FCAPs caused a significant decrease in heart rate variability when compared to FA but also blocked the decrement in cardiac function. On the other hand, O₃ co-exposure with UFCAPs significantly increased QRS-interval, QTc and non-conducted P-wave arrhythmias, and decreased LVDP, rate of contractility and relaxation when compared to controls., Conclusions: These data suggest that particle size and gaseous interactions may play a role in cardiac function decrements one day after exposure. Although FCAPs + O₃ only altered autonomic balance, UFCAPs + O₃ appeared to be more serious by increasing cardiac arrhythmias and causing mechanical decrements. As such, O₃ appears to interact differently with FCAPs and UFCAPs, resulting in varied cardiac changes, which suggests that the cardiovascular effects of particle-gas co-exposures are not simply additive or even generalizable. Additionally, the mode of toxicity underlying this effect may be subtle given none of the exposures described here impaired post-ischemia recovery.

Background: Exercise "stress" testing is a screening tool used to determine the amount of stress for which the heart can compensate before developing abnormal rhythm or ischemia, particularly in susceptible persons. Although this approach has been used to assess risk in humans exposed to air pollution, it has never been applied to rodent studies., Objective: We hypothesized that a single exposure to diesel exhaust (DE) would increase the risk of adverse cardiac events such as arrhythmia and myocardial ischemia in rats undergoing a dobutamine challenge test, which can be used to mimic exercise-like stress., Methods: Wistar-Kyoto normotensive (WKY) and spontaneously hypertensive (SH) rats implanted with radiotelemeters and a chronic intravenous catheter were whole-body exposed to 150 μg/m3 DE for 4 hr. Increasing doses of dobutamine, a β1-adrenergic agonist, were administered to conscious unrestrained rats 24 hr later to elicit the cardiac response observed during exercise while heart rate (HR) and electrocardiogram (ECG) were monitored., Results: A single exposure to DE potentiated the HR response of WKY and SH rats during dobutamine challenge and prevented HR recovery at rest. During peak challenge, DE-exposed SH rats had lower overall HR variability when compared with controls, in addition to transient ST depression. All DE-exposed animals also had increased arrhythmias., Conclusions: These results are the first evidence that rats exhibit stress-induced cardiac dysrhythmia and ischemia sensitivity comparable to humans after a single exposure to a toxic air pollutant, particularly when in the presence of underlying cardiovascular disease. Thus, exposure to low concentrations of air pollution can impair the heart's ability to respond to stress and increase the risk of subsequent triggered dysfunction.

Background: Ozone (O₃) is a well-documented respiratory oxidant, but increasing epidemiological evidence points to extrapulmonary effects, including positive associations between ambient O₃ concentrations and cardiovascular morbidity and mortality., Objective: With preliminary reports linking O₃ exposure with changes in heart rate (HR), we investigated the hypothesis that a single inhalation exposure to O₃ will cause concentration-dependent autonomic modulation of cardiac function in rats., Methods: Rats implanted with telemeters to monitor HR and cardiac electrophysiology [electrocardiography (ECG)] were exposed once by whole-body inhalation for 4 hr to 0.2 or 0.8 ppm O₃ or filtered air. A separate cohort was tested for vulnerability to aconitine-induced arrhythmia 24 hr after exposure., Results: Exposure to 0.8 ppm O₃ caused bradycardia, PR prolongation, ST depression, and substantial increases in atrial premature beats, sinoatrial block, and atrioventricular block, accompanied by concurrent increases in several HR variability parameters that were suggestive of increased parasympathetic tone. Low-O₃ exposure failed to elicit any overt changes in autonomic tone, heart rhythm, or ECG. However, both 0.2 and 0.8 ppm O₃ increased sensitivity to aconitine-induced arrhythmia formation, suggesting a latent O₃-induced alteration in myocardial excitability., Conclusions: O₃ exposure causes several alterations in cardiac electrophysiology that are likely mediated by modulation of autonomic input to the heart. Moreover, exposure to low O₃ concentrations may cause subclinical effects that manifest only when triggered by a stressor, suggesting that the adverse health effects of ambient levels of air pollutants may be insidious and potentially underestimated.

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.

Background: Diesel exhaust (DE), which is emitted from on- and off-road sources, is a complex mixture of toxic gaseous and particulate components that leads to triggered adverse cardiovascular effects such as arrhythmias., Objective: We hypothesized that increased risk of triggered arrhythmias 1 day after DE exposure is mediated by airway sensory nerves bearing transient receptor potential (TRP) channels [e.g., transient receptor potential cation channel, member A1 (TRPA1)] that, when activated by noxious chemicals, can cause a centrally mediated autonomic imbalance and heightened risk of arrhythmia., Methods: Spontaneously hypertensive rats implanted with radiotelemeters were whole-body exposed to either 500 μg/m³ (high) or 150 μg/m³ (low) whole DE (wDE) or filtered DE (fDE), or to filtered air (controls), for 4 hr. Arrhythmogenesis was assessed 24 hr later by continuous intravenous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR) and electrocardiogram (ECG) were monitored., Results: Rats exposed to wDE or fDE had slightly higher HRs and increased low-frequency:high-frequency ratios (sympathetic modulation) than did controls; ECG showed prolonged ventricular depolarization and shortened repolarization periods. Rats exposed to wDE developed arrhythmia at lower doses of aconitine than did controls; the dose was even lower in rats exposed to fDE. Pretreatment of low wDE-exposed rats with a TRPA1 antagonist or sympathetic blockade prevented the heightened sensitivity to arrhythmia., Conclusions: These findings suggest that a single exposure to DE increases the sensitivity of the heart to triggered arrhythmias. The gaseous components appear to play an important role in the proarrhythmic response, which may be mediated by activation of TRPA1, and subsequent sympathetic modulation. As such, toxic inhalants may partly exhibit their toxicity by lowering the threshold for secondary triggers, complicating assessment of their risk.

Ozone causes persistent airway hyperreactivity in humans and animals. One day after ozone exposure, airway hyperreactivity is mediated by release of eosinophil major basic protein that inhibits neuronal M(2) muscarinic receptors, resulting in increased acetylcholine release and increased smooth muscle contraction in guinea pigs. Three days after ozone, IL-1β, not eosinophils, mediates ozone-induced airway hyperreactivity, but the mechanism at this time point is largely unknown. IL-1β increases NGF and the tachykinin substance P, both of which are involved in neural plasticity. These experiments were designed to test whether there is a role for NGF and tachykinins in sustained airway hyperreactivity following a single ozone exposure. Guinea pigs were exposed to filtered air or ozone (2 parts per million, 4 h). In anesthetized and vagotomized animals, ozone potentiated vagally mediated airway hyperreactivity 24 h later, an effect that was sustained over 3 days. Pretreatment with antibody to NGF completely prevented ozone-induced airway hyperreactivity 3 days, but not 1 day, after ozone and significantly reduced the number of substance P-positive airway nerve bundles. Three days after ozone, NK(1) and NK(2) receptor antagonists also blocked this sustained hyperreactivity. Although the effect of inhibiting NK(2) receptors was independent of ozone, the NK(1) receptor antagonist selectively blocked vagal hyperreactivity 3 days after ozone. These data confirm mechanisms of ozone-induced airway hyperreactivity change over time and demonstrate 3 days after ozone that there is an NGF-mediated role for substance P, or another NK(1) receptor agonist, that enhances acetylcholine release and was not present 1 day after ozone.

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).

Background: Exposure to combustion-derived fine particulate matter (PM) is associated with increased cardiovascular morbidity and mortality especially in individuals with cardiovascular disease, including hypertension. PM inhalation causes several adverse changes in cardiac function that are reflected in the electrocardiogram (ECG), including altered cardiac rhythm, myocardial ischemia, and reduced heart rate variability (HRV). The sensitivity and reliability of ECG-derived parameters as indicators of the cardiovascular toxicity of PM in rats are unclear., Objective: We hypothesized that spontaneously hypertensive (SH) rats are more susceptible to the development of PM-induced arrhythmia, altered ECG morphology, and reduced HRV than are Wistar Kyoto (WKY) rats, a related strain with normal blood pressure., Methods: We exposed rats once by nose-only inhalation for 4 hr to residual oil fly ash (ROFA), an emission source particle rich in transition metals, or to air and then sacrificed them 1 or 48 hr later., Results: ROFA-exposed SH rats developed non-conducted P-wave arrhythmias but no changes in ECG morphology or HRV. We found no ECG effects in ROFA-exposed WKY rats. ROFA-exposed SH rats also had greater pulmonary injury, neutrophil infiltration, and serum C-reactive protein than did ROFA-exposed WKY rats., Conclusions: These results suggest that cardiac arrhythmias may be an early sensitive indicator of the propensity for PM inhalation to modify cardiovascular function.

Elevated levels of nerve growth factor (NGF) and NGF-mediated neural plasticity may have a role in airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Although NGF is known to affect sensory and sympathetic nerves, especially during development, little is known regarding its effect on parasympathetic nerves, especially on adult neurons. The purpose of this study was to analyze the acute and chronic effects of NGF on the electrophysiological and anatomical properties of neurons in airway parasympathetic ganglia from adult guinea pigs. Using single cell recording, direct application of NGF caused a lasting decrease in the cumulative action potential afterhyperpolarization (AHP) and increased the amplitude of vagus nerve-stimulated nicotinic fast excitatory postsynaptic potentials. Neuronal responsiveness to nicotinic receptor stimulation was increased by NGF, which was blocked by the tyrosine kinase inhibitor, K-252a, implicating neurotrophin-specific (Trk) receptors. Neurotrophin-3 and brain-derived neurotrophic factor had no effect on the synaptic potentials, AHP, or nicotinic response; inhibition of cyclooxygenase with indomethacin inhibited the effect of NGF on the cumulative AHP. Forty-eight hours after in vivo application of NGF to the trachealis muscle caused an increase in dendritic length on innervating neurons. These results are the first to demonstrate that NGF increases the excitability of lower airway parasympathetic neurons, primarily through enhanced synaptic efficacy and changes to intrinsic neuron properties. NGF also had dramatic effects on the growth of dendrites in vivo. Such effects may indicate a new role for NGF in the regulation of parasympathetic tone in the diseased or inflamed lower airways.

Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders with unclear etiology and significant heterogeneity that is emerging as a global public health concern. Increasing research suggests the involvement of hippocampal neurogenesis defects in the onset and development of ASD, drawing increasing amounts of attention to hippocampal neurogenesis issues in ASD. In this paper, we analyze relevant international studies on hippocampal neurogenesis in ASD, discuss the role of neurobiology in the pathogenesis of ASD, and explore the potential of improving hippocampal neurogenesis as a therapeutic approach for ASD. This review aims to provide new treatment perspectives and theoretical foundations for clinical practice. [ABSTRACT FROM AUTHOR]

There is controversy about the role of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). Although they appear to have little impact on airways obstruction or its progression, their use may reduce the frequency and/or severity of exacerbations in a subset of patients. We undertook the following study to determine the impact of inhaled corticosteroid on two noninvasive markers of airways inflammation. We assigned 20 stable nonsmoking patients with COPD in random, double-blind crossover fashion to two 2-wk treatment periods with inhaled beclomethasone 500 microg twice daily or matching placebo, followed by a 2-wk washout period. We measured exhaled nitric oxide (ENO), breath condensate H(2)O(2), and flow volume spirometry at weekly intervals. Median baseline ENO was 26.2 (19.3 to 54.8) ppb and fell significantly following 1 and 2 wk of beclomethasone (-10.6 ppb, p = 0.002, and -6.3 ppb, p = 0.013, respectively) but was unchanged by placebo inhalation. Breath condensate H(2)O(2) levels did not change significantly with inhaled beclomethasone or placebo. Although there were no significant changes in FEV(1) with BDP therapy, there was a moderate inverse correlation between changes in ENO and changes in FEV(1) (r -0.50). We conclude that inhaled beclomethasone reduces ENO levels in stable nonsmoking patients with COPD, a finding compatible with an antiinflammatory mechanism of action.

AIM: We aimed to investigate the possible cardioprotective effects of paricalcitol (PR), its vitamin D receptor agonist, and vitamin D³3 (VIT-D3) on an experimental model of doxorubicin (DX) cardiotoxicity by 99mTc-PYP scintigraphy, electrocardiographic (ECG) and biochemical methods. METHOD: Forty-two male Wistar/Albino rats (250-300 g; aged 10-12 weeks) were randomly separated into six groups, namely into control (CN), doxorubicin (DX), paricalcitol (PR), vitamin D³ (VIT-D³), paricalcitol + doxorubicin (PR+DX), and vitamin D³ + doxorubicin (VIT-D³+DX) groups. Cardiotoxicity was induced by three doses of DX (18 mg/kg, i.p.) at 24-hour intervals on days 18, 19 and 20. PR (0.5 ug/ kg, i.p) and VIT-D³ (5,000 IU/kg, i.p) were injected for 20 days before and after the application of DX (18 mg/kg, i.p.). On day 21 of the experiment, biochemical parameters [tumor necrosis factor TNF-alpha (TNF-α); interleukin-6 (IL-6), nitric oxide (NO), and cardiac troponin T (cTnT)], as well as ECG and scintigraphic (99mTc-PYP) features were assessed. RESULTS: Compared to CN, DX significantly raised TNF-α, IL-6, and NO in heart tissue, cTnT in serum, 99mTc-PYP uptake in the myocardium, and ECG parameters, specifically QRS complex duration, QT interval duration, and ST-segment amplitude, while also reducing heart rate (p<0.001). Pretreatment with PR and VIT-D³ mitigated these abnormalities produced by DX in the heart (p<0.001). CONCLUSION: Results show that vitamin D receptor agonist paricalcitol and vitamin D protect against DX-induced cardiotoxicity through anti-inflammatory and antioxidant effects [ABSTRACT FROM AUTHOR]

BACKGROUND: The association between prenatal household air pollution (HAP) exposure and childhood blood pressure (BP) is unknown. OBJECTIVE: Within the Ghana Randomized Air Pollution and Health Study (GRAPHS) we examined time-varying associations between a) maternal prenatal and b) first-year-of-life HAP exposure with BP at 4 years of age and, separately, whether a stove intervention delivered prenatally and continued through the first year of life could improve BP at 4 years of age. METHODS: GRAPHS was a cluster-randomized cookstove intervention trial wherein 푛=1,414 pregnant women were randomized to one of two stove interventions: a) a liquefied petroleum gas (LPG) stove or improved biomass stove, or b) control (open fire cooking). Maternal HAP exposure over pregnancy and child HAP exposure over the first year of life was quantified by repeated carbon monoxide (CO) measurements; a subset of women (푛=368) also performed one prenatal and one postnatal personal fine particulate matter (PM2.5) measurement. Systolic and diastolic BP (SBP and DBP) were measured in 푛=667 4-y-old children along with their PM2.5 exposure (푛=692). We examined the effect of the intervention on resting BP 푧-scores. We also employed reverse distributed lag models to examine time-varying associations between a) maternal prenatal and b) first-year-of-life HAP exposure and resting BP 푧-scores. Among those with PM2.5 measures, we examined associations between PM2.5 and resting BP 푧-scores. Sex-specific effects were considered. RESULTS: Intention-to-treat analyses identified that DBP 푧-score at 4 years of age was lower among children born in the LPG arm (LPG β= -0.20; 95% CI: -0.36, -0.03) as compared with those in the control arm, and females were most susceptible to the intervention. Higher CO exposure in late gestation was associated with higher SBP and DBP 푧-score at 4 years of age, whereas higher late-first-year-of-life CO exposure was associated with higher DBP 푧-score. In the subset with PM2.5 measurements, higher maternal postnatal PM2.5 exposure was associated with higher SBP 푧-scores. DISCUSSION: These findings suggest that prenatal and first-year-of-life HAP exposure are associated with child BP and support the need for reductions in exposure to HAP, with interventions such as cleaner cooking beginning in pregnancy. [ABSTRACT FROM AUTHOR]

Exposures to fine particulate matter (PM 1 ) have been associated with health impacts, but the understanding of the PM 1 concentration-response (PM 1 -CR) relationships, especially at low PM 1 , remains incomplete. Here, we present novel data using a methodology to mimic lung exposure to ambient air (2 < P M 1 < 60 μ g m - 3 ), with minimized sampling artifacts for nanoparticles. A reference model (Air Liquid Interface cultures of human bronchial epithelial cells, BEAS-2B) was used for aerosol exposure. Non-linearities observed in PM 1 -CR curves are interpreted as a result of the interplay between the aerosol total oxidative potential (OP t ) and its distribution across particle size (d p ). A d p -dependent condensation sink (CS) is assessed together with the distribution with d p of reactive species. Urban ambient aerosol high in OP t , as indicated by the DTT assay, with (possibly copper-containing) nanoparticles, shows higher pro-inflammatory and oxidative responses, this occurring at lower PM 1 concentrations (< 5 μ g m - 3 ). Among the implications of this work, there are recommendations for global efforts to go toward the refinement of actual air quality standards with metrics considering the distribution of OP t with d p also at relatively low PM 1 . [ABSTRACT FROM AUTHOR]

Electronic cigarette use has grown exponentially in recent years, and while their popularity has increased, the long-term effects on the heart are yet to be fully studied and understood. Originally designed as devices to assist with those trying to quit traditional combustible cigarette use, their popularity has attracted use by teens and adolescents who traditionally have not smoked combustible cigarettes. Acute effects on the heart have been shown to be similar to traditional combustible cigarettes, including increased heart rate and blood pressure. The main components of electronic cigarettes that contribute to these arrhythmic effects are found in the e-liquid that is aerosolized and inhaled, comprised of nicotine, flavourings, and a combination of vegetable glycerin (VG) and propylene glycol (PG). Nicotine can potentially induce both ventricular and atrial arrhythmogenesis, with both the atrial and ventricular effects resulting from the interactions of nicotine and the catecholamines they release via potassium channels. Atrial arrhythmogenesis, more specifically atrial fibrillation, can also occur due to structural alterations, which happens because of nicotine downregulating microRNAs 133 and 590, both post-transcriptional growth factor repressors. Liquid flavourings and the combination of PG and VG can possibly lead to arrhythmic events by exposing users to acrolein, an aldehyde that stimulates TRPA1 that in turn causes a change towards sympathetic activation and autonomic imbalance. The design of these electronic delivery devices is constantly changing; therefore, it has proven extremely difficult to study the long-term effects on the heart caused by electronic cigarettes but will be important to understand given their rising popularity. The arrhythmic effects of electronic cigarettes appear similar to traditional cigarettes as well; however, a comprehensive review has not been compiled and is the focus of this article. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heart failure (HF) poses a significant global disease burden. The current evidence on the impact of air pollution on HF remains inconsistent. OBJECTIVES: We aimed to conduct a systematic review of the literature and meta-analysis to provide a more comprehensive and multiperspective assessment of the associations between short- and long-term air pollution exposure and HF from epidemiological evidences. METHODS: Three databases were searched up to 31 August 2022 for studies investigating the association between air pollutants (PM2.5, PM10, NO2, SO2, CO, O3) and HF hospitalization, incidence, or mortality. A random effects model was used to derive the risk estimations. Subgroup analysis was conducted by geographical location, age of participants, outcome, study design, covered area, the methods of exposure assessment, and the length of exposure window. Sensitivity analysis and adjustment for publication bias were performed to test the robustness of the results. RESULTS: Of 100 studies covering 20 countries worldwide, 81 were for short-term and 19 were for long-term exposure. Almost all air pollutants were adversely associated with the risk of HF in both short- and long-term exposure studies. For short-term exposures, we found the risk of HF increased by 1.8% [relative risk (RR)=1.018, 95% confidence interval (CI): 1.011, 1.025] and 1.6% (RR=1.016, 95% CI: 1.011, 1.020) per 10-μg/m³ increment of PM2.5 and PM10, respectively. HF was also significantly associated with NO2, SO2, and CO, but not O3. Positive associations were stronger when exposure was considered over the previous 2 d (lag 0–1) rather than on the day of exposure only (lag 0). For long-term exposures, there were significant associations between several air pollutants and HF with RR (95% CI) of 1.748 (1.112, 2.747) per 10-μg/m³ increment in PM2.5, 1.212 (1.010, 1.454) per 10-μg/m³ increment in PM10, and 1.204 (1.069, 1.356) per 10-ppb increment in NO2, respectively. The adverse associations of most pollutants with HF were greater in low- and middle-income countries than in high-income countries. Sensitivity analysis demonstrated the robustness of our results. DISCUSSION: Available evidence highlighted adverse associations between air pollution and HF regardless of short- and long-term exposure. Air pollution is still a prevalent public health issue globally and sustained policies and actions are called for to reduce the burden of HF. [ABSTRACT FROM AUTHOR]

Background: Exposure to micro- and nanoplastic particles (MNPs) in humans is being identified in both the indoor and outdoor environment. Detection of these materials in the air has made inhalation exposure to MNPs a major cause for concern. One type of plastic polymer found in indoor and outdoor settings is polyamide, often referred to as nylon. Inhalation of combustion-derived, metallic, and carbonaceous aerosols generate pulmonary inflammation, cardiovascular dysfunction, and systemic inflammation. Additionally, due to the additives present in plastics, MNPs may act as endocrine disruptors. Currently there is limited knowledge on potential health effects caused by polyamide or general MNP inhalation. Objective: The purpose of this study is to assess the toxicological consequences of a single inhalation exposure of female rats to polyamide MNP during estrus by means of aerosolization of MNP. Methods: Bulk polyamide powder (i.e., nylon) served as a representative MNP. Polyamide aerosolization was characterized using particle sizers, cascade impactors, and aerosol samplers. Multiple-Path Particle Dosimetry (MPPD) modeling was used to evaluate pulmonary deposition of MNPs. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) cell content and H&E-stained tissue sections. Mean arterial pressure (MAP), wire myography of the aorta and uterine artery, and pressure myography of the radial artery was used to assess cardiovascular function. Systemic inflammation and endocrine disruption were quantified by measurement of proinflammatory cytokines and reproductive hormones. Results: Our aerosolization exposure platform was found to generate particles within the micro- and nano-size ranges (thereby constituting MNPs). Inhaled particles were predicted to deposit in all regions of the lung; no overt pulmonary inflammation was observed. Conversely, increased blood pressure and impaired dilation in the uterine vasculature was noted while aortic vascular reactivity was unaffected. Inhalation of MNPs resulted in systemic inflammation as measured by increased plasma levels of IL-6. Decreased levels of 17β-estradiol were also observed suggesting that MNPs have endocrine disrupting activity. Conclusions: These data demonstrate aerosolization of MNPs in our inhalation exposure platform. Inhaled MNP aerosols were found to alter inflammatory, cardiovascular, and endocrine activity. These novel findings will contribute to a better understanding of inhaled plastic particle toxicity. [ABSTRACT FROM AUTHOR]

Background: Microbial dysbiosis is a potential mediator of air pollution-induced adverse outcomes. However, a systemic comparison of the lung and gut microbiome alterations and lung-gut axis following air pollution exposure is scant. In this study, we exposed male C57BL/6J mice to inhaled air, CB (10 mg/m3), O3 (2 ppm) or CB + O3 mixture for 3 h/day for either one day or four consecutive days and were euthanized 24 h post last exposure. The lung and gut microbiome were quantified by 16 s sequencing. Results: Multiple CB + O3 exposures induced an increase in the lung inflammatory cells (neutrophils, eosinophils and B lymphocytes), reduced absolute bacterial load in the lungs and increased load in the gut. CB + O3 exposure was more potent as it decreased lung microbiome alpha diversity just after a single exposure. CB + O3 co-exposure uniquely increased Clostridiaceae and Prevotellaceae in the lungs. Serum short chain fatty acids (SCFA) (acetate and propionate) were increased significantly only after CB + O3 co-exposure. A significant increase in SCFA producing bacterial families (Ruminococcaceae, Lachnospiraceae, and Eubacterium) were also observed in the gut after multiple exposures. Co-exposure induced significant alterations in the gut derived metabolite receptors/mediator (Gcg, Glp-1r, Cck) mRNA expression. Oxidative stress related mRNA expression in lungs, and oxidant levels in the BALF, serum and gut significantly increased after CB + O3 exposures. Conclusion: Our study confirms distinct gut and lung microbiome alterations after CB + O3 inhalation co-exposure and indicate a potential homeostatic shift in the gut microbiome to counter deleterious impacts of environmental exposures on metabolic system. [ABSTRACT FROM AUTHOR]

Introduction: In adults, chronic exposure to air pollution is associated with elevated blood pressure, but few studies have examined this relationship in youth. We investigated the association between annual ambient concentrations of air pollutants (fine particulate matter [PM2.5] and nitrogen dioxide [NO2]) and systolic blood pressure (SBP) among adolescents in Montréal, Canada. Methods: Participants were students aged 15 to 17 years who provided SBP and residential postal code data in 2004/05 through their enrolment in the Nicotine Dependence in Teens study. Annual estimates for 2004 of residential exposure to NO2 and PM2.5 were provided by the Canadian Urban Environmental Health Research Consortium and linked to participants' residential postal code. Elevated SBP was defined as SBP = 90th percentile adjusted for age, sex and height. Logistic regression was used to estimate odds ratios and 95% confidence intervals (CIs) for each pollutant with respect to elevated SBP, adjusted for relevant confounders. Results: The sample consisted of 508 adolescents (mean age: 16.9, 46% male); 4% had elevated SBP. Although estimates were not statistically significant, there were generally modest positive associations between pollutant levels and SBP. The adjusted prevalence odds ratio of elevated SBP was 1.33 (95% CI: 0.64, 3.05) for every interquartile range (IQR) increase in residential PM2.5 levels (2.1µg/m³). Similarly, the adjusted prevalence odds ratio of elevated SBP was 1.17 (95% CI: 0.47, 2.70) for every IQR increase in residential NO2 levels (10.2 ppb). Conclusion: Findings support a possible relationship between exposure to air pollutants and increased SBP in adolescents, warranting further investigation for this important public health concern. [ABSTRACT FROM AUTHOR]

Longitudinal evidence on the association between air pollution and blood pressure (BP) in adolescence is scarce. We explored this association in an ethnically diverse cohort of schoolchildren. Sex-stratified, linear random-effects modelling was used to examine how modelled residential exposure to annual average nitrogen dioxide (NO2), particulate matter (PM2.5, PM10) and ozone (O3), measures in μg/m3, associated with blood pressure. Estimates were based on 3,284 adolescents; 80% from ethnic minority groups, recruited from 51 schools, and followed up from 11–13 to 14–16 years old. Ethnic minorities were exposed to higher modelled annual average concentrations of pollution at residential postcode level than their White UK peers. A two-pollutant model (NO2 & PM2.5), adjusted for ethnicity, age, anthropometry, and pubertal status, highlighted associations with systolic, but not diastolic BP. A μg/m3 increase in NO2 was associated with a 0.30 mmHg (95% CI 0.18 to 0.40) decrease in systolic BP for girls and 0.19 mmHg (95% CI 0.07 to 0.31) decrease in systolic BP for boys. In contrast, a 1 μg/m3 increase in PM2.5 was associated with 1.34 mmHg (95% CI 0.85 to 1.82) increase in systolic BP for girls and 0.57 mmHg (95% CI 0.04 to 1.03) increase in systolic BP for boys. Associations did not vary by ethnicity, body size or socio-economic advantage. Associations were robust to adjustments for noise levels and lung function at 11–13 years. In summary, higher ambient levels of NO2 were associated with lower and PM2.5 with higher systolic BP across adolescence, with stronger associations for girls. [ABSTRACT FROM AUTHOR]

Background: Cardiac hypertrophy (CH) is the asymptomatic enlargement of ventricular walls witnessed in diabetes and hypertension, for which early metabolite differences and prediction are less stated previously. Aim: The aim of the study was (i) to understand the metabolic and ventricular events in diabetes and nondiabetes induced CH at the end of 2 weeks and (ii) to identify significant metabolite predictors and pathways that influence the seven metabolic and physiological responders of CH, namely, 3-hydroxybutyrate (3-HB); lactic acid; urea; and electrocardiography (ECG) waves (QRS complex, R amplitude, R-R interval, and heart rate). Methods: Diabetic rat models of CH using streptozotocin (40 mg/kg, i. p., single dose), and nondiabetic models using adrenaline (0.3 mg/kg, i. p, 2 weeks) were developed. Blood glucose levels, ECG, heart weight/body weight ratio, histopathological analysis, and serum metabolite analysis using gas chromatography mass spectrometry were performed at the end of 2 weeks. Strong metabolite predictors and pathways were identified using Pearson's correlation, multiple regression (MRA) and metabolite set enrichment (MSEA) analyses. Results: The prevalence of CH was observed through preliminary screenings at the end of 2 weeks. Galactose, leucine, erythrose, sorbitol, and valine were identified as significant (P < 0.05) predictors in SZ model, whereas isoleucine, galactose, leucine, inositol, and palmitic acid were identified in ADR model. However, galactose metabolism, branched-chain amino acid, and lactose degradation pathways were mapped as the highly influential apparent pathways during early CH remodeling in both the models. Conclusion: This study identified putative initial metabolite shifts, significant predictors pathways that can aid in forecasting, intervention, and prevention of CH. [ABSTRACT FROM AUTHOR]

The impacts of air pollution on public health have become a great concern worldwide. Ambient particulate matter (PM) is a major air pollution that comprises a heterogeneous mixture of different particle sizes and chemical components. The chemical composition and physicochemical properties of PM change with space and time, which may cause different impairments. However, the mechanisms of the adverse effects of PM on various systems have not been fully elucidated and systematically integrated. The Adverse Outcome Pathway (AOP) framework was used to comprehensively illustrate the molecular mechanism of adverse effects of PM and its components, so as to clarify the causal mechanistic relationships of PM-triggered toxicity on various systems. The main conclusions and new insights of the correlation between public health and PM were discussed, especially at low concentrations, which points out the direction for further research in the future. With the deepening of the study on its toxicity mechanism, it was found that PM can still induce adverse health effects with low-dose exposure. And the recommended Air Quality Guideline level of PM2.5 was adjusted to 5 μg/m3 by World Health Organization, which meant that deeper and more complex mechanisms needed to be explored. Traditionally, oxidative stress, inflammation, autophagy and apoptosis were considered the main mechanisms of harmful effects of PM. However, recent studies have identified several emerging mechanisms involved in the toxicity of PM, including pyroptosis, ferroptosis and epigenetic modifications. This review summarized the comprehensive evidence on the health effects of PM and the chemical components of it, as well as the combined toxicity of PM with other air pollutants. Based on the AOP Wiki and the mechanisms of PM-induced toxicity at different levels, we first constructed the PM-related AOP frameworks on various systems. [ABSTRACT FROM AUTHOR]

E-cigarette use has surged, but the long-term health effects remain unknown. E-cigarette aerosols containing nicotine and acrolein, a combustion and e-cigarette byproduct, may impair cardiac electrophysiology through autonomic imbalance. Here we show in mouse electrocardiograms that acute inhalation of e-cigarette aerosols disturbs cardiac conduction, in part through parasympathetic modulation. We demonstrate that, similar to acrolein or combustible cigarette smoke, aerosols from e-cigarette solvents (vegetable glycerin and propylene glycol) induce bradycardia, bradyarrhythmias, and elevations in heart rate variability during inhalation exposure, with inverse post-exposure effects. These effects are slighter with tobacco- or menthol-flavored aerosols containing nicotine, and in female mice. Yet, menthol-flavored and PG aerosols also increase ventricular arrhythmias and augment early ventricular repolarization (J amplitude), while menthol uniquely alters atrial and atrioventricular conduction. Exposure to e-cigarette aerosols from vegetable glycerin and its byproduct, acrolein, diminish heart rate and early repolarization. The pro-arrhythmic effects of solvent aerosols on ventricular repolarization and heart rate variability depend partly on parasympathetic modulation, whereas ventricular arrhythmias positively associate with early repolarization dependent on the presence of nicotine. Our study indicates that chemical constituents of e-cigarettes could contribute to cardiac risk by provoking pro-arrhythmic changes and stimulating autonomic reflexes. The use of E-cigarettes has increased despite the unknown long-term effects. Here the authors show that e-cigarette aerosols alter cardiac conduction, repolarization, and autonomic regulation in mice, contingent on the chemical composition of e-liquids and partly through parasympathetic modulation. [ABSTRACT FROM AUTHOR]

The entire maternal circulation adapts to pregnancy, and this adaption is particularly extensive in the uterine circulation where the major vessels double in size to facilitate an approximately 15-fold increase in blood supply to this organ over the course of pregnancy. Several factors may play a role in both the remodeling and biomechanical function of the uterine vasculature including the paracrine microenvironment, passive properties of the vessel wall, and active components of vascular function (incorporating the myogenic response and response to shear stress induced by intravascular blood flow). However, the interplay between these factors and how this plays out in an organ-specific manner to induce the extent of remodeling observed in the uterus is not well understood. Here we present an integrated assessment of the uterine radial arteries, likely rate limiters to the flow of oxygenated maternal blood to the placental surface, via computational modeling and pressure myography. We show that uterine radial arteries behave differently to other systemic vessels (higher compliance and shear-mediated constriction) and that their properties change with the adaptation to pregnancy (higher myogenic tone, higher compliance, and ability to tolerate higher flow rates before constricting). Together, this provides a useful tool to improve our understanding of the role of uterine vascular adaptation in normal and abnormal pregnancies and highlights the need for vascular bed-specific investigations of vascular function in health and disease. [ABSTRACT FROM AUTHOR]

The available evidence on the effects of ambient air pollution on cardiovascular diseases (CVDs) has increased substantially. In this umbrella review, we summarized the current epidemiological evidence from systematic reviews and meta‐analyses linking ambient air pollution and CVDs, with a focus on geographical differences and vulnerable subpopulations. We performed a search strategy through multiple databases including articles between 2010 and 31 January 2021. We performed a quality assessment and evaluated the strength of evidence. Of the 56 included reviews, the most studied outcomes were stroke (22 reviews), all‐cause CVD mortality, and morbidity (19). The strongest evidence was found between higher short‐ and long‐term ambient air pollution exposure and all‐cause CVD mortality and morbidity, stroke, blood pressure, and ischemic heart diseases (IHD). Short‐term exposures to particulate matter <2.5 μm (PM2.5), <10 μm (PM10), and nitrogen oxides (NOx) were consistently associated with increased risks of hypertension and triggering of myocardial infarction (MI), and stroke (fatal and nonfatal). Long‐term exposures of PM2.5 were largely associated with increased risk of atherosclerosis, incident MI, hypertension, and incident stroke and stroke mortality. Few reviews evaluated other CVD outcomes including arrhythmias, atrial fibrillation, or heart failure but they generally reported positive statistical associations. Stronger associations were found in Asian countries and vulnerable subpopulations, especially among the elderly, cardiac patients, and people with higher weight status. Consistent with experimental data, this comprehensive umbrella review found strong evidence that higher levels of ambient air pollution increase the risk of CVDs, especially all‐cause CVD mortality, stroke, and IHD. These results emphasize the importance of reducing the alarming levels of air pollution across the globe, especially in Asia, and among vulnerable subpopulations. [ABSTRACT FROM AUTHOR]

Aims: Cardiac arrhythmias have been associated with intense solar and geomagnetic activity (SGA) and exposures to air pollution.Methods and Results: We examined whether oscillations of SGA can modify the effect of hourly exposures to air pollutants on atrial fibrillation ≥30 s (AF) risk in patients with dual-chamber implantable cardioverter-defibrillators. The effects of SGA on ambient particulate matter <2.5 µm (PM2.5), black carbon (BC), ultrafine particles (PN), and associations with AF were assessed. Measures of SGA included solar wind proton density (SW), total interplanetary magnetic field strength (IMF), and Kp index, a measure of global geomagnetic activity. Overall time lags between 0 and 24 h, periods of increased SGA (>50th percentile in IMF, SW, and Kp index) enhanced the effects of all three air pollutants on AF, while during periods of reduced SGA the associations were considerably weaker or absent. During periods of intense SW 6 h prior to an AF event, the odds ratio (OR) for PM2.5 exposure per interquartile range (IQR) of 5.6 µg/m3 was 1.7 [95% confident interval (CI) 1.3-2.3, P = 0.0001]. For periods of reduced SW, the OR for PM2.5 exposure per IQR was 1.2 (95% CI 0.9-1.5; P = 0.27). There were similar effects for PN and BC exposures. In patients with multiple AF events per hour, the associations with air pollutants during intense SGA were even greater.Conclusion: The effects of air pollutants up to 24 h before AF events were enhanced during periods of increased SGA. Our results suggest that these effects may account for variation in AF risk. [ABSTRACT FROM AUTHOR]

Objective: The exact biological mechanism whereby exposure to ambient ozone (O3) may contribute to clinical onset of cardiovascular events remains unclear. In this study, we aim to examine the impacts of O3 exposure on cardiac arrhythmias and potential pathways involved through autonomic dysfunction and myocardial injury. Methods: Seventy-three non-smoking healthy adults were followed with 4 repeated measurements of 24-hour ambulatory arrhythmias, heart rate variability, ST-segment deviation, and blood pressure (BP) in Beijing, China, 2014 ‒2016. Generalized additive mixed models coupled with distributed lag nonlinear models were constructed to evaluate the associations and potential interlinks between O3 exposure and outcome measurements. Results: During the study period, 24-hour average concentrations of ambient O3 were 47.4 μg/m³ (ranging from 1.0 to 165.9 μg/m³). Increased risks of premature ventricular contraction and ventricular tachycardia were associated with interquartile range increases in O3 exposure during the last 5 days before each participant's clinic visit, with relative risks of 2.14 (95% confidence interval [CI]: 1.95 to 2.32) and 5.47 (95% CI: 3.51 to 7.43), respectively. Mediation analyses further showed that sympathetic activation, parasympathetic inhibition, and elevated BP levels, as well as heightened risks of ST-segment depression could mediate up to 47.74% of the risks of arrhythmias attributable to O3 exposure. Conclusion: Our results suggest that short-term exposure to ambient O3 could prompt the genesis of arrhythmias partially through worsening autonomic function and myocardial burden. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) is considered the most severe environmental pollution problem due to its serious effects on human health associated with an increased risk of cardiovascular morbidity and mortality. In this work, a physicochemical characterization of PM10 from the city of Medellin was developed. The results evince that lead (Pb) is one of the most abundant elements since it is present in all analyzed samples. Therefore, Pb was chosen to perform an in-silico study to assess its effects on atrial arrhythmias generation. For this purpose, we developed a model representing the Pb2+ blocking effect on the L-type calcium channel. This formulation was incorporated in a human atrial cell mathematical model and in 2D and 3D models of human atria. The simulations showed a proarrhythmic effect at high Pb2+ concentrations, through shortening of action potential duration inducing the generation of reentrant activity and atrial flutter. The results contribute to the knowledge about the cardiac physiopathological processes, triggered by lead as one of the main PM10 metal components of air pollution, that yields the generation of arrhythmias. [ABSTRACT FROM AUTHOR]

BACKGROUND: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches. OBJECTIVES: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them. METHODS: An expert working group was convened to discuss mechanisms associated with CV toxicity. RESULTS: The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1–4 below), the vascular system (5–7), or both (8–12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling. DISCUSSION: These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM = 2.5 µm in aerodynamic diameter (PM2.5)] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. [ABSTRACT FROM AUTHOR]

Cardiac innervation density generally reflects the levels of nerve growth factor (NGF) produced by the heart—changes in NGF expression within the heart and vasculature contribute to neuronal remodelling (e.g. sympathetic hyperinnervation or denervation). Its synthesis and release are altered under different pathological conditions. Although NGF is well known for its survival effects on neurons, it is clear that these effects are more wide ranging. Recent studies reported both in vitro and in vivo evidence for beneficial actions of NGF on cardiomyocytes in normal and pathological hearts, including prosurvival and antiapoptotic effects. NGF also plays an important role in the crosstalk between the nervous and cardiovascular systems. It was the first neurotrophin to be implicated in postnatal angiogenesis and vasculogenesis by autocrine and paracrine mechanisms. In connection with these unique cardiovascular properties of NGF, we have provided comprehensive insight into its function and potential effect of NGF underlying heart sustainable/failure conditions. This review aims to summarize the recent data on the effects of NGF on various cardiovascular neuronal and non‐neuronal functions. Understanding these mechanisms with respect to the diversity of NGF functions may be crucial for developing novel therapeutic strategies, including NGF action mechanism‐guided therapies. [ABSTRACT FROM AUTHOR]

Air pollution is a global health concern. Particulate matter (PM)2.5, a component of ambient air pollution, has been identified by the World Health Organization as one of the pollutants that poses the greatest threat to public health. Cardiovascular health effects have been extensively documented, and these effects are still being researched to provide an overview of recent literature regarding air pollution-associated cardiovascular morbidity and mortality in humans. Additionally, potential mechanisms through which air pollutants affect the cardiovascular system are discussed based on human and additional animal studies. We used the strategy of a narrative review to summarize the scientific literature of studies that were published in the past 7 yr. Searches were carried out on PubMed and Web of Science using predefined search queries. We obtained an initial set of 800 publications that were filtered to 78 publications that were relevant to include in this review. Analysis of the literature showed significant associations between air pollution, especially PM2.5, and the risk of elevated blood pressure (BP), acute coronary syndrome, myocardial infarction (MI), cardiac arrhythmia, and heart failure (HF). Prominent mechanisms that underlie the adverse effects of air pollution include oxidative stress, systemic inflammation, endothelial dysfunction, autonomic imbalance, and thrombogenicity. The current review underscores the relevance of air pollution as a global health concern that affects cardiovascular health. More rigorous standards are needed to reduce the cardiovascular disease burden imposed by air pollution. Continued research on the health impact of air pollution is needed to provide further insight. [ABSTRACT FROM AUTHOR]