Effects of Controlled Ozone Exposure on Circulating microRNAs and Vascular and Coagulation Biomarkers: A Mediation Analysis.

Exposure to ozone (O3) is associated with adverse respiratory and cardiovascular outcomes. Alterations in circulating microRNAs (miRNAs) may contribute to the adverse vascular effects of O3 exposure through inter-cellular communication resulting in post-transcriptional regulation of messenger RNAs by miRNAs. In this study, we investigated whether O3 exposure induces alterations in circulating miRNAs that can mediate effects on downstream vascular and coagulation biomarkers. Twenty-three healthy male adults were exposed on successive days to filtered air and 300 ppb O3 for 2 h. Circulating miRNA and protein biomarkers were quantified after each exposure session. The data were subjected to mixed-effects model and mediation analyses for the statistical analyses. The results showed that the expression level of multiple circulating miRNAs (e.g., miR-19a-3p, miR-34a-5p) was significantly associated with O3 exposure. Pathway analysis showed that these miRNAs were predictive of changing levels of downstream biomarkers [e.g., D-dimer, C-reactive protein, tumor necrosis factor α (TNFα)]. Mediation analysis showed that miR-19a-3p may be a significant mediator of O3-exposure-induced changes in blood TNFα levels [0.08 (0.01, 0.15), p = 0.02]. In conclusion, this preliminary study showed that O3 exposure of healthy male adults resulted in changes in circulating miRNAs, some of which may mediate vascular effects of O3 exposure.

Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats.

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.

Associations between PFAS occurrence and multimorbidity as observed in an electronic health record cohort.

Per and polyfluoroalkyl substances (PFAS) are associated with health outcomes ranging from cancer to high cholesterol. However, there has been little examination of how PFAS exposure might impact the development of multiple chronic diseases, known as multimorbidity. Here, we associated the presence of one or more PFAS in water systems serving the zip code of residence with chronic disease and multimorbidity. Methods: We used data from the unregulated contaminant monitoring rule 3 to estimate exposure to PFAS for a random sample of 10,168 patients from the University of North Carolina Healthcare System. The presence of 16 chronic diseases was determined via. their electronic health records. We used a logistic regression model in a cross-sectional study design to associate the presence of one or more PFAS with multimorbidity. Models were adjusted for age, race, sex, smoking status, socioeconomic status, and 20 county-level confounders. Results: There were four PFAS found in water systems that served at least one zip code represented in our patient data: PFOA, PFHpA, PFOS, and PFHxS. Exposure to any PFAS was associated with a odds ratio of 1.25 for multimorbidity (95% confidence interval = 1.09, 1.45). Among the chronic diseases with at least 300 cases, we observed associations with dyslipidemia, hypertension, ischemic heart disease, and osteoporosis. Conclusion: Exposure to PFAS is associated with a range of chronic diseases as well as multimorbidity. Accounting for the joint impacts of PFAS on multiple chronic conditions may give an increasingly clear picture of the public health impacts of PFAS.

Exposures to low-levels of fine particulate matter are associated with acute changes in heart rate variability, cardiac repolarization, and circulating blood lipids in coronary artery disease patients.

Exposure to air pollution is a major risk factor for cardiovascular disease, disease risk factors, and mortality. Specifically, particulate matter (PM), and to some extent ozone, are contributors to these effects. In addition, exposures to these pollutants may be especially dangerous for susceptible populations. In this repeated-visit panel study, cardiovascular markers were collected from thirteen male participants with stable coronary artery disease. For 0-4 days prior to the health measurement collections, daily concentrations of fine PM (PM2.5) and ozone were obtained from local central monitoring stations located near the participant's homes. Then, single (PM2.5) and two-pollutant (PM2.5 and ozone) models were used to assess whether there were short-term changes in cardiovascular health markers. Per interquartile range increase in PM2.5, there were decrements in several heart rate variability metrics, including the standard deviation of the normal-to-normal intervals (lag 3, -5.8%, 95% confidence interval (CI) = -11.5, 0.3) and root-mean squared of successive differences (five day moving average, -8.1%, 95% CI = -15.0, -0.7). In addition, increases in PM2.5 were also associated with changes in P complexity (lag 1, 4.4%, 95% CI = 0.5, 8.5), QRS complexity (lag 1, 4.9%, 95% CI = 1.4, 8.5), total cholesterol (five day moving average, -2.1%, 95% CI = -4.1, -0.1), and high-density lipoprotein cholesterol (lag 2, -1.6%, 95% CI = -3.1, -0.1). Comparisons to our previously published work on ozone were conducted. We found that ozone affected inflammation and endothelial function, whereas PM2.5 influenced heart rate variability, repolarization, and lipids. All the health changes from these two studies were found at concentrations below the United States Environmental Protection Agency's National Ambient Air Quality Standards. Our results imply clear differences in the cardiovascular outcomes observed with exposure to the two ubiquitous air pollutants PM2.5 and ozone; this observation suggests different mechanisms of toxicity for these exposures.

Fish oil blunts lung function decrements induced by acute exposure to ozone in young healthy adults: A randomized trial.

BACKGROUND: Over one-third of the U.S. population is exposed to unsafe levels of ozone (O3). Dietary supplementation with fish oil (FO) or olive oil (OO) has shown protection against other air pollutants. This study evaluates potential cardiopulmonary benefits of FO or OO supplementation against acute O3 exposure in young healthy adults. METHODS: Forty-three participants (26 ± 4 years old; 47% female) were randomized to receive 3 g/day of FO, 3 g/day OO, or no supplementation (CTL) for 4 weeks prior to undergoing 2-hour exposures to filtered air and 300 ppb O3 with intermittent exercise on two consecutive days. Outcome measurements included spirometry, sputum neutrophil percentage, blood markers of inflammation, tissue injury and coagulation, vascular function, and heart rate variability. The effects of dietary supplementation and O3 on these outcomes were evaluated with linear mixed-effect models. RESULTS: Compared with filtered air, O3 exposure decreased FVC, FEV1, and FEV1/FVC immediately post exposure regardless of supplementation status. Relative to that in the CTL group, the lung function response to O3 exposure in the FO group was blunted, as evidenced by O3-induced decreases in FEV1 (Normalized CTL -0.40 ± 0.34 L, Normalized FO -0.21 ± 0.27 L) and FEV1/FVC (Normalized CTL -4.67 ± 5.0 %, Normalized FO -1.4 ± 3.18 %) values that were on average 48% and 70% smaller, respectively. Inflammatory responses measured in the sputum immediately post O3 exposure were not different among the three supplementation groups. Systolic blood pressure elevations 20-h post O3 exposure were blunted by OO supplementation. CONCLUSION: FO supplementation appears to offer protective effects against lung function decrements caused by acute O3 exposure in healthy adults.

Associations between short-term exposure to PM2.5 and cardiomyocyte injury in myocardial infarction survivors in North Carolina.

OBJECTIVE: Short-term ambient fine particulate matter (PM2.5) is associated with adverse cardiovascular events including myocardial infarction (MI). However, few studies have examined associations between PM2.5 and subclinical cardiomyocyte damage outside of overt cardiovascular events. Here we evaluate the impact of daily PM2.5 on cardiac troponin I, a cardiomyocyte specific biomarker of cellular damage. METHODS: We conducted a retrospective cohort study of 2924 patients identified using electronic health records from the University of North Carolina Healthcare System who had a recorded MI between 2004 and 2016. Troponin I measurements were available from 2014 to 2016, and were required to be at least 1 week away from a clinically diagnosed MI. Daily ambient PM2.5 concentrations were estimated at 1 km resolution and assigned to patient residence. Associations between log-transformed troponin I and daily PM2.5 were evaluated using distributed lag linear mixed effects models adjusted for patient demographics, socioeconomic status and meteorology. RESULTS: A 10 µg/m3 elevation in PM2.5 3 days before troponin I measurement was associated with 0.06 ng/mL higher troponin I (95% CI=0.004 to 0.12). In stratified models, this association was strongest in patients that were men, white and living in less urban areas. Similar associations were observed when using 2-day rolling averages and were consistently strongest when using the average exposure over the 5 days prior to troponin I measurement. CONCLUSIONS: Daily elevations in PM2.5 were associated with damage to cardiomyocytes, outside of the occurrence of an MI. Poor air quality may cause persistent damage to the cardiovascular system leading to increased risk of cardiovascular disease and adverse cardiovascular events.

Circulating microRNAs as putative mediators in the association between short-term exposure to ambient air pollution and cardiovascular biomarkers.

BACKGROUND: Exposure to ambient air pollution is associated with increased cardiovascular morbidity and mortality. Circulating microRNAs (miRNAs) may mediate cardiovascular effects of exposure to air pollution. This study aims to investigate whether circulating miRNAs mediate the associations between short-term human exposure to ambient air pollution and cardiovascular biomarkers. METHODS: Twenty-four healthy adults residing in the Research Triangle area of North Carolina, USA were enrolled between December 2016 and July 2019. Circulating miRNAs, protein, and lipid biomarkers were assessed repeatedly for 3 sessions separated by at least 7 days. Linear mixed-effects models were used to assess the associations between air pollutant concentrations obtained from nearby air quality monitoring stations and miRNAs controlling for covariates including omega-3 index, relative humidity, and temperature. miRNAs that were significantly altered were then matched with protein or blood lipid biomarkers using either Ingenuity Pathway Analysis or a literature search. A mediation analysis was performed to test the statistical significance of miRNA's mediating effects between exposure to air pollution and cardiovascular biomarkers. RESULTS: Short-term exposure to ambient fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) was associated with changes in 11, 9, and 24 circulating miRNAs, respectively. Pathway analysis showed that several miRNAs including miR-125b-5p, miR-144-5p, miR-26a-5p, and miR-34a-5p may mediate the effects of air pollutant exposure on the changes of downstream protein / lipid biomarkers including serum amyloid A (SAA), C-reactive protein (CRP), soluble vascular adhesive molecules 1 (sICAM1), total cholesterol, and high-density lipoproteins (HDL). Mediation analysis showed that only miR-26a-5p significantly mediated air pollutant (PM2.5 and NO2)-induced effects on blood CRP and total cholesterol levels. For example, 34.1% of PM2.5-associated changes in CRP were significantly mediated by miR-26a-5p at lag4 [indirect effects, 0.06 (0.02, 0.10), P = 0.005]. Similarly, the proportions of indirect effects of miR-26a-5p on the association between NO2 exposure and CRP were 46.8% at lag2 [0.06 (0.02, 0.11), P = 0.003], 61.2% at lag3 [0.05 (0.00, 0.09), P = 0.04], and 30.8% at 5-day moving average [0.06 (0.02, 0.10), P = 0.01]. In addition, omega-3 index may be a significant modifying factor of the mediated effects of miRNAs. CONCLUSIONS: This study demonstrates that short-term exposure to ambient PM2.5, O3, and NO2 was associated with specific circulating miRNAs, and some of which may mediate their effects on the downstream inflammation and blood lipid markers.

Short-term PM2.5 exposure and early-readmission risk: a retrospective cohort study in North Carolina heart failure patients.

BACKGROUND: Short-term changes in ambient fine particulate matter (PM2.5) increase the risk for unplanned hospital readmissions. However, this association has not been fully evaluated for high-risk patients or examined to determine if the readmission risk differs based on time since discharge. Here we investigate the relation between ambient PM2.5 and 30-day readmission risk in heart failure (HF) patients using daily time windows and examine how this risk varies with respect to time following discharge. METHODS: We performed a retrospective cohort study of 17,674 patients with a recorded HF diagnosis between 2004 and 2016. The cohort was identified using the EPA CARES electronic health record resource. The association between ambient daily PM2.5 (µg/m3) concentration and 30-day readmissions was evaluated using time-dependent Cox proportional hazard models. PM2.5 associated readmission risk was examined throughout the 30-day readmission period and for early readmissions (1-3 days post-discharge). Models for 30-day readmissions included a parametric continuous function to estimate the daily PM2.5 associated readmission hazard. Fine-resolution ambient PM2.5 data were assigned to patient residential address and hazard ratios are expressed per 10 µg/m3 of PM2.5. Secondary analyses examined potential effect modification based on the time after a HF diagnosis, urbanicity, medication prescription, comorbidities, and type of HF. RESULTS: The hazard of a PM2.5-related readmission within 3 days of discharge was 1.33 (95% CI 1.18-1.51). This PM2.5 readmission hazard was slightly elevated in patients residing in non-urban areas (1.43, 95%CI 1.22-1.67) and for HF patients without a beta-blocker prescription prior to the readmission (1.35; 95% CI 1.19-1.53). CONCLUSION: Our findings add to the evidence indicating substantial air quality-related health risks in individuals with underlying cardiovascular disease. Hospital readmissions are key metrics for patients and providers alike. As a potentially modifiable risk factor, air pollution-related interventions may be enacted that might assist in reducing costly and burdensome unplanned readmissions.

Household air pollution from wood-burning cookstoves and C-reactive protein among women in rural Honduras.

Household air pollution from solid fuel combustion was estimated to cause 2.31 million deaths worldwide in 2019; cardiovascular disease is a substantial contributor to the global burden. We evaluated the cross-sectional association between household air pollution (24-h gravimetric kitchen and personal particulate matter (PM2.5) and black carbon (BC)) and C-reactive protein (CRP) measured in dried blood spots among 107 women in rural Honduras using wood-burning traditional or Justa (an engineered combustion chamber) stoves. A suite of 6 additional markers of systemic injury and inflammation were considered in secondary analyses. We adjusted for potential confounders and assessed effect modification of several cardiovascular-disease risk factors. The median (25th, 75th percentiles) 24-h-average personal PM2.5 concentration was 115 µg/m3 (65,154 µg/m3) for traditional stove users and 52 µg/m3 (39, 81 µg/m3) for Justa stove users; kitchen PM2.5 and BC had similar patterns. Higher concentrations of PM2.5 and BC were associated with higher levels of CRP (e.g., a 25% increase in personal PM2.5 was associated with a 10.5% increase in CRP [95% CI: 1.2-20.6]). In secondary analyses, results were generally consistent with a null association. Evidence for effect modification between pollutant measures and four different cardiovascular risk factors (e.g., high blood pressure) was inconsistent. These results support the growing evidence linking household air pollution and cardiovascular disease.

Omega-3 fatty acids attenuate cardiovascular effects of short-term exposure to ambient air pollution.

BACKGROUND: Exposure to air pollution is associated with elevated cardiovascular risk. Evidence shows that omega-3 polyunsaturated fatty acids (omega-3 PUFA) may attenuate the adverse cardiovascular effects of exposure to fine particulate matter (PM2.5). However, it is unclear whether habitual dietary intake of omega-3 PUFA protects against the cardiovascular effects of short-term exposure to low-level ambient air pollution in healthy participants. In the present study, sixty-two adults with low or high dietary omega-3 PUFA intake were enrolled. Blood lipids, markers of vascular inflammation, coagulation and fibrinolysis, and heart rate variability (HRV) and repolarization were repeatedly assessed in 5 sessions separated by at least 7 days. This study was carried out in the Research Triangle area of North Carolina, USA between October 2016 and September 2019. Daily PM2.5 and maximum 8-h ozone (O3) concentrations were obtained from nearby air quality monitoring stations. Linear mixed-effects models were used to assess the associations between air pollutant concentrations and cardiovascular responses stratified by the omega-3 intake levels. RESULTS: The average concentrations of ambient PM2.5 and O3 were well below the U.S. National Ambient Air Quality Standards during the study period. Significant associations between exposure to PM2.5 and changes in total cholesterol, von Willebrand factor (vWF), tissue plasminogen activator, D-dimer, and very-low frequency HRV were observed in the low omega-3 group, but not in the high group. Similarly, O3-associated adverse changes in cardiovascular biomarkers (total cholesterol, high-density lipoprotein, serum amyloid A, soluable intracellular adhesion molecule 1, and vWF) were mainly observed in the low omega-3 group. Lag-time-dependent biphasic changes were observed for some biomarkers. CONCLUSIONS: This study demonstrates associations between short-term exposure to PM2.5 and O3, at concentrations below regulatory standard, and subclinical cardiovascular responses, and that dietary omega-3 PUFA consumption may provide protection against such cardiovascular effects in healthy adults.

Associations between neighborhood socioeconomic cluster and hypertension, diabetes, myocardial infarction, and coronary artery disease within a cohort of cardiac catheterization patients.

BACKGROUND: Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations. METHODS: We used Ward's Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status. RESULTS: Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations. CONCLUSIONS: We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease.

Lung Function and Short-Term Ambient Air Pollution Exposure: Differential Impacts of Omega-3 and Omega-6 Fatty Acids.

Rationale: Exposure to air pollution is associated with adverse respiratory effects. Polyunsaturated omega 3 (n-3) fatty acids (FAs) appear to attenuate the health effects of air pollution. Objectives: This panel study evaluated whether n-3 FA intake and blood levels of polyunsaturated omega 6 (n-6) FAs can modulate the associations between respiratory effects and short-term exposure to ambient air pollution in healthy adults. Methods: Sixty-two healthy adults were enrolled into either high or low n-3 FA groups on the basis of n-3 FA intake and erythrocyte n-3 FA concentrations. Low and high n-6 FA groups were dichotomized on the basis of blood n-6 FA levels. Participants underwent three to five testing sessions separated by at least 7 days. At each session, the forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and plasma markers of inflammation (IL-6 [interleukin-6]) and oxidative stress (ox-LDL [oxidized low-density lipoprotein]) were measured. Associations between the ambient ozone and fine particulate matter (PM) (PM with an aerodynamic diameter ⩽2.5 µm [PM2.5]) levels and the lung function and blood markers were assessed by using mixed-effect models stratified by FA levels. Results: Average levels of ozone (40.8 ± 11.1 ppb) and PM2.5 (10.2 ± 4.1 µg/m3) were below national ambient air quality standards during the study period. FVC was positively associated with ozone at a lag of 0 days (lag0) in the high n-3 FA group, whereas the association was null in the low n-3 FA group (for an interquartile range increase in ozone of 1.8% [95% confidence interval (CI): 0.5% to 3.2%] vs. 0.0% [95% CI: -1.4% to 1.5%]); however, the association shifted to being negative at lag4 (-1.9% [95% CI: -3.2 to -0.5] vs. 0.2% [95% CI: -1.2% to 1.5%]) and lag5 (-1.2% [95% CI: -2.4% to 0.0%] vs. 0.9% [95% CI: -0.4% to 2.3%]). A similar pattern was observed in the low n-6 FA group compared with the high n-6 FA group (lag0: 1.7% [95% CI: 0.3% to 3.0%] vs. 0.5% [95% CI: -0.9% to 2.0%] and lag4: -1.4% [95% CI: -2.8% to 0.0%] vs. -0.5% [95% CI: -1.8% to 0.9%]). The associations between FEV1 and ozone and between FVC and PM2.5 also followed a similar pattern. Elevated ozone levels were associated with an immediate decrease in ox-LDL in the high n-3 FA group at lag0 (-12.3% [95% CI: -24.8% to 0.1%]), whereas there was no change in the low n-3 FA group (-7.5% [95% CI: -21.4% to 6.5%]) and there was a delayed increase in IL-6 in the high n-3 FA group compared with the low n-3 FA group (lag4: 66.9% [95% CI: 27.9% to 106.0%] vs. 8.9% [95% CI: -31.8% to 49.6%], lag5: 58.2% [95% CI: 22.4% to 94.1%] vs. -7.4% [95% CI: -48.8% to 34.0%], and lag6: 45.8% [95% CI: 8.7% to 82.9%] vs. -8.5% [95% CI: -49.7% to 32.6%]). Conclusions: We observed lag-dependent associations between short-term ambient air pollutants and lung function that were differentially modulated by n-3 and n-6 FAs, suggesting that n-3 and n-6 FAs counteract the respiratory response to low levels of ambient air pollution in healthy adults.Clinical trial registered with clinicaltrials.gov (NCT02921048).

Health impacts of a randomized biomass cookstove intervention in northern Ghana.

BACKGROUND: Household air pollution (HAP) from cooking with solid fuels has adverse health effects. REACCTING (Research on Emissions, Air quality, Climate, and Cooking Technologies in Northern Ghana) was a randomized cookstove intervention study that aimed to determine the effects of two types of "improved" biomass cookstoves on health using self-reported health symptoms and biomarkers of systemic inflammation from dried blood spots for female adult cooks and children, and anthropometric growth measures for children only. METHODS: Two hundred rural households were randomized into four different cookstove groups. Surveys and health measurements were conducted at four time points over a two-year period. Chi-square tests were conducted to determine differences in self-reported health outcomes. Linear mixed models were used to assess the effect of the stoves on inflammation biomarkers in adults and children, and to assess the z-score deviance for the anthropometric data for children. RESULTS: We find some evidence that two biomarkers of oxidative stress and inflammation, serum amyloid A and C-reactive protein, decreased among adult primary cooks in the intervention groups relative to the control group. We do not find detectable impacts for any of the anthropometry variables or self-reported health. CONCLUSIONS: Overall, we conclude that the REACCTING intervention did not substantially improve the health outcomes examined here, likely due to continued use of traditional stoves, lack of evidence of particulate matter emissions reductions from "improved" stoves, and mixed results for HAP exposure reductions. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov (National Institutes of Health); Trial Registration Number: NCT04633135 ; Date of Registration: 11 November 2020 - Retrospectively registered. URL: https://clinicaltrials.gov/ct2/show/NCT04633135?term=NCT04633135&draw=2&rank=1.

The influence of dietary intake of omega-3 polyunsaturated fatty acids on the association between short-term exposure to ambient nitrogen dioxide and respiratory and cardiovascular outcomes among healthy adults.

BACKGROUND: Short-term exposure to ambient nitrogen dioxide (NO2) is associated with adverse respiratory and cardiovascular outcomes. Supplementation of omega-3 polyunsaturated fatty acids (PUFA) has shown protection against exposure to fine particulate matter. This study aims to investigate whether habitual omega-3 PUFA intake differentially modify the associations between respiratory and cardiovascular responses and short-term exposure to ambient NO2. METHODS: Sixty-two healthy participants were enrolled into low or high omega-3 groups based on their habitual omega-3 PUFA intake. Each participant was repeatedly assessed for lung function, blood lipids, markers of coagulation and fibrinolysis, vascular function, and heart rate variability (HRV) in up to five sessions, each separated by at least 7 days. This study was carried out in the Research Triangle area of North Carolina, USA between October 2016 and September 2019. Daily ambient NO2 concentrations were obtained from an area air quality monitoring station on the day of outcome assessment (Lag0), 4 days prior (Lag1-4), as well as 5-day moving average (5dMA). The associations between short-term exposure to NO2 and the measured indices were evaluated using linear mixed-effects models stratified by omega-3 levels and adjusted by covariates including relative humidity and temperature. RESULTS: The average concentration of ambient NO2 during the study periods was 5.3±3.8 ppb which was below the National Ambient Air Quality Standards (NAAQS). In the high omega-3 group, an interquartile range (IQR) increase in short-term NO2 concentrations was significantly associated with increased lung function [e.g. 1.2% (95%CI: 0.2%, 2.2%) in FVC at lag1, 2.6% (95%CI: 0.4%, 4.8%) in FEV1 at 5dMA], decreased blood lipids [e.g. -2.6% (95%CI: -4.4%, -0.9%) in total cholesterol at lag2, -3.1% (95%CI: -6.1%, 0.0%) in HDL at 5dMA, and -3.1% (95%CI: -5.5%, -0.7%) in LDL at lag2], improved vascular function [e.g. 8.9% (95%CI: 0.6%, 17.2%) increase in FMD and 43.1% (95%CI: -79.8%, -6.3%) decrease in endothelin-1 at 5dMA], and changed HRV parameters [e.g. -7.2% (95%CI: -13.6%, -0.8%) in HFn and 13.4% (95%CI: 0.2%, 28.3%) in LF/HF ratio at lag3]. In the low omega-3 group, an IQR increase in ambient NO2 was associated with elevations in coagulation markers (von Willebrand Factor, D-dimer) and a decrease in HRV (very-low frequency); however, null associations were observed between short-term NO2 exposure and changes in lung function, blood lipids, and vascular function. CONCLUSIONS: The results in this study imply that dietary omega-3 PUFA consumption may offer respiratory and vascular benefits in response to short-term exposure of healthy adults to NO2 levels below the NAAQS. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02921048 ).

Ozone Responsive Gene Expression as a Model for Describing Repeat Exposure Response Trajectories and Interindividual Toxicodynamic Variability In Vitro.

Inhaled chemical/material exposures are a ubiquitous part of daily life around the world. There is a need to evaluate potential adverse effects of both single and repeat exposures for thousands of chemicals and an exponentially larger number of exposure scenarios (eg, repeated exposures). Meeting this challenge will require the development and use of in vitro new approach methodologies (NAMs); however, 2 major challenges face the deployment of NAMs in risk assessment are (1) characterizing what apical outcome(s) acute assays inform regarding the trajectory to long-term events, especially under repeated exposure conditions, and (2) capturing interindividual variability as it informs considerations of potentially susceptible and/or vulnerable populations. To address these questions, we used a primary human bronchial epithelial cell air-liquid interface model exposed to ozone (O3), a model oxidant and ubiquitous environmental chemical. Here we report that O3-induced proinflammatory gene induction is attenuated in repeated exposures thus demonstrating that single acute exposure outcomes do not reliably represent the trajectory of responses after repeated or chronic exposures. Further, we observed 10.1-, 10.3-, 14.2-, and 7-fold ranges of induction of interleukin (IL)-8, IL-6, heme oxygenase 1, and cyclooxygenase 2 transcripts, respectively, within in our population of 25 unique donors. Calculation of sample size estimates that indicated that 27, 24, 299, and 13 donors would be required to significantly power similar in vitro studies to identify a 2-fold change in IL-8, IL-6, HMOX1, and cyclooxygenase 2 transcript induction, respectively, to inform considerations of the uncertainty factors to reflect variability within the human population for in vitro studies.

Evaluation of PM2.5 air pollution sources and cardiovascular health.

Long-term air pollution exposure, notably fine particulate matter, is a global contributor to morbidity and mortality and a known risk factor for coronary artery disease (CAD) and myocardial infarctions (MI). Knowledge of impacts related to source-apportioned PM2.5 is limited. New modeling methods allow researchers to estimate source-specific long-term impacts on the prevalence of CAD and MI. The Catheterization Genetics (CATHGEN) cohort consists of patients who underwent a cardiac catheterization at Duke University Medical Center between 2002 and 2010. Severity of coronary blockage was determined by coronary angiography and converted into a binary indicator of clinical CAD. History of MI was extracted from medical records. Annual averages of source specific PM2.5 were estimated using an improved gas-constrained source apportionment model for North Carolina from 2002 to 2010. We tested six sources of PM2.5 mass for associations with CAD and MI using mixed effects multivariable logistic regression with a random intercept for county and multiple adjustments. PM2.5 fractions of ammonium bisulfate and ammonium nitrate were associated with increased prevalence of CAD (odds ratio [OR] 1.20; 95% CI = 1.11, 1.22 and OR 1.18; 95% CI = 1.05, 1.32, respectively). PM2.5 from ammonium bisulfate and ammonium nitrate were also associated with increased prevalence of MI (OR 1.20; 95% CI = 1.10, 1.29 and OR 1.35; 95% CI = 1.20, 1.53, respectively). Greater PM2.5 concentrations of ammonium bisulfate and ammonium nitrate are associated with greater MI and CAD prevalence. The association with bisulfate suggests aerosol acidity may play a role. Our findings suggest analyses of source specific PM2.5 mass can reveal novel associations.

Long-Term Exposure to Particulate Air Pollution Is Associated With 30-Day Readmissions and Hospital Visits Among Patients With Heart Failure.

Background Long-term air pollution exposure is a significant risk factor for inpatient hospital admissions in the general population. However, we lack information on whether long-term air pollution exposure is a risk factor for hospital readmissions, particularly in individuals with elevated readmission rates. Methods and Results We determined the number of readmissions and total hospital visits (outpatient visits+emergency room visits+inpatient admissions) for 20 920 individuals with heart failure. We used quasi-Poisson regression models to associate annual average fine particulate matter at the date of heart failure diagnosis with the number of hospital visits and 30-day readmissions. We used inverse probability weights to balance the distribution of confounders and adjust for the competing risk of death. Models were adjusted for age, race, sex, smoking status, urbanicity, year of diagnosis, short-term fine particulate matter exposure, comorbid disease, and socioeconomic status. A 1-µg/m3 increase in fine particulate matter was associated with a 9.31% increase (95% CI, 7.85%-10.8%) in total hospital visits, a 4.35% increase (95% CI, 1.12%-7.68%) in inpatient admissions, and a 14.2% increase (95% CI, 8.41%-20.2%) in 30-day readmissions. Associations were robust to different modeling approaches. Conclusions These results highlight the potential for air pollution to play a role in hospital use, particularly hospital visits and readmissions. Given the elevated frequency of hospitalizations and readmissions among patients with heart failure, these results also represent an important insight into modifiable environmental risk factors that may improve outcomes and reduce hospital use among patients with heart failure.

Controlled human exposures to diesel exhaust: a human epigenome-wide experiment of target bronchial epithelial cells.

Diesel exhaust (DE) is a major contributor to ambient air pollution around the world. It is a known human carcinogen that targets the respiratory system and increases risk for many diseases, but there is limited research on the effects of DE exposure on the epigenome of human bronchial epithelial cells. Understanding the epigenetic impact of this environmental pollutant can elucidate biological mechanisms involved in the pathogenesis of harmful DE-related health effects. To estimate the causal effect of short-term DE exposure on the bronchial epithelial epigenome, we conducted a controlled single-blinded randomized crossover human experiment of exposure to DE and used bronchoscopy and Illumina 450K arrays for data collection and analysis, respectively. Of the 13 participants, 11 (85%) were male and 2 (15%) were female, and 12 (92%) were White and one (8%) was Hispanic; the mean age was 26 years (SD = 3.8 years). Eighty CpGs were differentially methylated, achieving the minimum possible exact P-value of P = 2.44 × 10-4 (i.e. 2/213). In regional analyses, we found two differentially methylated regions (DMRs) annotated to the chromosome 5 open reading frame 63 genes (C5orf63; 7-CpGs) and unc-45 myosin chaperone A gene (UNC45A; 5-CpGs). Both DMRs showed increased DNA methylation after DE exposure. The average causal effects for the DMRs ranged from 1.5% to 6.0% increases in DNA methylation at individual CpGs. In conclusion, we found that short-term DE alters DNA methylation of genes in target bronchial epithelial cells, demonstrating epigenetic level effects of exposure that could be implicated in pulmonary pathologies.

Association between short-term exposure to ambient fine particulate matter and myocardial injury in the CATHGEN cohort.

Exposure to fine particulate matter (PM2.5) has been associated with a higher risk for coronary events. Elevated circulating cardiac troponins (cTn) are suggestive of myocardial injury in both ischemic and non-ischemic conditions. However, little is known about the association between PM2.5 and cTn. In this study, we investigated short-term PM2.5 effects on cardiac troponin T (cTnT), as well as N-terminal-pro brain natriuretic peptide (NT-pro BNP) and inflammatory biomarkers among cardiac catheterized participants. We analyzed 7444 plasma cTnT measurements in 2732 participants who presented to Duke University Hospital with myocardial infarction symptoms between 2001 and 2012, partly along with measurements of NT-pro BNP and inflammatory biomarkers. Daily PM2.5 concentrations were predicted by a neural network-based hybrid model and were assigned to participants' residential addresses. We applied generalized estimating equations to assess associations of PM2.5 with biomarker levels and the risk of a positive cTnT test (cTnT > 0.1 ng/mL). The median plasma cTnT concentration at presentation was 0.05 ng/mL and the prevalence of a positive cTnT test was 35.4%. For an interquartile range (7.6 µg/m3) increase in PM2.5 on the previous day, cTnT concentrations increased by 7.7% (95% CI: 3.4-12.3) and the odds ratio of a positive cTnT test was 1.08 (1.01-1.16). Participants under 60 years (effect estimate: 15.2%; 95% CI: 7.4-23.5) or living in rural areas (12.3%; 95% CI: 4.8-20.3) were more susceptible. There was evidence for increases in fibrinogen and NT-pro BNP associated with elevated PM2.5 on the concurrent and previous two days. Our study suggests that acute PM2.5 exposure may elevate indicators of myocardial tissue damage. This finding substantiates the association of air pollution exposure with adverse cardiovascular events.

Accelerated epigenetic age as a biomarker of cardiovascular sensitivity to traffic-related air pollution.

BACKGROUND: Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures. METHODS: Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status. RESULTS: We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5. CONCLUSION: Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.