Multiomic Signatures of Traffic-Related Air Pollution in London Reveal Potential Short-Term Perturbations in Gut Microbiome-Related Pathways.

This randomized crossover study investigated the metabolic and mRNA alterations associated with exposure to high and low traffic-related air pollution (TRAP) in 50 participants who were either healthy or were diagnosed with chronic pulmonary obstructive disease (COPD) or ischemic heart disease (IHD). For the first time, this study combined transcriptomics and serum metabolomics measured in the same participants over multiple time points (2 h before, and 2 and 24 h after exposure) and over two contrasted exposure regimes to identify potential multiomic modifications linked to TRAP exposure. With a multivariate normal model, we identified 78 metabolic features and 53 mRNA features associated with at least one TRAP exposure. Nitrogen dioxide (NO2) emerged as the dominant pollutant, with 67 unique associated metabolomic features. Pathway analysis and annotation of metabolic features consistently indicated perturbations in the tryptophan metabolism associated with NO2 exposure, particularly in the gut-microbiome-associated indole pathway. Conditional multiomics networks revealed complex and intricate mechanisms associated with TRAP exposure, with some effects persisting 24 h after exposure. Our findings indicate that exposure to TRAP can alter important physiological mechanisms even after a short-term exposure of a 2 h walk. We describe for the first time a potential link between NO2 exposure and perturbation of the microbiome-related pathways.

Relationships between airborne pollutants, serum albumin adducts and short-term health outcomes in an experimental crossover study.

Exposure to air pollution can have both short-term and long-term effects on health. However, the relationships between specific pollutants and their effects can be obscured by characteristics of both the pollution and the exposed population. One way of elucidating the relationships is to link exposures and internal changes at the level of the individual. To this end, we combined personal exposure monitoring (59 individuals, Oxford Street II crossover study) with mass-spectrometry-based analyses of putative serum albumin adducts (fixed-step selected reaction monitoring). We attempted to infer adducts' identities using data from another, higher-resolution mass spectrometry method, and were able to detect a semi-synthetic standard with both methods. A generalised least squares regression method was used to test for associations between amounts of adducts and pollution measures (ambient concentrations of nitrogen dioxide and particulate matter), and between amounts of adducts and short-term health outcomes (measures of lung health and arterial stiffness). Amounts of some putative adducts (e.g., one with a positive mass shift of ∼143 Da) were associated with exposure to pollution (11 associations), and amounts of other adducts were associated with health outcomes (eight associations). Adducts did not appear to provide a link between exposures and short-term health outcomes.

Impact of short-term traffic-related air pollution on the metabolome - Results from two metabolome-wide experimental studies.

Exposure to traffic-related air pollution (TRAP) has been associated with adverse health outcomes but underlying biological mechanisms remain poorly understood. Two randomized crossover trials were used here, the Oxford Street II (London) and the TAPAS II (Barcelona) studies, where volunteers were allocated to high or low air pollution exposures. The two locations represent different exposure scenarios, with Oxford Street characterized by diesel vehicles and Barcelona by normal mixed urban traffic. Levels of five and four pollutants were measured, respectively, using personal exposure monitoring devices. Serum samples were used for metabolomic profiling. The association between TRAP and levels of each metabolic feature was assessed. All pollutant levels were significantly higher at the high pollution sites. 29 and 77 metabolic features were associated with at least one pollutant in the Oxford Street II and TAPAS II studies, respectively, which related to 17 and 30 metabolic compounds. Little overlap was observed across pollutants for metabolic features, suggesting that different pollutants may affect levels of different metabolic features. After observing the annotated compounds, the main pathway suggested in Oxford Street II in association with NO2 was the acyl-carnitine pathway, previously found to be associated with cardio-respiratory disease. No overlap was found between the metabolic features identified in the two studies.

Relationship between free and total malondialdehyde, a well-established marker of oxidative stress, in various types of human biospecimens.

BACKGROUND: Oxidative stress is involved in thoracic diseases and health responses to air pollution. Malondialdehyde (MDA) is a well-established marker of oxidative stress, but it may be present in unconjugated and conjugated forms. To our knowledge, no studies have conducted a systemic evaluation of both free MDA (unconjugated MDA) and total MDA (the sum of both unconjugated and conjugated MDA) across various types of human biospecimens. METHODS: Free MDA and total MDA were simultaneously measured in a range of human biospecimens, including nasal fluid (N=158), saliva (N=158), exhaled breath condensate (N=40), serum (N=232), and urine (N=429). All samples were analyzed using an HPLC-fluorescence method with high sensitivity and specificity. Due to the right skewed distribution of free MDA and total MDA, we performed natural-log transformation before subsequent statistical analyses. The relationship between the natural log of free and total MDA was evaluated by R2 of simple linear regression. T test was used for comparisons of means between two groups. One-way analysis of variance was used in combination with Tukey's test to compare the natural log of the ratio of free MDA to total MDA across various types of biospecimens. RESULTS: For exhaled breath condensate, serum, urine, nasal fluid and saliva samples, the R2 between free and total MDA were 0.61, 0.22, 0.59, 0.47 and 0.06, respectively; the medians of the free MDA to total MDA ratio were 48.1%, 17.4%, 9.8%, 5.1% and 3.0%, respectively; the free MDA to total MDA ratio in EBC > serum > urine > nasal fluid > saliva (P<0.001 for pairwise comparisons). CONCLUSIONS: For exhaled breath condensate and urine samples, using either free or total MDA can provide information regarding the level of oxidative stress; however, that is not the case for serum, nasal fluid, and saliva given the low correlations between free and total MDA.

The human circulating miRNome reflects multiple organ disease risks in association with short-term exposure to traffic-related air pollution.

Traffic-related air pollution is a complex mixture of particulate matter (PM) and gaseous pollutants, such as nitrogen dioxide (NO2). PM exposure contributes to the pathogenesis of many diseases including several types of cancer, as well as pulmonary, cardiovascular and neurodegenerative diseases. Also exposure to NO2 has been related to increased cardiovascular mortality. In search of an early diagnostic biomarker for improved air pollution-associated health risk assessment, recent human studies have shown that certain circulating miRNAs are altered upon exposure to traffic-related air pollutants. Here, we present for the first time a global analysis of the circulating miRNA genome in an experimental cross-over study of a human population exposed to traffic-related air pollution. By utilizing next-generation sequencing technology and detailed real-time exposure measurements we identified 54 circulating miRNAs to be dose- and pollutant species-dependently associated with PM10, PM2.5, black carbon, ultrafine particles and NO2 already after 2 h of exposure. Bioinformatics analysis suggests that these circulating miRNAs actually reflect the adverse consequences of traffic pollution-induced toxicity in target tissues including the lung, heart, kidney and brain. This study shows the strong potential of circulating miRNAs as novel biomarkers for environmental health risk assessment.

Cys34 Adductomes Differ between Patients with Chronic Lung or Heart Disease and Healthy Controls in Central London.

Oxidative stress generates reactive species that modify proteins, deplete antioxidant defenses, and contribute to chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD). To determine whether protein modifications differ between COPD or IHD patients and healthy subjects, we performed untargeted analysis of adducts at the Cys34 locus of human serum albumin (HSA). Biospecimens were obtained from nonsmoking participants from London, U.K., including healthy subjects (n = 20) and patients with COPD (n = 20) or IHD (n = 10). Serum samples were digested with trypsin and analyzed by liquid chromatography-high resolution mass spectrometry. Effects of air pollution on adduct levels were also investigated based on estimated residential exposures to PM2.5, O3 and NO2. For the 39 adducts with sufficient data, levels were essentially identical in blood samples collected from the same subjects on two consecutive days, consistent with the 28 day residence time of HSA. Multivariate linear regression revealed 21 significant associations, mainly with the underlying diseases but also with air-pollution exposures (p-value < 0.05). Interestingly, most of the associations indicated that adduct levels decreased with the presence of disease or increased pollutant concentrations. Negative associations of COPD and IHD with the Cys34 disulfide of glutathione and two Cys34 sulfoxidations, were consistent with previous results from smoking and nonsmoking volunteers and nonsmoking women exposed to indoor combustion of coal and wood.

Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study.

BACKGROUND: Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults. METHODS: In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured. FINDINGS: Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficial responses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles. In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles. INTERPRETATION: Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects. FUNDING: British Heart Foundation.

Sputum-to-serum hydrogen sulfide ratio in COPD.

OBJECTIVES: Hydrogen sulfide (H2S) is a gas produced by respiratory cells including smooth muscle cells and may play a role as a cellular gasotransmitter. We evaluated whether H2S levels in serum or sputum could represent a new biomarker of COPD in a cross-sectional study. METHODS: H2S levels in sputum and serum samples were measured using a sulfide-sensitive electrode in 64 patients with stable COPD (S-COPD), 29 COPD subjects during acute exacerbation (AE-COPD), 14 healthy smokers and 21 healthy non-smokers. RESULTS: Sputum H2S levels in AE-COPD subjects were higher than those in S-COPD, healthy smoking and non-smoking subjects (p<0.001), but serum H2S levels in AE-COPD were lower than those in S-COPD (p<0.001). Thus, the sputum-to-serum ratio of H2S (H2S ratio) in AE-COPD subjects were higher than those in stable COPD, healthy smoking and non-smoking subjects (p<0.001). In 14 COPD subjects whose H2S ratios were measured during and after an exacerbation, the mean ratio was increased during exacerbation (p<0.05). H2S ratio was positively correlated with St. George's Respiratory Questionnaire score, sputum neutrophils and IL-6 and IL-8 levels in sputum and serum (p<0.01) but inversely correlated with sputum macrophages (%), FEV1%predicted and FEV1/FVC (p<0.01). The cut-off level of H2S ratio to indicate an exacerbation was ≥0.44 (sensitivity of 93.1% and specificity of 84.5%). CONCLUSIONS: The ratio of sputum-to-serum levels of H2S may provide a useful marker of COPD indicative of obstructive neutrophilic inflammation and of potential ongoing exacerbation.