A systemic approach to identify signaling pathways activated during short-term exposure to traffic-related urban air pollution from human blood.

The molecular mechanisms that promote pathologic alterations in human physiology mediated by short-term exposure to traffic pollutants remains not well understood. This work was to develop mechanistic networks to determine which specific pathways are activated by real-world exposures of traffic-related air pollution (TRAP) during rest and moderate physical activity (PA). A controlled crossover study to compare whole blood gene expression pre and post short-term exposure to high and low of TRAP was performed together with systems biology analysis. Twenty-eight healthy volunteers aged between 21 and 53 years were recruited. These subjects were exposed during 2 h to different pollution levels (high and low TRAP levels), while either cycling or resting. Global transcriptome profile of each condition was performed from human whole blood samples. Microarrays analysis was performed to obtain differential expressed genes (DEG) to be used as initial input for GeneMANIA software to obtain protein-protein (PPI) networks. Two networks were found reflecting high or low TRAP levels, which shared only 5.6 and 15.5% of its nodes, suggesting specific cell signaling pathways being activated in each environmental condition. However, gene ontology analysis of each PPI network suggests that each level of TRAP regulate common members of NF-κB signaling pathway. Our work provides the first approach describing mechanistic networks to understand TRAP effects on a system level.

Short-term transcriptome and microRNAs responses to exposure to different air pollutants in two population studies.

Diesel vehicle emissions are the major source of genotoxic compounds in ambient air from urban areas. These pollutants are linked to risks of cardiovascular diseases, lung cancer, respiratory infections and adverse neurological effects. Biological events associated with exposure to some air pollutants are widely unknown but applying omics techniques may help to identify the molecular processes that link exposure to disease risk. Most data on health risks are related to long-term exposure, so the aim of this study is to investigate the impact of short-term exposure (two hours) to air pollutants on the blood transcriptome and microRNA expression levels. We analyzed transcriptomics and microRNA expression using microarray technology on blood samples from volunteers participating in studies in London, the Oxford Street cohort, and, in Barcelona, the TAPAS cohort. Personal exposure levels measurements of particulate matter (PM10, PM2.5), ultrafine particles (UFPC), nitrogen oxides (NO2, NO and NOx), black carbon (BC) and carbon oxides (CO and CO2) were registered for each volunteer. Associations between air pollutant levels and gene/microRNA expression were evaluated using multivariate normal models (MVN). MVN-models identified compound-specific expression of blood cell genes and microRNAs associated with air pollution despite the low exposure levels, the short exposure periods and the relatively small-sized cohorts. Hsa-miR-197-3p, hsa-miR-29a-3p, hsa-miR-15a-5p, hsa-miR-16-5p and hsa-miR-92a-3p are found significantly expressed in association with exposures. These microRNAs target also relevant transcripts, indicating their potential relevance in the research of omics-biomarkers responding to air pollution. Furthermore, these microRNAs are also known to be associated with diseases previously linked to air pollution exposure including several cancers such lung cancer and Alzheimer's disease. In conclusion, we identified in this study promising compound-specific mRNA and microRNA biomarkers after two hours of exposure to low levels of air pollutants during two hours that suggest increased cancer risks.

Effects of Leisure-Time and Transport-Related Physical Activities on the Risk of Incident and Recurrent Myocardial Infarction and Interaction With Traffic-Related Air Pollution: A Cohort Study.

BACKGROUND: Physical activity enhances the uptake of air pollutants, possibly reducing its beneficial effects. We examined the effects of leisure-time and transport-related physical activities on the risk of myocardial infarction (MI), and whether potential benefits on MI are reduced by exposure to traffic-related air pollution. METHODS AND RESULTS: A group of 57 053 participants (50-65 years of age) from the Danish Diet, Cancer, and Health cohort reported physical activity at baseline (1993-1997) and were linked to registry data on hospital contacts and out-of-hospital deaths caused by MI, until December 2015. Nitrogen dioxide levels were estimated at participants' baseline residences. We used Cox regressions to associate participation in sports, cycling, walking, and gardening with incident and recurrent MI, and tested for interaction by nitrogen dioxide. Of 50 635 participants without MI at baseline, 2936 developed incident MI, and of 1233 participants with MI before baseline, 324 had recurring MI during follow-up. Mean nitrogen dioxide concentration was 18.7 µg/m3 at baseline (1993-1997). We found inverse statistically significant associations between participation in sports (hazard ratio; 95% confidence interval: 0.85; 0.79-0.92), cycling (0.91; 0.84-0.98), gardening (0.87; 0.80-0.95), and incident MI, while the association with walking was statistically nonsignificant (0.95; 0.83-1.08). Recurrent MI was statistically nonsignificantly inversely associated with cycling (0.80; 0.63-1.02), walking (0.82, 0.57-1.16), and gardening (0.91; 0.71-1.18), and positively with sports (1.06; 0.83-1.35). There was no effect modification of the associations between physical activity and MI by nitrogen dioxide. CONCLUSIONS: Benefits of physical activity on both the incidence and the recurrence of MI are not reduced by exposure to high levels of air pollution.

Estimated effects of air pollution and space-time-activity on cardiopulmonary outcomes in healthy adults: A repeated measures study.

BACKGROUND: Exposure to air pollution is known to affect both short and long-term outcomes of the cardiopulmonary system; however, findings on short-term outcomes have been inconsistent and often from isolated and long-term rather than coexisting and short-term exposures, and among susceptible/unhealthy rather than healthy populations. AIMS: We aimed to investigate separately the annual, daily and daily space-time-activity-weighted effect of ambient air pollution, as well as confounding or modification by other environmental (including noise) or space-time-activity (including total daily physical activity) exposures, on cardiopulmonary outcomes in healthy adults. METHODS: Participants (N=57: 54% female) had indicators of cardiopulmonary outcomes [blood pressure (BP), pulse (HR) and heart rate variability (HRV {SDNN}), and lung function (spirometry {FEV1, FVC, SUM})] measured on four different mornings (at least five days apart) in a clinical setting between 2011 and 2014. Spatiotemporal ESCAPE-LUR models were used to estimate daily and annual air pollution exposures (including PM10, PMCoarse, but not Ozone {derived from closest station}) at participant residential and occupational addresses. Participants' time-activity diaries indicated time spent at either address to allow daily space-time-activity-weighted estimates, and capture total daily physical activity (total-PA {as metabolic-equivalents-of-task, METs}), in the three days preceding health measurements. Multivariate-adjusted linear mixed-effects models (using either annual or daily estimates) were adjusted for possible environmental confounders or mediators including levels of ambient noise and greenness. Causal mediation analysis was also performed separately considering these factors as well as total-PA. All presented models are controlled by age, height, sex and season. RESULTS: An increase in 5µg/m3 of daily space-time-activity-weighted PMCoarse exposure was statistically significantly associated with a 4.1% reduction in total heart rate variability (SDNN; p=0.01), and remained robust after adjusting for suspected confounders [except for occupational-address noise (ß=-2.7, p=0.20)]. An increase in 10ppb of annual mean Ozone concentration at the residential address was statistically significantly associated with an increase in diastolic BP of 6.4mmHg (p<0.01), which lost statistical significance when substituted with daily space-time-activity-weighted estimates. As for pulmonary function, an increase in 10µg/m3 of annual mean PM10 concentration at the residential address was significantly associated with a 0.3% reduction in FVC (p<0.01) and a 0.5% reduction in SUM (p<0.04), for which again significance was lost when substituted for daily space-time-activity-weighted estimates These associations with pulmonary function remained robust after adjusting for suspected confounders, including annual Ozone, as well as total-PA and bioaerosol (pollen and fungal spore) levels (but not residential-neighborhood greenness {ß=-0.22, p=0.09; ß=-0.34, p=0.15, respectively}). Multilevel mediation analysis indicated that the proportion mediated as a direct effect on cardiopulmonary outcomes by suspected confounders (including total-PA, residential-neighborhood greenness, and occupational-address noise level) from primary exposures (including PM10, PMCoarse, and O3) was not statistically significant. CONCLUSION: Our findings suggest that increased daily space-time-activity-weighted PMCoarse exposure levels significantly adversely affect cardiac autonomic modulation (as reduced total HRV) among healthy adults. Additionally, increased annual levels at the residential address of Ozone and PM10 significantly increase diastolic blood pressure and reduce lung function, respectively, among healthy adults. These associations typically remained robust when adjusting for suspected confounders. Occupational-address noise and residential-neighborhood greenness levels, however, were seen as mediators of cardiovascular and pulmonary outcomes, respectively. Total daily physical activity was not seen as a mediator of any of the studied outcomes, which supports the promotion of active mobility within cities.

Acute respiratory response to traffic-related air pollution during physical activity performance.

BACKGROUND: Physical activity (PA) has beneficial, whereas exposure to traffic related air pollution (TRAP) has adverse, respiratory effects. Few studies, however, have examined if the acute effects of TRAP upon respiratory outcomes are modified depending on the level of PA. OBJECTIVES: The aim of our study was to disentangle acute effects of TRAP and PA upon respiratory outcomes and assess the impact of participants TRAP pre-exposure. METHODS: We conducted a real-world crossover study with repeated measures of 30 healthy adults. Participants completed four 2-h exposure scenarios that included either rest or intermittent exercise in high- and low-traffic environments. Measures of respiratory function were collected at three time points. Pre-exposure to TRAP was ascertained from land-use-modeled address-attributed values. Mixed-effects models were used to estimate the impact of TRAP and PA on respiratory measures as well as potential effect modifications. RESULTS: We found that PA was associated with a statistically significant increases of FEV1 (48.5mL, p=0.02), FEV1/FVC (0.64%, p=0.005) and FEF25-75% (97.8mL, p=0.02). An increase in exposure to one unit (1µg/m3) of PMcoarse was associated with a decrease in FEV1 (-1.31mL, p=0.02) and FVC (-1.71mL, p=0.01), respectively. On the other hand, for an otherwise equivalent exposure an increase of PA by one unit (1%Heart rate max) was found to reduce the immediate negative effects of particulate matter (PM) upon PEF (PM2.5, 0.02L/min, p=0.047; PM10, 0.02L/min p=0.02; PMcoarse, 0.03L/min, p=0.02) and the several hours delayed negative effects of PM upon FVC (PMcoarse, 0.11mL, p=0.02). The negative impact of exposure to TRAP constituents on FEV1/FVC and PEF was attenuated in those participants with higher TRAP pre-exposure levels. CONCLUSIONS: Our results suggest that associations between various pollutant exposures and respiratory measures are modified by the level of PA during exposure and TRAP pre-exposure of participants.

Impact of traffic-related air pollution on acute changes in cardiac autonomic modulation during rest and physical activity: a cross-over study.

People are often exposed to traffic-related air pollution (TRAP) during physical activity (PA), but it is not clear if PA modifies the impact of TRAP on cardiac autonomic modulation. We conducted a panel study among 28 healthy adults in Barcelona, Spain to examine how PA may modify the impact of TRAP on cardiac autonomic regulation. Participants completed four 2-h exposure scenarios that included either rest or intermittent exercise in high- and low-traffic environments. Time- and frequency-domain measures of heart rate variability (HRV) were monitored during each exposure period along with continuous measures of TRAP. Linear mixed-effects models were used to estimate the impact of TRAP on HRV as well as potential effect modification by PA. Exposure to TRAP was associated with consistent decreases in HRV; however, exposure-response relationships were not always linear over the broad range of exposures. For example, each 10 µg/m(3) increase in black carbon was associated with a 23% (95% CI: -31, -13) decrease in high frequency power at the low-traffic site, whereas no association was observed at the high-traffic site. PA modified the impact of TRAP on HRV at the high-traffic site and tended to weaken inverse associations with measures reflecting parasympathetic modulation (P ≤ 0.001). Evidence of effect modification at the low-traffic site was less consistent. The strength and direction of the relationship between TRAP and HRV may vary across exposure gradients. PA may modify the impact of TRAP on HRV, particularly at higher concentrations.

Respiratory and inflammatory responses to short-term exposure to traffic-related air pollution with and without moderate physical activity.

OBJECTIVES: Exposure to traffic-related air pollution (TRAP) has been associated with adverse respiratory and systemic outcomes. Physical activity (PA) in polluted air may increase pollutant uptake and thereby health effects. The authors aimed to determine the short-term health effects of TRAP in healthy participants and any possible modifying effect of PA. METHODS: Crossover real-world exposure study comparing in 28 healthy participants pulmonary and inflammatory responses to four different exposure scenarios: 2 h exposure in a high and low TRAP environment, each at rest and in combination with intermittent moderate PA, consisting of four 15 min rest and cycling intervals. Data were analysed using mixed effect models for repeated measures. RESULTS: Intermittent PA compared to rest, irrespective of the TRAP exposure status, increased statistically significant (p≤0.05) pulmonary function (forced expiratory volume in 1 s (34 mL), forced vital capacity (29 mL), forced expiratory flow (FEF25-75%) (91 mL)), lung inflammation (fraction of exhaled nitric oxide, FeNO, (0.89 ppb)), and systemic inflammation markers interleukin-6 (52.3%), leucocytes (9.7%) and neutrophils count (18.8%). Interquartile increases in coarse particulate matter were statistically significantly associated with increased FeNO (0.80 ppb) and neutrophil count (5.7%), while PM2.5 and PM10 (particulate matter smaller than 2.5 and 10 µm in diameter, respectively) increased leucocytes (5.1% and 4.0%, respectively). We found no consistent evidence for an interaction between TRAP and PA for any of the outcomes of interest. CONCLUSIONS: In a healthy population, intermittent moderate PA has beneficial effects on pulmonary function even when performed in a highly polluted environment. This study also suggests that particulate air pollution is inducing pulmonary and systemic inflammatory responses.

Improving health through policies that promote active travel: a review of evidence to support integrated health impact assessment.

BACKGROUND: Substantial policy changes to control obesity, limit chronic disease, and reduce air pollution emissions, including greenhouse gasses, have been recommended. Transportation and planning policies that promote active travel by walking and cycling can contribute to these goals, potentially yielding further co-benefits. Little is known, however, about the interconnections among effects of policies considered, including potential unintended consequences. OBJECTIVES AND METHODS: We review available literature regarding health impacts from policies that encourage active travel in the context of developing health impact assessment (HIA) models to help decision-makers propose better solutions for healthy environments. We identify important components of HIA models of modal shifts in active travel in response to transport policies and interventions. RESULTS AND DISCUSSION: Policies that increase active travel are likely to generate large individual health benefits through increases in physical activity for active travelers. Smaller, but population-wide benefits could accrue through reductions in air and noise pollution. Depending on conditions of policy implementations, risk tradeoffs are possible for some individuals who shift to active travel and consequently increase inhalation of air pollutants and exposure to traffic injuries. Well-designed policies may enhance health benefits through indirect outcomes such as improved social capital and diet, but these synergies are not sufficiently well understood to allow quantification at this time. CONCLUSION: Evaluating impacts of active travel policies is highly complex; however, many associations can be quantified. Identifying health-maximizing policies and conditions requires integrated HIAs.

Systems to support health technology assessment (HTA) in member states of the European union with limited institutionalization of HTA.

OBJECTIVES: The aim of this study was to support health technology assessment (HTA) capacity building in Member States of the European Union with limited experience or without institutionalized HTA. The main output is a Handbook on HTA Capacity Building. METHODS: The methods used were worldwide surveys of (i) HTA organizations, (ii) information management units, and (iii) HTA educational programs. The results of two surveys (i & ii) were combined with expert opinion to produce the Handbook on HTA Capacity Building. RESULTS: Survey of HTA organizations (n = 41, response rate 35 percent). Most of the organizations were established by the government (61 percent), and all were not-for-profit. Working on HTA (80.5 percent) and doing research (63.4 percent) were the main lines of activity. Survey on information management units (n = 23, response rate 23 percent). Most (74.2 percent) of the responding HTA agencies reported having personnel dedicated to HTA information services. Survey on HTA educational programs (n = 48, response rate 60 percent). In total, nine Master of Science (MSc) programs were identified (three MSc in HTA and six MSc in HTA-related areas). Handbook on HTA Capacity Building. A group of twenty experts from thirteen countries developed the handbook. It consists of nine chapters focusing on HTA institutional development (structural setup, work processes, and visibility). CONCLUSIONS: Setting up organizational structures and establishing effective HTA programs that guide key policy decisions is a challenging task. There are no standard models or pathways. "One size fits all" is not a useful principle because of the wide systemic and cultural differences between countries. The Handbook on HTA Capacity Building includes approaches for overall institutional development, especially in formulating objectives, setting up structures, and defining work processes.