Air pollution and DNA methylation: effects of exposure in humans

Air pollution exposure is estimated to contribute to approximately seven million early deaths every year worldwide and more than 3% of disability-adjusted life years lost. Air pollution has numerous harmful effects on health and contributes to the development and morbidity of cardiovascular disease, metabolic disorders, and a number of lung pathologies, including asthma and chronic obstructive pulmonary disease (COPD). Emerging data indicate that air pollution exposure modulates the epigenetic mark, DNA methylation (DNAm), and that these changes might in turn influence inflammation, disease development, and exacerbation risk. Several traffic-related air pollution (TRAP) components, including particulate matter (PM), black carbon (BC), ozone (O₃), nitrogen oxides (NOx), and polyaromatic hydrocarbons (PAHs), have been associated with changes in DNAm; typically lowering DNAm after exposure. Effects of air pollution on DNAm have been observed across the human lifespan, but it is not yet clear whether early life developmental sensitivity or the accumulation of exposures have the most significant effects on health. Air pollution exposure-associated DNAm patterns are often correlated with long-term negative respiratory health outcomes, including the development of lung diseases, a focus in this review. Recently, interventions such as exercise and B vitamins have been proposed to reduce the impact of air pollution on DNAm and health. Ultimately, improved knowledge of how exposure-induced change in DNAm impacts health, both acutely and chronically, may enable preventative and remedial strategies to reduce morbidity in polluted environments.Medicine, Faculty ofOther UBCNon UBCMedicine, Department ofPopulation and Public Health (SPPH), School ofRespiratory Medicine, Division ofReviewedFacult

Controlled human exposure to diesel exhaust: results illuminate health effects of traffic-related air pollution and inform future directions

Air pollution is an issue of increasing interest due to its globally relevant impacts on morbidity and mortality. Controlled human exposure (CHE) studies are often employed to investigate the impacts of pollution on human health, with diesel exhaust (DE) commonly used as a surrogate of traffic related air pollution (TRAP). This paper will review the results derived from 104 publications of CHE to DE (CHE-DE) with respect to health outcomes. CHE-DE studies have provided mechanistic evidence supporting TRAP’s detrimental effects on related to the cardiovascular system (e.g., vasomotor dysfunction, inhibition of fibrinolysis, and impaired cardiac function) and respiratory system (e.g., airway inflammation, increased airway responsiveness, and clinical symptoms of asthma). Oxidative stress is thought to be the primary mechanism of TRAP-induced effects and has been supported by several CHE-DE studies. A historical limitation of some air pollution research is consideration of TRAP (or its components) in isolation, limiting insight into the interactions between TRAP and other environmental factors often encountered in tandem. CHE-DE studies can help to shed light on complex conditions, and several have included co-exposure to common elements such as allergens, ozone, and activity level. The ability of filters to mitigate the adverse effects of DE, by limiting exposure to the particulate fraction of polluted aerosols, has also been examined. While various biomarkers of DE exposure have been evaluated in CHE-DE studies, a definitive such endpoint has yet to be identified. In spite of the above advantages, this paradigm for TRAP is constrained to acute exposures and can only be indirectly applied to chronic exposures, despite the critical real-world impact of living long-term with TRAP. Those with significant medical conditions are often excluded from CHE-DE studies and so results derived from healthy individuals may not apply to more susceptible populations whose further study is needed to avoid potentially misleading conclusions. In spite of limitations, the contributions of CHE-DE studies have greatly advanced current understanding of the health impacts associated with TRAP exposure, especially regarding mechanisms therein, with important implications for regulation and policy.Medicine, Faculty ofMedicine, Department ofRespiratory Medicine, Division ofReviewedFacult

Controlled human exposure to diesel exhaust: a method for understanding health effects of traffic-related air pollution

Diesel exhaust (DE) is a major component of air pollution in urban centers. Controlled human exposure (CHE) experiments are commonly used to investigate the acute effects of DE inhalation specifically and also as a paradigm for investigating responses to traffic-related air pollution (TRAP) more generally. Given the critical role this model plays in our understanding of TRAP’s health effects mechanistically and in support of associated policy and regulation, we review the methodology of CHE to DE (CHE–DE) in detail to distill critical elements so that the results of these studies can be understood in context. From 104 eligible publications, we identified 79 CHE–DE studies and extracted information on DE generation, exposure session characteristics, pollutant and particulate composition of exposures, and participant demographics. Virtually all studies had a crossover design, and most studies involved a single DE exposure per participant. Exposure sessions were typically 1 or 2 h in duration, with participants alternating between exercise and rest. Most CHE–DE targeted a PM concentration of 300 μg/m3. There was a wide range in commonly measured co-pollutants including nitrogen oxides, carbon monoxide, and total organic compounds. Reporting of detailed parameters of aerosol composition, including particle diameter, was inconsistent between studies, and older studies from a given lab were often cited in lieu of repeating measurements for new experiments. There was a male predominance in participants, and over half of studies involved healthy participants only. Other populations studied include those with asthma, atopy, or metabolic syndrome. Standardization in reporting exposure conditions, potentially using current versions of engines with modern emissions control technology, will allow for more valid comparisons between studies of CHE–DE, while recognizing that diesel engines in much of the world remain old and heterogeneous. Inclusion of female participants as well as populations more susceptible to TRAP will broaden the applicability of results from CHE–DE studies.Medicine, Faculty ofMedicine, Department ofRespiratory Medicine, Division ofReviewedFacult

Controlled human exposures to wood smoke: a synthesis of the evidence

Background Exposure to particulate matter (PM) from wood combustion represents a global health risk, encompassing diverse exposure sources; indoor exposures due to cooking in developing countries, ambient PM exposures from residential wood combustion in developed countries, and the predicted increasing number of wildfires due to global warming. Although physicochemical properties of the PM, as well as the exposure levels vary considerably between these sources, controlled human exposure studies may provide valuable insight to the harmful effects of wood smoke (WS) exposures in general. However, no previous review has focused specifically on controlled human exposure studies to WS. Results The 22 publications identified, resulting from 12 controlled human studies, applied a range of combustion conditions, exposure levels and durations, and exercise components in their WS exposure. A range of airway, cardiovascular and systemic endpoints were assessed, including lung function and heart rate measures, inflammation and oxidative stress. However, the possibility for drawing general conclusions was precluded by the large variation in study design, resulting in differences in physicochemical properties of WS, effective dose, as well as included endpoints and time-points for analysis. Overall, there was most consistency in reported effects for airways, while oxidative stress, systemic inflammation and cardiovascular physiology did not show any clear patterns. Conclusion Based on the reviewed controlled human exposure studies, conclusions regarding effects of acute WS exposure on human health are premature. Thus, more carefully conducted human studies are needed. Future studies should pay particular attention to the applied WS exposure, to assure that both exposure levels and PM properties reflect the research question.Medicine, Faculty ofNon UBCMedicine, Department ofRespiratory Medicine, Division ofReviewedFacultyResearche

The pulmonary and autonomic effects of high-intensity and low-intensity exercise in diesel exhaust

Background: Exposure to air pollution impairs aspects of pulmonary and autonomic function and causes pulmonary inflammation. However, how exercising in air pollution affects these indices is poorly understood. Therefore, the purpose of this study was to determine the effects of low-intensity and high-intensity cycling with diesel exhaust (DE) exposure on pulmonary function, heart rate variability (HRV), fraction of exhaled nitric oxide (FeNO), norepinephrine and symptoms. Methods: Eighteen males performed 30-min trials of low-intensity or high-intensity cycling (30 and 60% of power at VO2peak) or a resting control condition. For each subject, each trial was performed once breathing filtered air (FA) and once breathing DE (300μg/m3 of PM2.5, six trials in total). Pulmonary function, FeNO, HRV, norepinephrine and symptoms were measured prior to, immediately post, 1 h and 2 h post-exposure. Data were analyzed using repeated-measures ANOVA. Results: Throat and chest symptoms were significantly greater immediately following DE exposure than following FA (p < 0.05). FeNO significantly increased 1 h following high-intensity exercise in DE (21.9 (2.4) vs. 19.3 (2.2) ppb) and FA (22.7 (1.7) vs. 19.9 (1.4)); however, there were no differences between the exposure conditions. All HRV indices significantly decreased following high-intensity exercise (p < 0.05) in DE and FA. The exception to this pattern was LF (nu) and LF/HF ratio, which significantly increased following high-intensity exercise (p < 0.05). Plasma norepinephrine (NE) significantly increased following high-intensity exercise in DE and FA, and this increase was greater than following rest and low-intensity exercise (p < 0.05). DE exposure did not modify any effects of exercise intensity on HRV or norepinephrine. Conclusions: Healthy individuals may not experience greater acute pulmonary and autonomic effects from exercising in DE compared to FA; therefore, it is unclear if such individuals will benefit from reducing vigorous activity on days with high concentrations on particulate matter.Education, Faculty ofMedicine, Faculty ofOther UBCNon UBCKinesiology, School ofMedicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult

Stability of serum precipitins to Aspergillus fumigatus for the diagnosis of allergic bronchopulmonary aspergillosis

Background: Allergic bronchopulmonary aspergillosis (ABPA) reflects hypersensitivity and an exaggerated immune response to Aspergillus fumigatus. ABPA typically occurs in individuals with airway diseases such as asthma or cystic fibrosis and is associated with worse outcomes for individuals with these conditions. Each year, physicians across the province of British Columbia submit over 2600 diagnostic testing requests to a centralized location in Vancouver, requiring specimen collection, storage, and shipment from different clinics across the province. Timely and reliable testing of Aspergillus precipitins is critical to optimizing diagnosis and management of ABPA. At our centre, we analyzed sample stability in varying storage conditions to provide guidance to those using this routine diagnostic test. Methods: To determine temperature and time stability, 31 serum specimens positive for Aspergillus fumigatus precipitins from routine clinical testing were each aliquoted and incubated at 4 and 37 °C. Samples were repeatedly assayed for precipitins to Aspergillus fumigatus via agarose gel double immunodiffusion (AGID) at 7, 14, and 28 days post-incubation. To determine freeze–thaw stability, 39 serum specimens submitted for routine clinical testing for Aspergillus precipitins were randomly selected. Each specimen was aliquoted and stored at 4 or −20 °C. 4 °C samples were maintained at 4 °C while −20 °C samples were split into three groups corresponding to one, two, or three freeze–thaw cycles. −20 °C samples were thawed at room temperature in the morning and then immediately frozen overnight for up to a total of three freeze–thaw cycles. Results: Regarding temperature and time stability, median stability time was 47 and 34 days at 4 and 37 °C, respectively. The log-rank model indicates no statistically significant difference between the two temperature storage conditions (p = 0.14) with a hazard ratio of 0.61 (95% CI, 0.31–1.2). In terms of freeze–thaw stability, no indication of serum degradation with regards to Aspergillus fumigatus precipitins was found with repeated freeze–thaw cycles as compared to refrigerated storage. Conclusions: The stability of serum precipitins to Aspergillus fumigatus was found to be dependent on time, but not temperature and freeze–thaw cycles. Specimens for Aspergillus fumigatus precipitins testing should be shipped at ambient temperature and tested within 2 weeks from collection.Medicine, Faculty ofNon UBCMedicine, Department ofRespiratory Medicine, Division ofReviewedFacult

Concentration-dependent increase in symptoms due to diesel exhaust in a controlled human exposure study

Background: Traffic-related air pollution (TRAP) exposure causes adverse effects on wellbeing and quality of life, which can be studied non-invasively using self-reported symptoms. However, little is known about the effects of different TRAP concentrations on symptoms following controlled exposures, where acute responses can be studied with limited confounding. We investigated the concentration–response relationship between diesel exhaust (DE) exposure, as a model TRAP, and self-reported symptoms. Methods: We recruited 17 healthy non-smokers into a double-blind crossover study where they were exposed to filtered air (FA) and DE standardized to 20, 50, 150 µg/m3 PM2.5 for 4 h, with a ≥ 4-week washout between exposures. Immediately before, and at 4 h and 24 h from the beginning of the exposure, we administered visual analog scale (VAS) questionnaires and grouped responses into chest, constitutional, eye, neurological, and nasal categories. Additionally, we assessed how the symptom response was related to exposure perception and airway function. Results: An increase in DE concentration raised total (β ± standard error = 0.05 ± 0.03, P = 0.04), constitutional (0.01 ± 0.01, P = 0.03) and eye (0.02 ± 0.01, P = 0.05) symptoms at 4 h, modified by perception of temperature, noise, and anxiety. These symptoms were also correlated with airway inflammation. Compared to FA, symptoms were significantly increased at 150 µg/m3 for the total (8.45 ± 3.92, P = 0.04) and eye (3.18 ± 1.55, P = 0.05) categories, with trends towards higher values in the constitutional (1.49 ± 0.86, P = 0.09) and nasal (1.71 ± 0.96, P = 0.08) categories. Conclusion: DE exposure induced a concentration-dependent increase in symptoms, primarily in the eyes and body, that was modified by environmental perception. These observations emphasize the inflammatory and sensory effects of TRAP, with a potential threshold below 150 µg/m3 PM2.5. We demonstrate VAS questionnaires as a useful tool for health monitoring and provide insight into the TRAP concentration–response at exposure levels relevant to public health policy.Medicine, Faculty ofMedicine, Department ofReviewedFacultyResearcherGraduat

Particulate matter exposure and health impacts of urban cyclists: a randomized crossover study

Background: Cycling and other forms of active transportation provide health benefits via increased physical activity. However, direct evidence of the extent to which these benefits may be offset by exposure and intake of traffic-related air pollution is limited. The purpose of this study is to measure changes in endothelial function, measures of oxidative stress and inflammation, and lung function in healthy participants before and after cycling along a high- and low- traffic route. Methods: Participants (n = 38) bicycled for 1 h along a Downtown and a Residential designated bicycle route in a randomized crossover trial. Heart rate, power output, particulate matter air pollution (PM10, PM2.5, and PM1) and particle number concentration (PNC) were measured. Lung function, endothelial function (reactive hyperemia index, RHI), C-reactive protein, interleukin-6, and 8-hydroxy-2′-deoxyguanosine were assessed within one hour pre- and post-trial. Results: Geometric mean PNC exposures and intakes were higher along the Downtown (exposure = 16,226 particles/cm3; intake = 4.54 × 1010 particles) compared to the Residential route (exposure = 9367 particles/cm3; intake = 3.13 × 1010 particles). RHI decreased following cycling along the Downtown route and increased on the Residential route; in mixed linear regression models, the (post-pre) change in RHI was 21% lower following cycling on the Downtown versus the Residential route (−0.43, 95% CI: -0.79, −0.079) but RHI decreases were not associated with measured exposure or intake of air pollutants. The differences in RHI by route were larger amongst females and older participants. No consistent associations were observed for any of the other outcome measures. Conclusions: Although PNC exposures and intakes were higher along the Downtown route, the lack of association between air pollutant exposure or intake with RHI and other measures suggests other exposures related to cycling on the Downtown route may have been influential in the observed differences between routes in RHI. Trial registration ClinicalTrials.gov, NCT01708356 . Registered 16 October 2012.Education, Faculty ofMedicine, Faculty ofKinesiology, School ofMedicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult

When physical activity meets the physical environment: precision health insights from the intersection

Background The physical environment can facilitate or hinder physical activity. A challenge in promoting physical activity is ensuring that the physical environment is supportive and that these supports are appropriately tailored to the individual or group in question. Ideally, aspects of the environment that impact physical activity would be enhanced, but environmental changes take time, and identifying ways to provide more precision to physical activity recommendations might be helpful for specific individuals or groups. Therefore, moving beyond a “one size fits all” to a precision-based approach is critical. Main body To this end, we considered 4 critical aspects of the physical environment that influence physical activity (walkability, green space, traffic-related air pollution, and heat) and how these aspects could enhance our ability to precisely guide physical activity. Strategies to increase physical activity could include optimizing design of the built environment or mitigating of some of the environmental impediments to activity through personalized or population-wide interventions. Conclusions Although at present non-personalized approaches may be more widespread than those tailored to one person’s physical environment, targeting intrinsic personal elements (e.g., medical conditions, sex, age, socioeconomic status) has interesting potential to enhance the likelihood and ability of individuals to participate in physical activity.Education, Faculty ofMedicine, Faculty ofKinesiology, School ofMedicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult

Comparison of weighting approaches for genetic risk scores in gene-environment interaction studies

Background: Weighted genetic risk scores (GRS), defined as weighted sums of risk alleles of single nucleotide polymorphisms (SNPs), are statistically powerful for detection gene-environment (GxE) interactions. To assign weights, the gold standard is to use external weights from an independent study. However, appropriate external weights are not always available. In such situations and in the presence of predominant marginal genetic effects, we have shown in a previous study that GRS with internal weights from marginal genetic effects (“GRS-marginal-internal”) are a powerful and reliable alternative to single SNP approaches or the use of unweighted GRS. However, this approach might not be appropriate for detecting predominant interactions, i.e. interactions showing an effect stronger than the marginal genetic effect. Methods: In this paper, we present a weighting approach for such predominant interactions (“GRS-interaction-training”) in which parts of the data are used to estimate the weights from the interaction terms and the remaining data are used to determine the GRS. We conducted a simulation study for the detection of GxE interactions in which we evaluated power, type I error and sign-misspecification. We compared this new weighting approach to the GRS-marginal-internal approach and to GRS with external weights. Results: Our simulation study showed that in the absence of external weights and with predominant interaction effects, the highest power was reached with the GRS-interaction-training approach. If marginal genetic effects were predominant, the GRS-marginal-internal approach was more appropriate. Furthermore, the power to detect interactions reached by the GRS-interaction-training approach was only slightly lower than the power achieved by GRS with external weights. The power of the GRS-interaction-training approach was confirmed in a real data application to the Traffic, Asthma and Genetics (TAG) Study (N = 4465 observations). Conclusion: When appropriate external weights are unavailable, we recommend to use internal weights from the study population itself to construct weighted GRS for GxE interaction studies. If the SNPs were chosen because a strong marginal genetic effect was hypothesized, GRS-marginal-internal should be used. If the SNPs were chosen because of their collective impact on the biological mechanisms mediating the environmental effect (hypothesis of predominant interactions) GRS-interaction-training should be applied.Medicine, Faculty ofOther UBCNon UBCMedicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult