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Associations between exposure to traffic-related air pollutants and changes in fractional exhaled nitric oxide in children with asthma
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JI, Nan. Associations between exposure to traffic-related air pollutants and changes in fractional exhaled nitric oxide in children with asthma. Retrieved from https://doi.org/doi:10.7282/t3-f52r-ne80
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TitleAssociations between exposure to traffic-related air pollutants and changes in fractional exhaled nitric oxide in children with asthma
NameJI, Nan (author); Laumbach, Robert (chair); Hong, Junyan (internal member); Ohman-Strickland, Pamela (internal member); Meng, Qingyu (outside member); Tsai, Stella (outside member); Rutgers University; School of Graduate Studies
Date Created2021
Other Date2021-05 (degree)
Extent1 online resource (xii, 129 pages)
DescriptionBackground: Motor vehicles are an important source of urban air pollution. Many countries have implemented more stringent regulations to reduce the vehicle emission. Nonetheless, the benefits of these regulations may be compromised because of the rising of the number of vehicles globally and the increasing reliance on motor vehicles. Exposure to air pollutants emitted from vehicles, defined here as traffic-related air pollution (TRAP), has been associated with exacerbation of asthma among children. Accurate quantification of TRAP exposure is critical in epidemiological studies of health effects. The challenge in estimating individual exposure is that human exposure to TRAP by inhalation is not a static but a dynamic process. Personal exposure to TRAP could be impacted by 1) the spatial and temporal variation of TRAP concentrations; 2) variations of personal time-activity pattern. Due to these dynamics, uncertainty arises regarding the extent to which current methods are representative of individual-level exposure. These uncertainties may cause non-differential misclassification of exposure, which biases associations between exposure to TRAP and health-related outcomes. Previously conducted research assessed individual-level TRAP exposure using pollutant concentration collected from central-site or personal monitors; however, the former did not well characterize the spatial and temporal variation of exposure. Both methods failed to account for the dynamics of inhalation rates.
Previous studies also suggest that nitric oxide (NO) production in the respiratory tract plays an important role in asthmatic airway’s response to TRAP. There is increasing evidence that TRAP-induced changes in airway inflammation (measured as fractional exhaled nitric oxide, FeNO) may at least partly result from epigenetic modifications that alter the expression of genes involved in the synthesis of NO. Meanwhile, exposure to air pollution has been associated with changes in DNA methylation, suggesting a mode of action by which air pollution may alter NO production and FeNO. However, the current epidemiological evidence relied mainly on fixed-site measurements and did not examine the temporal sequence of TRAP, DNA methylation and FeNO.
Specific Aims: The main objectives of this dissertation project were to 1) determine the effects of alternative exposure assessment methods on the estimated associations between FeNO and potential inhaled dose of TRAP derived from central sites, personal monitors, and an individual dosimetry model (Air Pollution Exposure Model, APEX) that incorporates personal time-activity data to assess individual-level potential TRAP dose; and 2) to test the time-lag patterns of personal dose to TRAP, airway inflammation, and DNA methylation in the promoter regions of genes involved in nitric oxide synthesis among children with asthma.
Methods and Materials: The study included 35 school-aged children with mild-to-moderate physician-diagnosed asthma who live near the Newark-Elizabeth Port in New Jersey from 2011-2016. Each subject was followed for up to 30 days. Black carbon (BC) (an indicator for TRAP) concentration was collected from the nearest central-site station and the personal monitors. FeNO was measured at the same time (around 4 pm) for all subjects at the community field site. We collected 90 buccal cell samples for 20 DNA methylation analysis from 18 children (5 per child). BC concentrations were calculated at seven lag periods prior to the buccal sample collection: 0-6 hours, 7-12 hours, 13-24 hours, 0-24 hours (lag 0 day), 25-48 hours (lag 1 day) 49-72 hours (lag 2 days) 73-96 hours (lag 3 days). Demographic information, including age, gender, and race/ethnicity, and time-activity information were obtained through questionnaires. Real-time inhalation rate was calculated from the time-activity data while the default inhalation rate was obtained from the US EPA Exposure handbook. Four types of exposure metrics for TRAP exposure assessment include: dose calculated by BC concentration collected from central site (Model A) and personal monitors (Model B) using the default inhalation rate as well as by BC from central site (Model C) and personal monitors (Model D) using the dynamic inhalation rate calculated from the self-reported time-activity questionnaire. Correlation and agreement were measured between exposure metrics. Compartment was defined as a binary variable: 1) residential area, 2) other area. Time was defined as a four-level categorical variable: 1) 3 a.m. - 9 a.m., 2) 9 a.m. - 3 p.m., 3) 3 p.m.- 9 p.m., and 4) 9 p.m.- 3 a.m.. Linear mixed effect models were used to examine the difference of exposure by time and compartment, the associations between TRAP exposure and FeNO, and the DNA methylation in the selected genes.
Results: The median (interquartile range, IQR) dose of BC from Model A and Model C were 16.0 ng (16.9 ng) and 14.1 ng (15.6 ng). However, the median (IQR) of BC dose in Model B and Model D were 9.0 ng (15.2 ng) and 7.9 ng (14.2 ng). We observed a significant difference in the BC dose by compartment and a significant interaction between time and compartment in all Models (p<0.05). No significant difference in dose from Model A by time was observed. Compared to the indoor environment, doses of BC were higher outdoors for all exposure models. Except for Model A, doses during daytime (9 a.m. - 3 p.m. and 3 p.m. - 9 p.m.) were higher than nighttime (3 a.m. - 9 a.m. and 9 p.m. - 3 a.m.).
In the unadjusted model, there was a 5% increase (95%CI: 1% - 10%) in FeNO per log-transformed IQR increase in BC from Model B at lag 0-6 hours (p=0.01). At lag 7-12 hours and 0-24 hours, there was a 4% increase (95%CI: 0% - 9%) in FeNO in response to BC from Model B. The strength of associations decreased and became non-significant at longer lag periods. Exposure to BC from Model D was positively associated with FeNO at lag 0-6 hours (p=0.01) and lag 0-24 hours (p=0.03). No significant associations were detected in the unadjusted model between FeNO and BC from Model A and C. In the adjusted model, individuals with log-transformed IQR increase in BC measured from Model A had 10% decrease (95%CI: -18% - -2%) in FeNO at lag 13-24 hours (p=0.02) and 11% decrease (95%CI: -19% - -2%) at lag 0-24 hours. Significant negative associations were observed between FeNO and BC measured from Model C at lag 13-24 hours and lag 0-24 hours (p=0.03).
Exposure to BC was positively associated with FeNO, and negatively associated with DNA methylation in NOS3. We found strongest association between FeNO and BC at lag 0–6 hours while strongest associations between methylation at positions 1 and 2 in NOS3 and BC were at lag 13-24 hours and lag 0-24 hours, respectively. The strengths of associations were attenuated at longer lag periods. No significant associations between exposure to TRAP and methylation levels in other NOS and ARG isoforms were observed.
Conclusions: Exposure metric that failed to account for the spatial, temporal variation and personal activity pattern (Model A) were not able to capture the difference of individual-level exposure to TRAP at different time. Relying only on the central-site monitored data (Model A and C) underestimate personal TRAP exposure level. Models that did not account for the time-activity pattern (Model A vs. Model C and Model B vs. Model D) tend to bias the personal exposure towards null. Exposure metrics that considered the dynamics of TRAP concentrations and personal time-activity pattern could better characterize individual TRAP exposure. However, inaccurate information of the time-activity pattern and noises from personal monitors may introduce errors and bias the estimated associations. Exposure to TRAP was associated with higher levels of FeNO and lower levels of DNA methylation in the promoter regions of the NOS3 gene, indicating that DNA methylation of the NOS3 gene could be an important epigenetic mechanism in physiological responses to TRAP in children with asthma.
Previous studies also suggest that nitric oxide (NO) production in the respiratory tract plays an important role in asthmatic airway’s response to TRAP. There is increasing evidence that TRAP-induced changes in airway inflammation (measured as fractional exhaled nitric oxide, FeNO) may at least partly result from epigenetic modifications that alter the expression of genes involved in the synthesis of NO. Meanwhile, exposure to air pollution has been associated with changes in DNA methylation, suggesting a mode of action by which air pollution may alter NO production and FeNO. However, the current epidemiological evidence relied mainly on fixed-site measurements and did not examine the temporal sequence of TRAP, DNA methylation and FeNO.
Specific Aims: The main objectives of this dissertation project were to 1) determine the effects of alternative exposure assessment methods on the estimated associations between FeNO and potential inhaled dose of TRAP derived from central sites, personal monitors, and an individual dosimetry model (Air Pollution Exposure Model, APEX) that incorporates personal time-activity data to assess individual-level potential TRAP dose; and 2) to test the time-lag patterns of personal dose to TRAP, airway inflammation, and DNA methylation in the promoter regions of genes involved in nitric oxide synthesis among children with asthma.
Methods and Materials: The study included 35 school-aged children with mild-to-moderate physician-diagnosed asthma who live near the Newark-Elizabeth Port in New Jersey from 2011-2016. Each subject was followed for up to 30 days. Black carbon (BC) (an indicator for TRAP) concentration was collected from the nearest central-site station and the personal monitors. FeNO was measured at the same time (around 4 pm) for all subjects at the community field site. We collected 90 buccal cell samples for 20 DNA methylation analysis from 18 children (5 per child). BC concentrations were calculated at seven lag periods prior to the buccal sample collection: 0-6 hours, 7-12 hours, 13-24 hours, 0-24 hours (lag 0 day), 25-48 hours (lag 1 day) 49-72 hours (lag 2 days) 73-96 hours (lag 3 days). Demographic information, including age, gender, and race/ethnicity, and time-activity information were obtained through questionnaires. Real-time inhalation rate was calculated from the time-activity data while the default inhalation rate was obtained from the US EPA Exposure handbook. Four types of exposure metrics for TRAP exposure assessment include: dose calculated by BC concentration collected from central site (Model A) and personal monitors (Model B) using the default inhalation rate as well as by BC from central site (Model C) and personal monitors (Model D) using the dynamic inhalation rate calculated from the self-reported time-activity questionnaire. Correlation and agreement were measured between exposure metrics. Compartment was defined as a binary variable: 1) residential area, 2) other area. Time was defined as a four-level categorical variable: 1) 3 a.m. - 9 a.m., 2) 9 a.m. - 3 p.m., 3) 3 p.m.- 9 p.m., and 4) 9 p.m.- 3 a.m.. Linear mixed effect models were used to examine the difference of exposure by time and compartment, the associations between TRAP exposure and FeNO, and the DNA methylation in the selected genes.
Results: The median (interquartile range, IQR) dose of BC from Model A and Model C were 16.0 ng (16.9 ng) and 14.1 ng (15.6 ng). However, the median (IQR) of BC dose in Model B and Model D were 9.0 ng (15.2 ng) and 7.9 ng (14.2 ng). We observed a significant difference in the BC dose by compartment and a significant interaction between time and compartment in all Models (p<0.05). No significant difference in dose from Model A by time was observed. Compared to the indoor environment, doses of BC were higher outdoors for all exposure models. Except for Model A, doses during daytime (9 a.m. - 3 p.m. and 3 p.m. - 9 p.m.) were higher than nighttime (3 a.m. - 9 a.m. and 9 p.m. - 3 a.m.).
In the unadjusted model, there was a 5% increase (95%CI: 1% - 10%) in FeNO per log-transformed IQR increase in BC from Model B at lag 0-6 hours (p=0.01). At lag 7-12 hours and 0-24 hours, there was a 4% increase (95%CI: 0% - 9%) in FeNO in response to BC from Model B. The strength of associations decreased and became non-significant at longer lag periods. Exposure to BC from Model D was positively associated with FeNO at lag 0-6 hours (p=0.01) and lag 0-24 hours (p=0.03). No significant associations were detected in the unadjusted model between FeNO and BC from Model A and C. In the adjusted model, individuals with log-transformed IQR increase in BC measured from Model A had 10% decrease (95%CI: -18% - -2%) in FeNO at lag 13-24 hours (p=0.02) and 11% decrease (95%CI: -19% - -2%) at lag 0-24 hours. Significant negative associations were observed between FeNO and BC measured from Model C at lag 13-24 hours and lag 0-24 hours (p=0.03).
Exposure to BC was positively associated with FeNO, and negatively associated with DNA methylation in NOS3. We found strongest association between FeNO and BC at lag 0–6 hours while strongest associations between methylation at positions 1 and 2 in NOS3 and BC were at lag 13-24 hours and lag 0-24 hours, respectively. The strengths of associations were attenuated at longer lag periods. No significant associations between exposure to TRAP and methylation levels in other NOS and ARG isoforms were observed.
Conclusions: Exposure metric that failed to account for the spatial, temporal variation and personal activity pattern (Model A) were not able to capture the difference of individual-level exposure to TRAP at different time. Relying only on the central-site monitored data (Model A and C) underestimate personal TRAP exposure level. Models that did not account for the time-activity pattern (Model A vs. Model C and Model B vs. Model D) tend to bias the personal exposure towards null. Exposure metrics that considered the dynamics of TRAP concentrations and personal time-activity pattern could better characterize individual TRAP exposure. However, inaccurate information of the time-activity pattern and noises from personal monitors may introduce errors and bias the estimated associations. Exposure to TRAP was associated with higher levels of FeNO and lower levels of DNA methylation in the promoter regions of the NOS3 gene, indicating that DNA methylation of the NOS3 gene could be an important epigenetic mechanism in physiological responses to TRAP in children with asthma.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/t3-f52r-ne80
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
Statistical ProfileVersion 8.5.5
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