Nrf2-related gene expression and exposure to traffic-related air pollution in elderly subjects with cardiovascular disease: An exploratory panel study.
ABSTRACT: Gene expression changes are linked to air pollutant exposures in in vitro and animal experiments. However, limited data are available on how these outcomes relate to ambient air pollutant exposures in humans. We performed an exploratory analysis testing whether gene expression levels were associated with air pollution exposures in a Los Angeles area cohort of elderly subjects with coronary artery disease. Candidate genes (35) were selected from published studies of gene expression-pollutant associations. Expression levels were measured weekly in 43 subjects (? 12 weeks) using quantitative PCR. Exposures included gaseous pollutants O3, nitrogen oxides (NOx), and CO; particulate matter (PM) pollutants elemental and black carbon (EC, BC); and size-fractionated PM mass. We measured organic compounds from PM filter extracts, including polycyclic aromatic hydrocarbons (PAHs), and determined the in vitro oxidative potential of particle extracts. Associations between exposures and gene expression levels were analyzed using mixed-effects regression models. We found positive associations of traffic-related pollutants (EC, BC, primary organic carbon, PM 0.25-2.5 PAH and/or PM 0.25 PAH, and NOx) with NFE2L2, Nrf2-mediated genes (HMOX1, NQO1, and SOD2), CYP1B1, IL1B, and SELP. Findings suggest that NFE2L2 gene expression links associations of traffic-related air pollution with phase I and II enzyme genes at the promoter transcription level.
Project description:BACKGROUND:Air pollution has been related to brain structural alterations, but a relationship with white matter microstructure is unclear. OBJECTIVES:We assessed whether pregnancy and childhood exposures to air pollution are related to white matter microstructure in preadolescents. METHODS:We used data of 2,954 children from the Generation R Study, a population-based birth cohort from Rotterdam, Netherlands (2002-2006). Concentrations of 17 air pollutants including nitrogen oxides (NOX), particulate matter (PM), and components of PM were estimated at participants' homes during pregnancy and childhood using land-use regression models. Diffusion tensor images were obtained at child's 9-12 years of age, and fractional anisotropy (FA) and mean diffusivity (MD) were computed. We performed linear regressions adjusting for socioeconomic and lifestyle characteristics. Single-pollutant analyses were followed by multipollutant analyses using the Deletion/Substitution/Addition (DSA) algorithm. RESULTS:In the single-pollutant analyses, higher concentrations of several air pollutants during pregnancy or childhood were associated with significantly lower FA or higher MD (p<0.05). In multipollutant models of pregnancy exposures selected by DSA, higher concentration of fine particles was associated with significantly lower FA [-0.71 (95% CI: -1.26, -0.16) per 5??g/m3 fine particles] and higher concentration of elemental silicon with significantly higher MD [0.06 (95% CI: 0.01, 0.11) per 100?ng/m3 silicon]. Multipollutant models of childhood exposures selected by DSA indicated significant associations of NOX with FA [-0.14 (95% CI: -0.23, -0.04) per 20-?g/m3 NOX increase], and of elemental zinc and the oxidative potential of PM with MD [0.03 (95% CI: 0.01, 0.04) per 10-ng/m3 zinc increase and 0.07 (95% CI: 0.00, 0.44) per 1-nmol?DTT/min/m3 oxidative potential increase]. Mutually adjusted models of significant exposures during pregnancy and childhood indicated significant associations of silicon during pregnancy, and zinc during childhood, with MD. DISCUSSION:Exposure in pregnancy and childhood to air pollutants from tailpipe and non-tailpipe emissions were associated with lower FA and higher MD in white matter of preadolescents. https://doi.org/10.1289/EHP4709.
Project description:High concentrations of air pollutants on roadways, relative to ambient concentrations, contribute significantly to total personal exposure. Estimation of these exposures requires measurements or prediction of roadway concentrations. Our study develops, compares, and evaluates linear regression and nonlinear generalized additive models (GAMs) to estimate on-road concentrations of four key air pollutants, particle-bound polycyclic aromatic hydrocarbons (PB-PAH), particle number count (PNC), nitrogen oxides (NOx), and particulate matter with diameter <2.5 ?m (PM2.5) using traffic, meteorology, and elevation variables. Critical predictors included wind speed and direction for all the pollutants, traffic-related variables for PB-PAH, PNC, and NOx, and air temperatures and relative humidity for PM2.5. GAMs explained 50%, 55%, 46%, and 71% of the variance for log or square-root transformed concentrations of PB-PAH, PNC, NOx, and PM2.5, respectively, an improvement of 5% to over 15% over the linear models. Accounting for temporal autocorrelation in the GAMs further improved the prediction, explaining 57-89% of the variance. We concluded that traffic and meteorological data are good predictors in estimating on-road traffic-related air pollutant concentrations and GAMs perform better for nonlinear variables, such as meteorological parameters.
Project description:Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin.We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations).Inflammation biomarkers were measured weekly in each subject (? 12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-? (TNF-?), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NOx), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (<0.25 µm, 0.25-2.5 µm, and 2.5-10 µm in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed-effects models.IL-6 and TNF-? were associated with traffic-related air pollutants (BC, CO, NOx and PAH), and with mass and oxidative potential of quasi-ultrafine particles <0.25 µm. These associations were stronger for haplogroup H than haplogroup U.Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects.
Project description:BACKGROUND:Exposure to air pollution has been associated with cardiorespiratory morbidity and mortality. However, the chemical constituents and pollution sources underlying these associations remain unclear. METHOD:We conducted a cohort panel study involving 97 elderly subjects living in the Los Angeles metropolitan area. Airway and circulating biomarkers of oxidative stress and inflammation were measured weekly over 12 weeks and included, exhaled breath condensate malondialdehyde (EBC MDA), fractional exhaled nitric oxide (FeNO), plasma oxidized low-density lipoprotein (oxLDL), and plasma interleukin-6 (IL-6). Exposures included 7-day personal nitrogen oxides (NOx), daily criteria-pollutant data, five-day average particulate matter (PM) measured in three size-fractions and characterized by chemical components including transition metals, and in vitro PM oxidative potential (dithiothreitol and macrophage reactive oxygen species). Associations between biomarkers and pollutants were assessed using linear mixed effects regression models. RESULTS:We found significant positive associations of airway oxidative stress and inflammation with traffic-related air pollutants, ultrafine particles and transition metals. Positive but nonsignificant associations were observed with PM oxidative potential. The strongest associations were observed among PM variables in the ultrafine range (PM <0.18µm). It was estimated that an interquartile increase in 5-day average ultrafine polycyclic aromatic hydrocarbons was associated with a 6.3% (95% CI: 1.1%, 11.6%) increase in EBC MDA and 6.7% (95% CI: 3.4%, 10.2%) increase in FeNO. In addition, positive but nonsignificant associations were observed between oxLDL and traffic-related pollutants, ultrafine particles and transition metals while plasma IL-6 was positively associated with 1-day average traffic-related pollutants. CONCLUSION:Our results suggest that exposure to pollutants with high oxidative potential (traffic-related pollutants, ultrafine particles, and transition metals) may lead to increased airway oxidative stress and inflammation in elderly adults. This observation was less clear with circulating biomarkers.
Project description:Short-term exposure to ambient air pollution has been associated with acute increases in cardiovascular hospitalization and mortality. However, causative chemical components and underlying pathophysiological mechanisms remain to be clarified. We hypothesized that endothelial dysfunction would be associated with mobile-source (traffic) air pollution and that pollutant components with higher oxidative potential to generate reactive oxygen species (ROS) would have stronger associations.We carried out a cohort panel study in 93 elderly non-smoking adults living in the Los Angeles metropolitan area, during July 2012-February 2014. Microvascular function, represented by reactive hyperemia index (RHI), was measured weekly for up to 12 weeks (N?=?845). Air pollutant data included daily data from regional air-monitoring stations, five-day average PM chemical components and oxidative potential in three PM size-fractions, and weekly personal nitrogen oxides (NOx). Linear mixed-effect models estimated adjusted changes in microvascular function with exposure.RHI was inversely associated with traffic-related pollutants such as ambient PM2.5 black carbon (BC), NOx, and carbon monoxide (CO). An interquartile range change increase (1.06 ?g/m(3)) in 5-day average BC was associated with decreased RHI, -0.093 (95 % CI: -0.151, -0.035). RHI was inversely associated with other mobile-source components/tracers (polycyclic aromatic hydrocarbons, elemental carbon, and hopanes), and PM oxidative potential as quantified in two independent assays (dithiothreitol and in vitro macrophage ROS) in accumulation and ultrafine PM, and transition metals.Our findings suggest that short-term exposures to traffic-related air pollutants with high oxidative potential are major components contributing to microvascular dysfunction.
Project description:Numerous studies have associated air pollutant exposures with adverse birth outcomes, but there is still relatively little information to attribute effects to specific emission sources or air toxics. We used three exposure data sources to examine risks of preterm birth in Los Angeles women when exposed to high levels of traffic-related air pollutants--including specific toxics--during pregnancy.We identified births during 6/1/04-3/31/06 to women residing within five miles of a Southern California Air Quality Management District (SCAQMD) Multiple Air Toxics Exposure Study (MATES III) monitoring station. We identified preterm cases and, using a risk set approach, matched cases to controls based on gestational age at birth. Pregnancy period exposure averages were estimated for a number of air toxics including polycyclic aromatic hydrocarbons (PAHs), source-specific PM2.5 (fine particulates with aerodynamic diameter less than 2.5 ?m) based on a Chemical Mass Balance model, criteria air pollutants based on government monitoring data, and land use regression (LUR) estimates of nitric oxide (NO), nitrogen dioxide (NO2) and nitrogen oxides (NOx). Associations between these metrics and odds of preterm birth were estimated using conditional logistic regression.Odds of preterm birth increased 6-21% per inter-quartile range increase in entire pregnancy exposures to organic carbon (OC), elemental carbon (EC), benzene, and diesel, biomass burning and ammonium nitrate PM2.5, and 30% per inter-quartile increase in PAHs; these pollutants were positively correlated and clustered together in a factor analysis. Associations with LUR exposure metrics were weaker (3-4% per inter-quartile range increase).These latest analyses provide additional evidence of traffic-related air pollution's impact on preterm birth for women living in Southern California and indicate PAHs as a pollutant of concern that should be a focus of future studies. Other PAH sources besides traffic were also associated with higher odds of preterm birth, as was ammonium nitrate PM2.5, the latter suggesting potential importance of secondary pollutants. Future studies should focus on accurate modeling of both local and regional spatial and temporal distributions, and incorporation of source information.
Project description:BACKGROUND:Maternal air pollution exposure has been related to orofacial clefts but the literature is equivocal. Potential chronic preconception effects have not been studied. OBJECTIVES:Criteria air pollutant exposure during three months preconception and gestational weeks 3-8 was studied in relation to orofacial defects. METHODS:Among 188,102 live births and fetal deaths from the Consortium on Safe Labor (2002-2008), 63 had isolated cleft palate (CP) and 159 had isolated cleft lip with or without cleft palate (CL ±CP). Exposures were estimated using a modified Community Multiscale Air Quality model. Logistic regression with generalized estimating equations adjusted for site/region and maternal demographic, lifestyle and clinical factors calculated the odds ratio (OR) and 95% CI per interquartile increase in each pollutant. RESULTS:Preconception, carbon monoxide (CO; OR=2.24; CI: 1.21, 4.16) and particulate matter (PM) ?10 µm (OR=1.72; CI: 1.12, 2.66) were significantly associated with CP, while sulfur dioxide (SO2) was associated with CL ±CP (OR=1.93; CI: 1.16, 3.21). During gestational weeks 3-8, CO remained a significant risk for CP (OR=2.74; CI: 1.62, 4.62) and nitrogen oxides (NOx; OR=3.64; CI: 1.73, 7.66) and PM ?2.5 µm (PM2.5; OR=1.74; CI: 1.15, 2.64) were also related to the risk. Analyses by individual week revealed that positive associations of NOx and PM2.5 with CP were most prominent from weeks 3-6 and 3-5, respectively. CONCLUSIONS:Exposure to several criteria air pollutants preconception and during early gestation was associated with elevated odds for CP, while CL ±CP was only associated with preconception SO2 exposure.
Project description:Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007 to 2009. Participants attended 1 study visit during which blood pressure, heart rate, and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and sociodemographic characteristics, and a 12-hour fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency's Air Quality System database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 ?m (±54 SD). A 2 standard deviation (SD) increase in childhood (aged 0-5 years) or elementary school (aged 6-12 years) O(3) exposure was associated with a 7.8-?m (95% confidence interval, -0.3-15.9) or 10.1-?m (95% confidence interval, 1.8-18.5) higher CIMT, respectively. Lifetime exposure to O(3) showed similar but nonsignificant associations. No associations were observed for PM(2.5), PM(10), or NO(2), although adjustment for these pollutants strengthened the childhood O(3) associations.Childhood exposure to O(3) may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.
Project description:Studies in a number of countries have reported associations between exposure to ambient air pollutants and adverse birth outcomes, including low birth weight, preterm birth (PTB) and, less commonly, small for gestational age (SGA). Despite their growing number, the available studies have significant limitations, e.g., incomplete control of temporal trends in exposure, modest sample sizes, and a lack of information regarding individual risk factors such as smoking. No study has yet examined large numbers of susceptible individuals. We investigated the association between ambient air pollutant concentrations and term SGA and PTB outcomes among 164,905 singleton births in Detroit, Michigan occurring between 1990 and 2001. SO(2), CO, NO(2), O(3) and PM(10) exposures were used in single and multiple pollutant logistic regression models to estimate odds ratios (OR) for these outcomes, adjusted for the infant's sex and gestational age, the mother's race, age group, education level, smoking status and prenatal care, birth season, site of residence, and long-term exposure trends. Term SGA was associated with CO levels exceeding 0.75ppm (OR=1.14, 95% confidence interval=1.02-1.27) and NO(2) exceeding 6.8ppb (1.11, 1.03-1.21) exposures in the first month, and with PM(10) exceeding 35?g/m(3) (1.22, 1.03-1.46) and O(3) (1.11, 1.02-1.20) exposure in the third trimester. PTB was associated with SO(2) (1.07, 1.01-1.14) exposure in the last month, and with (hourly) O(3) exceeding 92ppb (1.08, 1.02-1.14) exposure in the first month. Exposure to several air pollutants at modest concentrations was associated with adverse birth outcomes. This study, which included a large Black population, suggests the importance of the early period of pregnancy for associations between term SGA with CO and NO(2), and between O(3) with PTB; and the late pregnancy period for associations between term SGA and O(3) and PM(10), and between SO(2) with PTB. It also highlights the importance of accounting for individual risk factors such as maternal smoking, maternal race, and long-term trends in air pollutant levels and adverse birth outcomes in evaluating relationships between pollutant exposures and adverse birth outcomes.
Project description:BACKGROUND:The current single-pollutant approach to regulating ambient air pollutants is effective at protecting public health, but efficiencies may be gained by addressing issues in a multipollutant context since multiple pollutants often have common sources and individuals are exposed to more than one pollutant at a time. OBJECTIVE:We performed a cross-disciplinary review of the effects of multipollutant exposures on cardiovascular effects. METHODS:A broad literature search for references including at least two criteria air pollutants (particulate matter [PM], ozone [O3], oxides of nitrogen, sulfur oxides, carbon monoxide) was conducted. References were culled based on scientific discipline then searched for terms related to cardiovascular disease. Most multipollutant epidemiologic and experimental (i.e., controlled human exposure, animal toxicology) studies examined PM and O3 together. DISCUSSION:Epidemiologic and experimental studies provide some evidence for O3 concentration modifying the effect of PM, although PM did not modify O3 risk estimates. Experimental studies of combined exposure to PM and O3 provided evidence for additivity, synergism, and/or antagonism depending on the specific health endpoint. Evidence for other pollutant pairs was more limited. CONCLUSIONS:Overall, the evidence for multipollutant effects was often heterogeneous, and the limited number of studies inhibited making a conclusion about the nature of the relationship between pollutant combinations and cardiovascular disease.