Respiratory Effects of Traffic-Related Air Pollution: A Randomized, Crossover Analysis of Lung Function, Airway Metabolome, and Biomarkers of Airway Injury

Abstract

Background: Exposure to traffic-related air pollution (TRAP) has been associated with increased risks of respiratory diseases, but the biological mechanisms are not yet fully elucidated.

Objectives: Our aim was to evaluate the respiratory responses and explore potential biological mechanisms of TRAP exposure in a randomized crossover trial.

Methods: We conducted a randomized crossover trial in 56 healthy adults. Each participant was exposed to high- and low-TRAP exposure sessions by walking in a park and down a road with high traffic volume for 4 h in random order. Respiratory symptoms and lung function, including forced expiratory volume in the first second (${\text{FEV}}_1$), forced vital capacity (FVC), the ratio of ${\text{FEV}}_1$ to FVC, and maximal mid-expiratory flow (MMEF), were measured before and after each exposure session. Markers of 8-isoprostane, tumor necrosis $\text{factor-}\alpha$ ($\text{TNF-}\alpha$), and ezrin in exhaled breath condensate (EBC), and surfactant proteins D (SP-D) in serum were also measured. We used linear mixed-effects models to estimate the associations, adjusted for age, sex, body mass index, meteorological condition, and batch (only for biomarkers). Liquid chromatography-mass spectrometry was used to profile the EBC metabolome. Untargeted metabolome-wide association study (MWAS) analysis and pathway enrichment analysis using mummichog were performed to identify critical metabolomic features and pathways associated with TRAP exposure.

Results: Participants had two to three times higher exposure to traffic-related air pollutants except for fine particulate matter while walking along the road compared with in the park. Compared with the low-TRAP exposure at the park, high-TRAP exposure at the road was associated with a higher score of respiratory symptoms [2.615 (95% CI: 0.605, 4.626), $p=1.2\times {10}^{-2}$] and relatively lower lung function indicators [$-0.075L$ (95% CI: $-0.138$, $-0.012$), $p=2.1\times {10}^{-2}$] for ${\text{FEV}}_1$ and $-0.190L/s$ (95% CI: $-0.351$, $-0.029$; $p=2.4\times {10}^{-2}$) for MMEF]. Exposure to TRAP was significantly associated with changes in some, but not all, biomarkers, particularly with a $0.494\text{-ng}/\mathrm{mL}$ (95% CI: 0.297, 0.691; $p=9.5\times {10}^{-6}$) increase for serum SP-D and a $0.123\text{-ng}/\mathrm{mL}$ (95% CI: $-0.208$, $-0.037$; $p=7.2\times {10}^{-3}$) decrease for EBC ezrin. Untargeted MWAS analysis revealed that elevated TRAP exposure was significantly associated with perturbations in 23 and 32 metabolic pathways under positive- and negative-ion modes, respectively. These pathways were most related to inflammatory response, oxidative stress, and energy use metabolism.

Conclusions: This study suggests that TRAP exposure might lead to lung function impairment and respiratory symptoms. Possible underlying mechanisms include lung epithelial injury, inflammation, oxidative stress, and energy metabolism disorders. https://doi.org/10.1289/EHP11139.

Figure 1.

The identified metabolic pathways associated with TRAP and individual air pollutants in positive-ionization mode (POS) and negative-ionization mode (NEG) based on the untargeted metabolome-wide association study (MWAS) conducted for exhaled breath condensate (EBC) metabolomics in a randomized crossover trial in China ($n=56$ adults). TRAP exposure was fitted as a binary indicator of exposure (low/high); individual pollutants were modeled as continuous variables. The linear mixed-effect models and the mummichog pathway analysis (version 1.0.10; Python) were applied for pathway enrichment analysis. Fisher’s exact test (FET) as an enrichment test of metabolic features on pathways was applied, and an adjusted $p<0.05$ from FET was considered statistically significant. $p$-Values are shown in Table S4. Note: BC, black carbon; CO, carbon monoxide; ${\mathrm{NO}}_2$, nitrogen dioxide; ${\mathrm{PM}}_{2.5}$, fine particulate matter; TCA, tricarboxylic acid; TRAP, traffic-related air pollution; UFP, ultrafine particles.

Figure 2.

Possible mechanisms underlying the respiratory effects of TRAP exposure identified in this randomized crossover study in China ($n=56$ adults). Note: 13-HODE, 13-hydroxyoctadecadienoic acid; 13-HPODE, 13-hydroperxyoctadecadienoic acid; 13-OxoODE, 13-oxooctadecadienoic acid; EBC, exhaled breath condensate; ${\text{FADH}}_2$, reduced form of flavin adenine dinucleotide; ${\text{FEV}}_1$, forced expiratory volume in the first second; FVC, forced vital capacity; iNOS, inducible nitric oxide synthase; MMEF, maximal mid-expiratory flow; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; p, phosphate; PLA2, phospholipase A2; ROS, reactive oxygen species; SP-D, surfactant proteins D; TCA, tricarboxylic acid; $\text{TNF-}\mathrm{\alpha }$, tumor necrosis $\text{factor-}\mathrm{\alpha }$; TRAP, traffic-related air pollution; XOR, xanthine oxidoreductase.