Circulating microRNAs as putative mediators in the association between short-term exposure to ambient air pollution and cardiovascular biomarkers
Background: Exposure to ambient air pollution is associated with increased cardiovascular morbidity and mortality.
Circulating microRNAs (miRNAs) may mediate cardiovascular effects of exposure to air pollution. This
study aims to investigate whether circulating miRNAs mediate the associations between short-term human
exposure to ambient air pollution and cardiovascular biomarkers.
Methods: Twenty-four healthy adults residing in the Research Triangle area of North Carolina, USA were enrolled
between December 2016 and July 2019. Circulating miRNAs, protein, and lipid biomarkers were assessed
repeatedly for 3 sessions separated by at least 7 days. Linear mixed-effects models were used to assess the associations
between air pollutant concentrations obtained from nearby air quality monitoring stations and miRNAs
controlling for covariates including omega-3 index, relative humidity, and temperature. miRNAs that were
significantly altered were then matched with protein or blood lipid biomarkers using either Ingenuity Pathway
Analysis or a literature search. A mediation analysis was performed to test the statistical significance of miRNA’s
mediating effects between exposure to air pollution and cardiovascular biomarkers.
Results: Short-term exposure to ambient fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2)
was associated with changes in 11, 9, and 24 circulating miRNAs, respectively. Pathway analysis showed that
several miRNAs including miR-125b-5p, miR-144–5p, miR-26a-5p, and miR-34a-5p may mediate the effects of air
pollutant exposure on the changes of downstream protein / lipid biomarkers including serum amyloid A (SAA),
C-reactive protein (CRP), soluble vascular adhesive molecules 1 (sICAM1), total cholesterol, and high-density
lipoproteins (HDL). Mediation analysis showed that only miR-26a-5p significantly mediated air pollutant
(PM2.5 and NO2)-induced effects on blood CRP and total cholesterol levels. For example, 34.1% of
PM2.5–associated changes in CRP were significantly mediated by miR-26a-5p at lag4 [indirect effects, 0.06 (0.02,
0.10), P = 0.005]. Similarly, the proportions of indirect effects of miR-26a-5p on the association between NO2
exposure and CRP were 46.8% at lag2 [0.06 (0.02, 0.11), P = 0.003], 61.2% at lag3 [0.05 (0.00, 0.09), P = 0.04],
and 30.8% at 5-day moving average [0.06 (0.02, 0.10), P = 0.01]. In addition, omega-3 index may be a significant
modifying factor of the mediated effects of miRNAs.