Lipidomics profiling with instrumental variable analysis revealed distinct causal effect of exposure to ambient ozone...

Lipid metabolism has been suggested as a major mechanism underlying air pollution-associated health hazards, but evidence remains limited. Based on targeted lipidomics profiling of 161 lipid species, we conducted observational and instrumental variable analyses, the latter using planetary boundary layer height (PBLH), wind speed, thermal inversion, and sea level pressure as instrumental variables and a two-stage regression process, to examine the causal associations of ambient ozone (O₃) and fine particulate matter (PM_2.5) exposure with 161 circulating lipids in 3881 middle-to-elderly aged Chinese adults. We found that, both O₃ and PM_2.5 exposures were more strongly associated with lipids in long-term than short-term (61 and 38 vs 34 and 8 significant associations), and glycerophospholipids showed most extensive associations with both O₃ and PM_2.5 exposure. For O₃ exposure, we identified an association pattern that triacylglycerols (TAGs) positively associated with short-term O₃ exposure were containing shorter fatty acid chains and less double bonds, while those showing negative associations were with longer fatty acid chains and higher level of unsaturation, the latter consistently being observed in the long-term exposure scenario. We also observed more pronounced association of O₃ and PM_2.5 exposure with their associated lipids under high-level co-exposure of each other, consistently in direction between observational and instrumental variable analyses, although significance was achieved in one of the analyses (P for interaction < 0.05). Our findings provided evidence on the novel, plausibly causal, lipid implications of O₃ and PM_2.5 exposure, and new mechanistic clues regarding the involvement of lipid metabolism in health hazards induced by the exposure.