Plasma untargeted metabolomics reveals distinct metabolic disturbances between sexes following inhalation of ultrafine particles and exposure to aircraft noise in mice

Traffic noise and air pollution, particularly ultrafine particles (UFP), are significantly associated with health risks. However, the systemic metabolic consequences of the combined effects of UFP and aircraft noise (AN) exposure on health remain poorly understood. We aimed to investigate changes in plasma metabolites in healthy wildtype C57BL/6J mice following whole-body inhalation exposure to UFP (average diameter <40 nm), AN and their combination (UFP+AN). Liquid chromatography-mass spectrometry (LC-MS)-based untargeted plasma metabolomics analysis was undertaken for UFP, AN, and combined UFP+AN-exposed mice of both sexes. This study identified a total of 1146 plasma metabolites. Across exposure groups, AN induced the greatest plasma metabolomic changes in both sexes, while UFP significantly altered metabolites only in females, indicating a sex-specific response. The combined UFP+AN exposure produced a modestly enhanced effect in males compared with either single exposure but showed an attenuated effect in females. Pathway analyses revealed that lipid and amino acid metabolism were the most affected, followed by xenobiotics, and cofactors and vitamins, after exposure in both female and male mice. Additionally, in the clean air control group, we identified sex differences in 49 plasma metabolites, which mostly included lipids and amino acids. Following exposure, however, sex-dependent metabolic differences became more pronounced and exposure-specific, suggesting that UFP and AN have distinct effects on plasma metabolome of male and female mice that extend beyond baseline sexual dimorphism observed in unexposed animals. To our knowledge, this study is the first comprehensive characterization of systemic metabolic changes in mice after combination of UFP and AN exposure, providing new insight into the interplay between traffic noise and air pollution health risks.