Endogenous Metabolic Incorporation of Inhaled Soot Particles Revealed by Bottom-up ¹³ C Labeling

Inhalation of soot particles generated from both wildfires and incomplete combustion of fossil fuels poses a severe threat to global human health and is associated with many diseases. However, the metabolic transformation of soot particles, a key link between soot exposure and health outcomes, remains poorly understood. Here, we develop a novel bottom-up method to rapidly synthesize ¹³C-labeled soot, enabling <i>in vivo</i> tracking of soot metabolism by mass spectrometry. <i>In vitro</i> metabolic experiments utilizing human liver postmitochondrial liver supernatant (S9) fractions show the potential involvement of soot in human endogenous metabolism. Using animal exposure models combined with nontargeted metabolic flux analysis, we further demonstrate that soot particles can be utilized as a carbon source by the organism and directly integrated into biological metabolic processes, subsequently affecting metabolites and potential pathways associated with diseases. Our findings suggest that no clear-cut boundary exists between exogenous inert soot particles and endogenous metabolites, offering novel insights into the "black box" of internal exposure of air pollution and their associated pathogenic mechanisms.