Identification of Key Components with Cardiovascular Effect in Airborne Particulate Matter Using an Expanded...

Environmental exposures contribute significantly to the global disease burden. However, identifying key toxicants within these complex exposures remains a challenge. Here, we propose an effect-based identification framework with expanded component-separation strategy that encompasses both organic and previously overlooked inorganic components to identify key components with cardiovascular effect in fine particulate matter (PM_2.5). This framework integrates a high-efficiency extraction and separation method, high-content imaging for vascular morphometric outcomes in a zebrafish model, and multidimensional single-particle analysis for ultrafine particles (UFPs). We identified the effect components in PM_2.5, with combustion-derived Fe₃O₄ nanoparticles (NPs) as the strongest effect component. This unanticipated focus on NPs significantly expands the current scope of potential toxicant candidates. Validation using human cell exposure models confirmed that Fe₃O₄ NPs exhibit higher cardiovascular toxicity than other PM_2.5 components. Our results reveal the crucial toxic contributions of previously overlooked components and provide a revolutionary strategy for identifying effect components within complex environmental matrices.