Identification of Key Components with Cardiovascular Effect in Airborne Particulate Matter Using an Expanded Component-separation Strategy

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.