Network-Based Identification of Key Toxic Compounds in Airborne Chemical Exposome

Air pollution is a leading contributor to the global disease burden. However, the complex nature of the chemicals to which humans are exposed through inhalation has obscured the identification of the key compounds responsible for diseases. Here, we develop a network topology-based framework to identify key toxic compounds in the airborne chemical exposome. Using cardiovascular diseases (CVDs) as a model disease, we found that toxic network modules of various compounds are closely linked to the modules of CVDs. The proximity of compound target modules to disease modules can indicate the extent of toxicity induced by the compounds. By integrating mass spectrometry-based external exposure concentrations and machine learning-predicted internal exposure concentrations, we established a comprehensive linkage connecting exposure to disease-related risk for the identification of toxic compounds. These findings were subsequently validated using exposure and disease data on the regional scale. This work provides an effective strategy for identifying key compounds within environmental exposomes and establishes a new paradigm for understanding the pathogenicity of air pollution.