ExposomeMap-PM: fine and ultrafine particle-induced toxicity - from adverse outcome pathways to systems biomedicine disease models

Background Air pollution is one of the leading global environmental health risks, associated with millions of premature deaths annually. It represents a substantial share of the global disease burden. Despite well-established epidemiological associations, the underlying molecular mechanisms remain only partially understood. There is a need for systematic approaches toward mechanistic understanding that connect particulate matter exposure to downstream pathways and pathophysiological effects. Results We present ExposomeMap-PM ( https://disease-maps.io/markopolo ), a model of mechanistic progression from fine and ultrafine particle exposure. ExposomeMap-PM includes 304 entities and 497 processes across five mechanistic blocks. The model identifies key components, including alveolar deposition, oxidative stress, barrier disruption, mitochondrial dysfunction, and pro-inflammatory signalling. Adverse outcomes are associated with conditions such as asthma, chronic obstructive pulmonary disease, atherosclerosis and neurodegeneration. Differential-expression values from transcriptomics and proteomics datasets were overlaid onto protein, mRNA and gene nodes of ExposomeMap-PM, providing a pathway-level view of particle-induced effects. In this application, based on a single reference particle type and a short 3-day exposure, the map nodes captured a significantly enriched share of the differentially expressed transcripts: 1.50-fold over size-matched random gene sets, permutation p = 0.0074. The proteomics overlay pointed in the same direction, 1.13-fold. This indicates that the transcriptomic response is concentrated within the mechanistic scope of the map. Methods The approach combines the adverse outcome pathway concept from toxicology with the disease map concept from systems biomedicine. The model was constructed in CellDesigner using Systems Biology Graphical Notation standard and made available online via the MINERVA Platform to facilitate exploration and reuse. Conclusion The ExposomeMap-PM provides a mechanistic layer of understanding, a missing step between epidemiological evidence of particle-induced harmful effects and the molecular events that drive it and connect to outcomes. This reusable and extendable resource bridges toxicological and biomedical perspectives, advancing the understanding of how fine and ultrafine particles contribute to the onset and progression of complex diseases. It supports community annotation and is accessible online for browsing, community feedback and data visualisation.