Metabolite correlation permutation after mice acute exposure to PM2.5: Holistic exploration of toxicometabolomics by network analysis

Many environmental toxicants can cause systemic effects, such as fine particulate matter (PM 2.5 ), which can penetrate the respiratory barrier and induce effects in multiple tissues. Although metabolomics has been used to identify biomarkers for PM 2.5 , its multi-tissue toxicology has not yet been explored holistically. Our objective is to explore PM 2.5 induced metabolic alterations and unveil the intra-tissue responses along with inter-tissue communicational effects. In this study, following a single intratracheal instillation of multiple doses (0, 25, and 150 μg as the control, low, and high dose), non-targeted metabolomics was employed to evaluate the metabolic impact of PM 2.5 across multiple tissues. PM 2.5 induced tissue-specific and dose-dependent disturbances of metabolites and their pathways. The remarkable increase of both intra- and inter-tissue correlations was observed, with emphasis on the metabolism connectivity among lung, spleen, and heart; the tissues’ functional specificity has marked their toxic modes. Beyond the inter-status comparison of the metabolite fold-changes, the current correlation network built on intra-status can offer additional insights into how the multiple tissues and their metabolites coordinately change in response to external stimuli such as PM 2.5 exposure.