Metabolite correlation permutation after mice acute exposure to PM_2.5: Holistic exploration of toxicometabolomics by...

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.