Untargeted Metabolomics for PM2.5 Toxicity in Rodent Models: A Systematic Review

Abstract

The adverse health effects of fine particulate matter (PM2.5) remain a pressing public-health concern. Untargeted metabolomics, which provides global and relatively unbiased profiling of small-molecule metabolites, offers unique opportunities to discover new exposure biomarkers and clarify toxicity mechanisms beyond those of conventional approaches. This systematic review synthesizes 42 untargeted metabolomics studies in PM2.5-exposed rodent models. Integrative analysis identifies 1,276 unique exposure-associated metabolites under the predefined lenient screening criteria, with 24 high-frequency metabolites (e.g., taurine, citric acid, alanine) and 31 recurrently perturbed pathways (e.g., purine metabolism, linoleic acid metabolism, and tricarboxylic acid cycle). These convergent alterations suggest three recurring mechanistic themes: an energy-crisis-driven redox imbalance, oxidative-stress-mediated epigenetic dysregulation, and inflammatory signaling via polyunsaturated fatty acids. Tissue-specific metabolic alterations were prominent in lungs (e.g., altered arachidonic acid), liver (e.g., purine catabolism), and brain (e.g., lipid homeostasis disruption), demonstrating multiorgan pathophysiological responses. Nevertheless, substantial methodological heterogeneity across exposure protocols, animal models, and analytical platforms complicates cross-study comparisons. These findings support untargeted metabolomics as a high-throughput approach for characterizing PM2.5-induced metabolic toxicity and offer an applicable framework that may also inform studies of other emerging contaminants and mixtures. Further progress will require more standardized analytical workflows, complementary platform integration, and cross-species validation.