Revealing Hidden Exposures: Multi-omic and Mass Spectrometry Approaches for Decoding the Chemical Exposome

Human-made chemical pollutants pose a pervasive threat to environmental and human health, yet global chemical production continues to rise while toxicological data often remains unavailable. Since regulations lag behind innovation, much of our understanding of real‑world chemical exposure frequently comes from observed biological consequences such as infertility, chronic disease, neurocognitive decline, and threats to food security. These knowledge gaps therefore illuminate major limitations in our current ability to evaluate chemical risks and highlight the need for analytical strategies capable of capturing the complexity of environmental exposures and their biological effects. The exposome provides a framework for characterizing the totality of exposures across the lifespan. Within this framework, the chemical exposome focuses specifically on exposures and effects from exogenous small molecules. Traditional targeted mass spectrometry and single-omic approaches have offered valuable but limited insights into this chemical space but often overlook co‑occurring contaminants and perturbations in interconnected molecular pathways. In contrast, multi‑omic measurements enable a more comprehensive assessment of both exposure and biological response, revealing mechanistic links between contaminants and adverse health outcomes. Developments in these areas position chemical exposomics and multi‑omics as essential tools for environmental precision health, an emerging paradigm that seeks to identify exposure‑specific molecular signatures, predict susceptibility, and guide targeted interventions. This review highlights how multi-omics, advanced analytical chemistry techniques, and sophisticated computational tools are collectively advancing a more holistic understanding of the chemical exposome.