Integrated Metabolic Profiling of Coexposure to Legacy and Emerging Contaminants: A Perspective of Paired Serum and Urine Metabolomics

High-resolution metabolomics has enhanced our understanding of pollutants' adverse effects on humans, particularly in multipollutant exposure scenarios. However, whether metabolic profiles differ across biological matrices in response to contaminants remains unclear. In this study, we analyzed urinary concentrations of 38 legacy and emerging contaminants, including 15 metal(loid)s and 23 metabolites of polycyclic aromatic hydrocarbons, phthalates, and alternative plasticizers in 74 general residents from southern China using inductively coupled plasma mass spectrometry and high-performance liquid chromatography-tandem mass spectrometry. High-resolution metabolomics of paired serum and urine samples identified 186 serum and 774 urine metabolites significantly associated with measured contaminant, enriching 12 serum and 22 urine metabolic pathways. Cross-validation across serum and urine metabolomes revealed 37 overlapping metabolites (mainly as 12 lipids and 9 organic acids) and 8 metabolic pathways (7 amino acid-related and 1 sphingolipid pathway) as primary metabolic perturbations. Notwithstanding shared signatures, organic nitrogen and organ heterocyclic compounds comprise a significantly higher proportion in serum and urine. Only serum phenylalanine and leucine were associated with globulin. These findings first characterize metabolic responses to pollutant mixtures and highlight the complementary value of serum (for biomarker screening) and urine (for exposure assessment) metabolomics in environmental health research.