Column switching liquid chromatography dual mass spectrometry system for simultaneous untargeted metabolomics and targeted exposomics

Exposome-wide association studies (ExWAS) require the detection of metabolites and exposures with diverse chemical properties across wide concentration ranges, a task that typically demands multiple analytical methods. To address this challenge, we develop an integrated column-switching two-dimensional liquid chromatography-dual mass spectrometry (2DLC-dual-MS) system. This system employs a 2DLC setup to sequentially separate polar and non-polar compounds with log P ranging from −8 to 15. The separated fractions are directed via a three-way valve to a high-resolution MS (HRMS) and a triple quadrupole MS (TQMS), enabling simultaneous untargeted metabolome analysis and targeted quantification of 601 exposures. The method is particularly suited for the concurrent analysis of metabolome and exposome in human blood, where their concentrations typically differ by 2–3 orders of magnitude. In a demonstration application on lung adenocarcinoma ExWAS, the system exhibits good stability over more than 300 consecutive injections for both metabolome and exposome analysis, confirming its robustness for ExWAS applications. Exposome-wide association studies require measuring many metabolites and environmental chemicals in the same samples. Here, the authors develop a column-switching dual-mass-spectrometry method that profiles metabolites and quantifies 601 chemical exposures in one injection.