Multi-Modal Mass Spectrometry Imaging Reveals Isomer-Specific PFOS Distribution and Spatial Lipid Disruption in Mouse Liver

Abstract

The linear and branched isomers of perfluorooctane sulfonate (PFOS), a legacy per- and polyfluoroalkyl substances (PFAS), show differential bioaccumulation and toxicological responses. However, their spatial distribution within tissues and their effects in spatial contexts remain insufficiently resolved. In this work, we present a multi-modal mass spectrometry imaging (MSI) strategy to resolve the on-tissue distribution of linear (n-) and branched (br-) PFOS isomers in mouse liver and PFOS-induced spatial lipid disruption. Liver samples from exposed mice were analyzed by multi-modal MSI, integrating matrix-assisted laser desorption/ionization-trapped ion mobility spectrometry (MALDI-TIMS)-MSI and post-MALDI immunofluorescence of canonical zonation markers. We found that PFOS exhibited dose-dependent and zonation-specific distribution, with enrichment in pericentral regions compared to periportal. br-PFOS displayed a more homogeneous distribution compared to n-PFOS. Spatial lipidomics revealed concomitant zonal disruptions in hepatic lipid abundance and distribution, reflecting zonal lipid disruptions not accessible by bulk measurements. Together, this study establishes a multi-modal, spatial-resolved analytical workflow for mapping on-tissue PFOS isomer distribution and lipid disruptions. By demonstrating that PFOS isomeric structure governs tissue localization and is associated with zonal lipid disruptions, our findings provide new insights into the spatial dimension of toxicokinetics/ toxicodynamics and underscore the need for isomer-resolved, spatial-focusing approaches on environmental and toxicology research.