Isomer-specific distribution of perfluorooctane sulfonate (PFOS) in hepatic zonation in mouse

Per- and polyfluoroalkyl substances (PFAS) are a class of emerging contaminants that are widely distributed and persistent in the environment, accumulated in biological organisms and associated with adverse health outcomes. Evidence has shown a wide existence of branched PFAS isomers from source to applications. Notably, linear and branched isomeric PFAS structures are associated with differential toxicity outcomes and health effects. Herein, we investigated distribution of perfluorooctane sulfonate (PFOS) isomers in mouse liver tissue after exposure using matrix-assisted laser desorption/ionization-trapped ion mobility spectrometry-mass spectrometry imaging (MALDI-TIMS-MSI). Mice were treated with vehicle control or commercially sourced PFOS, a mixture of linear and branched isomers, at concentrations to achieve doses of 0.1 and 1 mg/kg/day for 84 days. Liver tissues were collected, followed by sample preparation and MALDI-TIMS-MSI analysis. Using a TIMS ramp time of 150 ms, we successfully separated linear and branched isomers on-tissue. Coupling with post-MALDI immunofluorescence imaging of canonical zonation markers, we discovered hepatic zonation-specific distribution for linear isomer but more homogenous distribution of branched PFOS. Dual-polarity MSI was performed on the same tissue for hepatic metabolites and lipids, and results showed concomitant alteration of liver lipid zonation upon PFOS exposure. With MALDI-TIMS-MSI, our results for the first time demonstrated on-tissue differentiation of PFOS isomers. Multi-modal imaging revealed isomer-specific PFOS distribution and spatial lipidomic changes, both mapped to canonical hepatic zonation markers, to reveal zone-selective PFOS toxicokinetics/toxicodynamics. Together our results demonstrate the critical need for further investigating isomer-specific PFAS toxicity.