A Human-Composition PFAS Mixture Induces Liver Metabolome Signatures in Male Rats

Background: Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants. Humans are ubiquitously exposed to PFASs as mixtures over long periods. The liver is the primary target organ for PFAS accumulation and toxicity. However, metabolic tools for assessing mixture-specific internal exposure effects in this organ remain limited. Methods: Rats were administered a PFAS mixture by oral gavage for 30 days. The mixture was formulated based on the human composition of dietary exposure. Liver PFAS quantification was combined with non-targeted metabolomics to systematically evaluate liver metabolic perturbations. Results: PFAS exposure induced a dose-dependent remodeling of the liver metabolome. The perturbed metabolic pathways were highly consistent across the dose groups. Through stringent correlation screening, we identified a panel of endogenous metabolites that were strongly and monotonically associated with hepatic ΣPFAS concentration. These metabolites collectively point to coordinated dysregulation of fatty acid metabolism, amino acid metabolism, and oxidative stress defense. Conclusions: This metabolite panel may serve as a candidate metabolic exposure exploratory signature reflecting the internal effect of PFAS mixtures in the liver. It offers a new strategy for health risk assessment of environmental pollutant mixtures.