Multi-Organ Per- and Polyfluoroalkyl Substances Accumulation Reveals Brain-Peripheral Metabolic Coupling and Glucocorticoid-Related Dysregulation in Mice.

Per- and polyfluoroalkyl substances (PFASs) are persistent synthetic chemicals increasingly linked to systemic metabolic dysregulation and potential Alzheimer's disease (AD) risk. However, whether chronic PFASs exposure disrupts metabolic crosstalk between peripheral organs and the brain remains unclear. This study aimed to systematically investigate multi-organ PFASs accumulation and associated metabolic disturbances under chronic PFASs exposure, with a particular focus on the brain. Six-month-old mice were exposed to PFASs for 7 weeks, and PFAS accumulation profiles and metabolic profiles across multiple tissues were characterized using liquid chromatography-mass spectrometry (LC-MS). Across most peripheral tissues, PFAS concentrations were generally comparable to those observed in the brain and showed a relatively consistent distribution pattern, with PFOS exhibiting the highest levels, followed by PFDA and PFNA at similar concentrations, and lower levels of PFHxS and PFOA. Brain differential metabolites (DEMs) showed substantial overlap with those detected in peripheral tissues, with the greatest number of overlapping DEMs and the strongest correlations observed between brain and plasma. Among PFAS exposure-associated DEMs, steroid hormones and their precursor-related metabolites showed the most pronounced fold changes in the brain, followed by metabolites involved in energy metabolism. Notably, 11-dehydrocorticosterone (11-DHC), a shared marker, showed an upregulated trend in both APP/PS1 model mice and PFAS-exposed mice. These findings indicate that PFASs induce concordant metabolic perturbations in the brain and peripheral tissues, prominently involving steroid hormone and energy metabolism pathways. The concordant metabolic signatures between brain and plasma suggest the potential utility of peripheral biomarkers for PFAS-related brain dysfunction. Moreover, metabolites commonly altered in both APP/PS1 model mice and PFAS-exposed mice may implicate glucocorticoid dysregulation as a mechanism that amplifies neuroendocrine stress and AD susceptibility.