Early-life PFAS exposure induces systemic metabolic alterations in plasma and brain in mice

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with adverse health effects, including emerging neurodevelopmental and neurological outcomes. Although PFAS can cross the placental and blood-brain barriers, the metabolic mechanisms underlying their neurotoxicity and potential sex-specific effects remain poorly understood. Here, we investigated the effects of prenatal and early-life exposure to a human-relevant PFAS mixture on plasma and brain metabolism in mice. The mixture contained perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), and perfluorononanoic acid (PFNA) at environmentally relevant, subtoxic concentrations. Mass spectrometry-based metabolomics revealed pronounced, sex-dependent metabolic alterations in both plasma and brain. Female brains exhibited more extensive metabolic changes, particularly in lipid and arachidonic acid metabolism, steroid hormone pathways, and carbohydrate and energy metabolism. In contrast, male brains showed more selective perturbations, predominantly involving amino acid and neuroactive signaling pathways related to neurotransmitter metabolism. These distinct metabolic signatures indicate that early-life PFAS exposure affects brain metabolism through sex-dependent mechanisms. Our findings identify the brain metabolome as a sensitive target of early-life PFAS exposure and emphasize the importance of considering sex as a biological variable when assessing the neurotoxicity of persistent environmental contaminants.