PFAS disrupt adult hippocampal neurogenesis and synaptic remodeling associated with NOX2/ROS/Ferroptosis activation

Per- and polyfluoroalkyl substances (PFAS) accumulate in the hippocampus, yet their effects on adult hippocampal neurogenesis (AHN) remain unclear. In this study, adult male mice were orally exposed to PFOA or GenX (2 or 10 mg/kg/day) for 28 days. Behavioral performance, AHN, synaptic remodeling, microglial morphology, and redox status were evaluated using behavioral assays, Nissl and Golgi staining, BrdU immunolabeling, microglial morphometric analyses, and Western blotting. PFOA exposure and high-dose GenX exposure reduced time spent and distance traveled in the center area of the open field and impaired spatial learning and memory performance in the Morris water maze, as indicated by increased escape latency and fewer platform crossings. In contrast, PFOA and low-dose GenX exposure reduced exploration of the open arms in the elevated plus maze. PFOA and GenX reduced dendritic spine density with fewer mushroom/thin spines and more stubby spines. PFOA preferentially decreased PSD95 (postsynaptic marker), whereas GenX reduced synaptophysin (presynaptic marker). In the subgranular zone (SGZ), survival and neuronal differentiation of neural stem cells were diminished, and asymmetric divisions of radial glia-like cells increased, suggesting stem-cell pool depletion. Microglia exhibited a hyper-ramified/bushy reactive phenotype. Hippocampal ROS/MDA rose, NOX2 components (GP91^phox/P22^phox) were upregulated, and ferroptosis defenses (SLC7A11/GLS2/GPX4) were downregulated. Collectively, PFOA and GenX disrupt hippocampal synaptic remodeling and AHN and are associated with increased oxidative stress and ferroptosis-related alterations. Differential pre- versus postsynaptic vulnerabilities may contribute to the distinct behavioral alterations observed following PFOA and GenX exposure. This work provides new insights into the neurotoxic effects of PFOA and GenX and identifies potential pathways involved in PFAS-induced hippocampal dysfunction.