PFOS Impairs Cognitive Function in Female Rats by Disrupting Astrocyte-Derived Estrogen–ERβ–NDRG2 Signaling Axis

Epidemiological investigations have indicated that females are particularly susceptible to perfluorooctane sulfonate (PFOS)-induced cognitive impairment, yet the mechanisms underlying this sex-specific vulnerability remain obscure. Estrogen and estrogen receptor β (ERβ) signaling are essential for female brain function, but their role in PFOS-induced neurotoxicity has not been explored. We therefore hypothesized that disruption of astrocyte-derived estrogen–ERβ signaling, leading to downregulation of N-myc downstream-regulated gene 2 (NDRG2) and subsequent synaptic dysfunction, contributes to PFOS-induced neurotoxicity in females. Female rats were exposed to PFOS for 30 days, followed by behavioral tests and hippocampal analysis. PC12 cells were treated with astrocyte-conditioned medium (ACM) to assess synaptic injury. Molecular docking was further performed to predict the binding affinity between PFOS and ERβ. In vivo, PFOS exposure impaired cognitive performance and caused hippocampal dysfunction, accompanied by decreased levels of estradiol (E2), aromatase (AROM), ERβ, N-myc downstream regulated gene 2 (NDRG2), and AMPA receptors (AMPARs), together with increased glial fibrillary acidic protein (GFAP) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus. In vitro, PFOS-exposed C6 cells showed reduced E2, AROM, ERβ, and NDRG2, along with elevated GFAP and extracellular glutamate concentration. PC12 cells treated with PFOS-ACM exhibited decreased synaptophysin (SYP), postsynaptic density protein 95 (PSD-95), and AMPARs, as well as increased CaMKII, indicative of synaptic injury. Pretreatment with E2 or the ERβ agonist diarylpropionitrile (DPN) could reverse these molecular alterations and mitigate neuronal dysfunction. Molecular docking revealed a strong binding affinity between PFOS and ERβ. Collectively, these findings support our hypothesis that PFOS impairs cognitive function in female rats by disrupting astrocyte-derived estrogen–ERβ–NDRG2 signaling, with NDRG2 as a potential downstream effector. This provides a mechanistic basis for the heightened female susceptibility to PFOS neurotoxicity and highlighting ERβ as a potential therapeutic target.