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

Area of Science:

• Neuroscience
• Environmental Health
• Toxicology

Background:

• Females exhibit higher susceptibility to perfluorooctane sulfonate (PFOS)-induced cognitive impairment.
• Mechanisms of sex-specific neurotoxicity from PFOS are not well understood.
• Estrogen and estrogen receptor beta (ERβ) signaling are crucial for female brain function but their role in PFOS neurotoxicity is unexplored.

Purpose of the Study:

• To investigate the hypothesis that disrupted astrocyte-derived estrogen-ERβ signaling contributes to PFOS-induced neurotoxicity in females.
• To elucidate the role of N-myc downstream-regulated gene 2 (NDRG2) in PFOS-induced synaptic dysfunction.
• To identify potential therapeutic targets for mitigating PFOS neurotoxicity in females.

Main Methods:

• Female rats were exposed to PFOS (30 days), followed by behavioral tests and hippocampal analysis.
• In vitro studies used PC12 cells and astrocyte-conditioned medium (ACM) to assess synaptic injury.
• Molecular docking was employed to predict the binding affinity between PFOS and ERβ.

Main Results:

• PFOS exposure impaired cognitive performance and hippocampal function in female rats.
• PFOS decreased estradiol (E2), aromatase (AROM), ERβ, NDRG2, and AMPA receptors (AMPARs) while increasing GFAP and CaMKII.
• In vitro, PFOS disrupted synaptic proteins (SYP, PSD-95, AMPARs) and increased CaMKII, indicating synaptic injury. E2 or ERβ agonist DPN reversed these effects.
• Molecular docking showed strong binding between PFOS and ERβ.

Conclusions:

• PFOS impairs cognitive function in female rats by disrupting astrocyte-derived estrogen-ERβ-NDRG2 signaling.
• NDRG2 acts as a downstream effector in PFOS-induced neurotoxicity.
• This study provides mechanistic insights into female susceptibility to PFOS neurotoxicity and highlights ERβ as a potential therapeutic target.