Neurodegeneration, Oxidative Stress, NGF/TrkA/P75NTR, and PGE2 Dysregulation Induced by PFOS Single and Repeated Treatment: Partial Protection by T3 and Other Therapeutic Approaches

Key findings from this study

• The study found that PFOS exposure in basal forebrain cholinergic cells induces reactive oxygen species accumulation paired with reduced NRF2 pathway activity across both single and repeated treatment protocols.
• The researchers demonstrate that PFOS disrupts PGE2 signaling and impairs the NGF/TrkA/P75NTR neurotrophic pathway, with both effects contributing to cholinergic cell death.
• The authors report that triiodothyronine treatment provides partial neuroprotection against PFOS-induced neurotoxicity, suggesting thyroid hormone signaling restoration as a potential therapeutic strategy.

Overview

PFOS (perfluorooctane sulfonic acid), a persistent industrial chemical, induces neurodegeneration in basal forebrain cholinergic neurons (BFCNs) through multiple interconnected mechanisms. The study investigates oxidative stress generation, prostaglandin E2 (PGE2) dysregulation, nerve growth factor (NGF) pathway disruption, and potential therapeutic interventions using the SN56 cholinergic cell line.

Methods and approach

SN56 basal forebrain cholinergic cells were exposed to PFOS across concentrations from 0.1 to 40 μM in single 1-day or repeated 14-day treatment paradigms. Pharmacological agents administered included triiodothyronine (T3; 15 nM), recombinant NGF (20 μM), MF-63 (1 μM), and N-acetylcysteine (1 mM). The researchers assessed reactive oxygen species accumulation, NRF2 pathway activity, PGE2 signaling, NGF/TrkA/P75NTR neurotrophic pathway function, and cell viability outcomes.

Results

PFOS exposure triggered robust oxidative stress marked by reactive oxygen species accumulation alongside diminished NRF2 pathway activity in both acute and chronic treatment conditions. The compound disrupted PGE2 signaling mechanisms and impaired NGF/TrkA/P75NTR neurotrophic pathway function, converging toward BFCN cell death. T3 treatment partially mitigated these neurotoxic effects, suggesting thyroid hormone signaling restoration provides neuroprotective benefits in PFOS-exposed cholinergic neurons.

Implications

These findings elucidate multiple mechanistic pathways through which PFOS induces cholinergic neurodegeneration, addressing a gap in understanding the molecular substrates of PFOS-associated cognitive impairment. The convergence of oxidative stress, prostaglandin dysregulation, and neurotrophic pathway disruption suggests BFCN vulnerability to PFOS involves coordinated dysfunction across distinct cellular systems rather than isolated targets.

The partial neuroprotection afforded by T3 treatment and other pharmacological agents indicates potential therapeutic avenues for mitigating PFOS-induced cognitive decline. However, the incomplete rescue across experimental conditions highlights the complexity of PFOS neurotoxicity and suggests combination approaches or alternative mechanisms warrant further investigation. These mechanistic insights may inform strategies for remediating cognitive dysfunction in populations exposed to persistent fluorinated compounds.

The study reinforces thyroid hormone signaling as a critical node in PFOS-induced neurotoxicity while identifying oxidative stress and neurotrophic pathway dysfunction as additional intervention targets. Future research should evaluate whether these findings translate to in vivo cognitive outcomes and characterize downstream consequences of NGF/TrkA/P75NTR pathway disruption in intact neural circuits relevant to cognition.

Scope and limitations

This summary is based on the study abstract and available metadata. It does not include a full analysis of the complete paper, supplementary materials, or underlying datasets unless explicitly stated. Findings should be interpreted in the context of the original publication.