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

## TL;DR

This study shows how PFOS, a harmful chemical, causes brain cell death and cognitive issues, and suggests possible treatments to reduce its effects.

## Contribution

The study identifies multiple interconnected pathways through which PFOS causes neurodegeneration and evaluates potential therapeutic interventions.

## Key findings

- PFOS exposure increases oxidative stress and reduces NRF2 pathway activity in cholinergic neurons.
- PFOS disrupts PGE2 and NGF/TrkA/P75NTR pathways, leading to cell death in BFCNs.
- T3 treatment partially protects against PFOS-induced neurotoxicity.

## Abstract

Background/Objectives: Perfluorooctane sulfonic acid (PFOS), a persistent industrial chemical, has been associated with impairments in cognition. While several studies have attempted to identify the underlying mechanisms, the precise pathways mediating these cognitive deficits remain incompletely understood. PFOS induces cell death in basal forebrain cholinergic neurons (BFCNs), a population critically involved in maintaining cognitive function, partially through the disruption of thyroid hormone signaling. These neurotoxic effects could be mediated through multiple interconnected pathways, including the generation of oxidative stress, dysregulation of prostaglandin E2 (PGE2) signaling, and disruption of nerve growth factor (NGF) homeostasis, all of which have been independently linked to BFCN degeneration and cognitive dysfunction and reported to be induced after PFOS exposure. Methods: To systematically evaluate PFOS-induced neurodegeneration in BFCNs, we employed the SN56 cholinergic cell line derived from the basal forebrain. Cells were exposed to PFOS across a concentration range (0.1–40 μM) in combination with various pharmacological agents: triiodothyronine (T3; 15 nM), recombinant NGF (20 μM), MF-63 (1 μM), and N-acetylcysteine (1 mM). Results: Our experimental results show that PFOS exposure (both single 1-day and repeated 14-day treatments) triggers oxidative stress through reactive oxygen species accumulation coupled with diminished NRF2 pathway activity. Furthermore, PFOS disrupts both PGE2 signaling and the NGF/TrkA/P75NTR neurotrophic pathways, ultimately leading to BFCN cell death. These neurotoxic effects appear to be partially mitigated through T3 treatment, among other mechanisms. Conclusions: These findings provide valuable mechanistic insights into PFOS-induced BFCN neurodegeneration and the consequent cognitive decline while simultaneously suggesting potential therapeutic strategies to counteract these detrimental effects.