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Perfluoroalkyl substance pollutants disrupt microglia function and trigger transcriptional and epigenomic changes
Yating Cheng1, Jian-Rong Li2, Hangjin Yu1
1Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Neurosurgery, Houston Methodist Neurological Institute, Houston, TX 77030, USA.
Toxicology
|May 26, 2025
Summary
Per- and polyfluoroalkyl substances (PFAS) disrupt brain immune cells called microglia, mimicking aging and potentially worsening neurodegenerative diseases. These "forever chemicals" cause lasting epigenetic changes in the brain.
Area of Science:
- Neuroscience
- Toxicology
- Epigenetics
Background:
- Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants linked to various health issues.
- Exposure to PFAS, including perfluorooctane sulfonate (PFOS), is associated with neurodevelopmental and neurodegenerative disorders.
- The molecular mechanisms of PFAS neurotoxicity, particularly in the central nervous system (CNS), are not well understood.
Purpose of the Study:
- To investigate the transcriptomic and epigenetic effects of PFOS exposure on microglia.
- To elucidate the molecular pathways through which PFOS impacts microglial function and homeostasis.
- To determine if PFOS-induced changes in microglia are persistent.
Main Methods:
- Exposure of primary microglia to PFOS (25 and 50 µM) for 24 hours.
- Transcriptomic analysis to assess gene expression changes.
- Chromatin profiling (H3K27ac) to identify alterations in active regulatory regions.
- Bioinformatic analysis including comparative transcriptomics and transcription factor analysis.
Main Results:
- PFOS exposure significantly altered the microglial transcriptome, increasing inflammation and impairing actin cytoskeleton remodeling.
- Gene expression profiles of PFOS-exposed microglia resembled those of aged microglia.
- PFOS induced widespread changes in H3K27ac landscape, with some alterations persisting after chemical withdrawal, indicating lasting epigenetic modifications.
- Transcription factor families AP-1 and TEAD were identified as potential regulators of these changes.
Conclusions:
- PFOS exposure disrupts microglial homeostasis and function through transcriptomic and persistent epigenetic alterations.
- PFOS-induced changes in microglia resemble aging-related profiles, suggesting a role in exacerbating neurodegeneration.
- This study provides mechanistic insights into PFOS neurotoxicity, highlighting the need for further investigation into its long-term CNS effects.
