ROS-driven rewiring of Hippo-inflammation-polycomb axis by PFOA in 2D and 3D lung epithelial models

Area of Science:

• Environmental Health
• Toxicology
• Cell Biology

Background:

• Perfluorooctanoic acid (PFOA) is a persistent organic pollutant and PFAS chemical with known systemic toxicity.
• PFOA's effects on lung epithelial integrity, especially at environmentally relevant levels, require further investigation.

Purpose of the Study:

• To investigate the cellular and molecular responses of human alveolar lung epithelial cells (A549) to PFOA exposure.
• To explore PFOA's impact on inflammatory mediators, stress responses, epigenetic modifications, and signaling pathways.

Main Methods:

• A549 cells cultured in 2D and 3D air-liquid interface (ALI) models were exposed to 10-1000nM PFOA.
• Assessed pro-inflammatory mediators (NF-κB, STAT3, TLR4, RAGE, IL-6, IL-8, CCL2, CCL5), stress responses (stress granules, P-bodies), Hippo signaling (YAP/TAZ), and epigenetic markers (H3K27me3, H2AK119Ub).
• Investigated the role of oxidative stress and N-acetylcysteine (NAC) in mediating PFOA effects.

Main Results:

• PFOA exposure induced pro-inflammatory mediator release and translational stress responses.
• PFOA activated Polycomb Repressive Complexes and associated histone marks, indicating epigenetic gene silencing.
• Oxidative stress was identified as the primary driver of epigenetic and Hippo pathway disruptions, mitigated by NAC.
• Epithelial cell migration remained unaffected by acute PFOA exposure.

Conclusions:

• PFOA disrupts redox homeostasis, immune signaling, and epigenetic plasticity in lung epithelial cells.
• Identified key molecular mechanisms and potential biomarkers for PFOA toxicity.
• Findings inform biomonitoring and regulatory frameworks for PFAS chemicals.