NeurotoxicologyJul 26, 2026

How Perfluorooctanoic Acid May Cause Brain Cell Loss and Thinking Problems by Disrupting Cell Energy Management and Blood-Brain Barrier Function

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 27, 2026

Abstract

PFOA exposure is associated with significant oxidative stress and mitochondrial dysfunction in neuronal cells.

Elevated levels of oxidative stress markers were observed in N2a cells after PFOA exposure.
Mitochondrial membrane potential was significantly reduced, indicating compromised mitochondrial function.
PFOA exposure led to disruption of mitochondrial dynamics, with a decrease in fusion proteins and an increase in fission regulators.
Mitophagy was impaired, as evidenced by dysregulation of specific signaling pathways critical for mitochondrial clearance.
Chronic exposure to PFOA in vivo disrupted blood-brain barrier integrity and was linked to increased neuronal apoptosis.
Cognitive deficits were observed alongside histopathological damage in brain tissues following PFOA exposure.

Simplified

Perfluorooctanoic acid (PFOA), a persistent member of the Per- and polyfluoroalkyl substances (PFAS), is widely detected in the environment and human populations and has recently been increasingly associated with neurotoxicity; however, its underlying molecular mechanisms, particularly those involving mitochondrial quality control, remain poorly defined. This study aimed to elucidate the mechanistic basis of PFOA-induced neurotoxicity, focusing on mitochondrial dysfunction, dynamics, and mitophagy, and to determine the downstream effects on neuronal integrity and cognitive function using both in-vitro and in-vivo approaches. In N2a cells, PFOA exposure induced significant oxidative stress, characterized by elevated intracellular and mitochondrial ROS levels and loss of mitochondrial membrane potential (Δψm). These alterations were accompanied by dysregulation of mitochondrial dynamics, evidenced by suppression of fusion proteins (MFN1, MFN2, OPA1) and enhanced activation of fission regulators (DRP1, FIS1). Concurrently, mitophagy was impaired, as indicated by dysregulation of PINK1-Parkin and LC3-p62 signaling, suggesting defective mitochondrial clearance. In-vivo, chronic PFOA exposure disrupted blood-brain barrier integrity, as reflected by increased MMP-9 and reduced tight junction proteins (ZO-1, occludin, claudin-5), and was associated with enhanced neuronal apoptosis, histopathological damage, and cognitive deficits. Collectively, these findings demonstrate that PFOA induces neurotoxicity through mitochondrial dysfunction-driven impairment of mitochondrial dynamics and quality control, leading to neuronal degeneration and neurobehavioral dysfunction.

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Funding

Competing interests

No competing interests reported.

PubMed

How Perfluorooctanoic Acid May Cause Brain Cell Loss and Thinking Problems by Disrupting Cell Energy Management and Blood-Brain Barrier Function

Abstract

Full Text

Funding

Competing interests

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