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6PPDQ Exposure Exacerbates Seizure-Induced Neuronal Damage via the TP53/Nrf2 Axis: An Integrated Strategy Combining
Ruijin Xie1,2, Wei Xiao2, Hua Xu2
1School of Normal Education, Yangzhou Polytechnic College, Yangzhou 225009, China.
Toxics
|May 27, 2026
Summary
Tire wear contaminant 6PPD-quinone (6PPDQ) directly harms brain cells by disrupting the TP53 and Nrf2 pathways, increasing epilepsy risk. Targeting these pathways may offer neuroprotection against this environmental toxin.
Area of Science:
- Environmental toxicology
- Neuroscience
- Molecular biology
Background:
- 6PPD-quinone (6PPDQ), a tire wear contaminant, poses neurotoxic risks, especially to children.
- The precise molecular mechanisms linking 6PPDQ to neurological disorders like epilepsy are not well understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying 6PPDQ-induced neurotoxicity.
- To identify potential therapeutic targets for mitigating 6PPDQ's harmful effects on the nervous system.
Main Methods:
- Integrative network toxicology
- Analysis of human epileptic brain tissues
- Mendelian randomization
- Molecular dynamics simulations
- CETSA-WB and SPR validation
- Cellular and co-culture models
Main Results:
- 6PPDQ directly binds and stabilizes neuronal TP53.
- A synergistic mechanism involves 6PPDQ activating TP53 and microglial IL-6 release.
- This leads to Nrf2 suppression, glutathione depletion, and increased reactive oxygen species (ROS).
- Targeting the TP53/Nrf2 axis or ROS significantly reduces 6PPDQ neurotoxicity.
Conclusions:
- 6PPDQ poses significant risks to pediatric neurological health.
- The TP53/Nrf2 pathway is a key mediator of 6PPDQ neurotoxicity and a potential therapeutic target.
- Findings support improved risk assessment and regulation of tire-derived contaminants.
