Adverse Outcome Pathway-Based Strategies to Mitigate Ag₂Se Quantum Dot-Induced Neurotoxicity

Area of Science:

• Nanomaterial toxicology
• Neuroscience
• Risk assessment

Background:

• Silver selenide quantum dots (Ag2Se QDs) offer excellent optical properties for tumor imaging but their small size poses neurotoxicity risks.
• The adverse outcome pathway (AOP) framework provides a mechanism-based approach for evaluating nanomaterial risks.

Purpose of the Study:

• To construct an AOP for Ag2Se QD-induced neurotoxicity.
• To identify key events and pathways involved in Ag2Se QD neurotoxicity.
• To explore mitigation strategies for Ag2Se QD neurotoxicity.

Main Methods:

• Utilized the AOP framework to map causal relationships from molecular initiation to adverse outcomes.
• Investigated the role of mitochondrial reactive oxygen species (mtROS), NLRP3 inflammasome, and microglia activation.
• Employed molecular docking and biological experiments to assess quercetin's effect.

Main Results:

• Established an AOP detailing Ag2Se QD neurotoxicity, with excess mtROS triggering NLRP3 inflammasome activation as the molecular initiation event.
• Identified neuroinflammation and neuronal damage as key events, leading to altered hippocampal physiology.
• Demonstrated that Nrf2/PINK1-mitophagy pathway activation mitigates neurotoxicity, and quercetin enhances this protective mechanism.

Conclusions:

• The AOP framework is crucial for understanding and managing nanomaterial neurotoxicity.
• Ag2Se QDs can induce neurotoxicity through a defined pathway involving oxidative stress and neuroinflammation.
• Natural compounds like quercetin can mitigate Ag2Se QD-induced neurotoxicity, offering a potential therapeutic strategy.