6-Chloronicotinic Acid Induces Toxicity in Mouse Neural Stem Cells via the C3ar1 Signaling

Area of Science:

• Neuroscience
• Toxicology
• Developmental Biology

Background:

• Neural stem cells (NSCs) are crucial for brain development, with proliferation and differentiation capabilities.
• Neonicotinoid insecticides (NNIs) are widely used, and prenatal exposure is linked to neurodevelopmental disorders.
• 6-chloronicotinic acid (6-ClNA), an NNI metabolite, is a suspected neurotoxin with unexplored effects on NSCs.

Purpose of the Study:

• To investigate the impact of 6-ClNA on NSC proliferation and differentiation.
• To elucidate the molecular mechanisms underlying 6-ClNA's neurotoxicity in NSCs.
• To identify potential therapeutic targets for mitigating NNI-induced neurodevelopmental risks.

Main Methods:

• In vitro exposure of NSCs to 6-ClNA.
• Transcriptomic analysis to identify altered cellular pathways.
• Genetic manipulation (siRNA) to target the C3ar1 pathway.

Main Results:

• 6-ClNA significantly inhibited NSC proliferation and differentiation in vitro.
• Transcriptomics revealed altered pathways involved in proliferation, apoptosis, and inflammation, notably activating the C3ar1/C1qa axis.
• siRNA-mediated C3ar1 ablation restored NSC proliferation and neurosphere formation and reduced apoptosis.

Conclusions:

• 6-ClNA exposure disrupts NSC function, impacting critical developmental processes.
• The C3ar1/C1qa signaling axis is a key mediator of 6-ClNA's neurotoxic effects on NSCs.
• Early-life exposure to NNIs may compromise NSC health and function via the C3ar1 pathway.