Chlorpyrifos Acts as a Positive Modulator and an Agonist of N-Methyl-d-Aspartate (NMDA) Receptors: A Novel Mechanism of Chlorpyrifos-Induced Neurotoxicity

Sherif, Mahmoud Awad; Carter, Wayne G.; Mellor, Ian R.

Abstract

Chlorpyrifos (CPF) is a broad-spectrum organophosphate insecticide. Long-term exposure to low levels of CPF is associated with neurodevelopmental and neurodegenerative disorders. The mechanisms leading to these effects are still not fully understood. Normal NMDA receptor (NMDAR) function is essential for neuronal development and higher brain functionality, while its inappropriate stimulation results in neurological deficits. Thus, the current study aimed to investigate the role of NMDARs in CPF-induced neurotoxicity. We show that NMDARs mediate CPF-induced excitotoxicity in differentiated human fetal cortical neuronal ReNcell CX stem cells. In addition, by using two-electrode voltage clamp electrophysiology of Xenopus oocytes expressing NMDARs, we show CPF potentiation of both GluN1-1a/GluN2A (EC50 ≈ 40 nM) and GluN1-1a/GluN2B (EC50 ≈ 55 nM) receptors, as well as reductions (approximately halved) in the NMDA EC50s and direct activation by 10 μM CPF of both receptor types. In silico molecular docking validated CPF’s association with NMDARs through relatively high affinity binding (−8.82 kcal/mol) to a modulator site at the GluN1–GluN2A interface of the ligand-binding domains.

Citation

Sherif, M. A., Carter, W. G., & Mellor, I. R. (2025). Chlorpyrifos Acts as a Positive Modulator and an Agonist of N-Methyl-d-Aspartate (NMDA) Receptors: A Novel Mechanism of Chlorpyrifos-Induced Neurotoxicity. Journal of Xenobiotics, 15(1), Article 12. https://doi.org/10.3390/jox15010012

• Journal Article Type: Article
• Acceptance Date: Jan 14, 2025
• Online Publication Date: Jan 16, 2025
• Publication Date: 2025-02
• Deposit Date: Jan 15, 2025
• Publicly Available Date: Jan 17, 2025
• Journal: Journal of Xenobiotics
• Electronic ISSN: 2039-4713
• Publisher: PAGEpress
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 1
• Article Number: 12
• DOI: https://doi.org/10.3390/jox15010012
• Keywords: Chlorpyrifos; organophosphate; neurotoxicity; NMDA receptors; stem cells; Xenopus oo-26 cytes; two-electrode voltage clamp
• Public URL: https://nottingham-repository.worktribe.com/output/44229032
• Publisher URL: https://www.mdpi.com/2039-4713/15/1/12