Molecular docking analysis of chlorpyrifos at the human α7-nAChR and its potential relationship with neurocytoxicity in SH-SY5Y cells

Abstract

The organophosphate insecticide chlorpyrifos (CPF), an acetylcholinesterase inhibitor, has raised serious concerns about human safety. Apart from inducing synaptic acetylcholine accumulation, CPF could also act at nicotinic acetylcholine receptors, like the α7-isoform (α7-nAChR), which could potentially be harmful to developing brains. Our aims were to use molecular docking to assess the binding interactions between CPF and α7-nAChR through, to test the neurocytotoxic and oxidative effects of very low concentrations of CPF on SH-SY5Y cells, and to hypothesize about the potential mediation of α7-nAChR. Docking analysis showed a significant binding affinity of CPH for the E fragment of the α7-nAChR (ΔGibbs: −5.63 to −6.85 Kcal/mol). According to the MTT- and Trypan Blue-based viability assays, commercial CPF showed concentration- and time-dependent neurotoxic effects at a concentration range (2.5–20 µM), ten-folds lower than those reported to have crucial effects for sheer CPF. A rise of the production of radical oxygen species (ROS) was seen at even lower concentrations (1–2.5 µM) of CPF after 24h. Notably, our docking analysis supports the antagonistic actions of CPF on α7-nAChR that were recently published. In conclusion, while α7-nAChR is responsible for neuronal survival and neurodevelopmental processes, its activity may also mediate the neurotoxicity of CPF.

Keywords:

• Acetylcholine
• antagonism
• binding interactions
• cytotoxicity
• MTT test
• neuroblastoma cells
• pesticide
• radical oxygen species
• Trypan blue test

Acknowledgments

We are grateful to the Programa de las Naciones Unidas para el Desarrollo (PENUD) of ECUADOR for the sponsorship of the SENESCYT grant (PIC-18-INE-YACHAY-002).

Disclosure statement

The authors have no competing interests to declare.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Additional information

Funding

This article is dedicated to Jenny Andrade. This work was supported by the Secretaria Nacional, Ciencia, Tecnología e Innovación (SENESCYT) of the Ecuadorian Government (Ref. PIC-18-INE-YACHAY-002) to Santiago Ballaz and Lenin Ramirez-Cando.