Assessing the Nicotinic Acetylcholine Receptor-Mediated Enantioselective Neurotoxicity of a Neonicotinoid-Like Pollutant, Chiral Sulfoxaflor: Insight from the Two Asymmetric Centers

Abstract

Sulfoxaflor with two asymmetric centers is existed in environmental matrices, but the health hazards of human exposure to the neonicotinoid-like pollutant remain vague. This assay investigated the nicotinic acetylcholine receptor (nAChR)-mediated neurotoxicity of sulfoxaflor at the enantiomeric level, and anatomized the mechanistic reasons why the two chiral centers have different significance. The findings showed that the asymmetric center can affect the spatial orientation of cyano group, triggering the toxic response of neuronal nAChR to chiral sulfoxaflor to display strong enantioselectivity. When sulfur atom is in the S configuration, the neurotoxic affinity of human α7 nAChR with (R,S)-sulfoxaflor and (S,S)-sulfoxaflor is greater than that with (R,R)-sulfoxaflor and (S,R)-sulfoxaflor. Meanwhile, (R,S)-sulfoxaflor and (S,S)-sulfoxaflor could induce important residues in loop regions to shift toward the binding position, and this disturbs the intrinsic conformational flexibility of human α7 nAChR, prompting (R,S)-sulfoxaflor and (S,S)-sulfoxaflor to exhibit larger activated efficacy. Further, chirality at sulfur atom is the key element that drives the electrostatic contribution (ΔGele) to be different, provoking chiral sulfoxaflor to pose a higher enantioselective neurotoxicity risk to human health. Clearly, this study may cast new light on assessing the health threats of exposure of humans to pollutants with multiple chiral centers such as sulfoxaflor.

Keywords: Chiral organic pollutant, Sulfoxaflor, Enantioselective neurotoxicity, Nicotinic acetylcholine receptor, Neurotoxic effect