Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nACh receptors relevant for neuronal signaling

Abstract

Several neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, desnitro-imidacloprid (DN-IMI) is of special toxicological interest, as there is evidence (i) for human dietary exposure to this metabolite, (ii) and that DN-IMI is a strong trigger of mammalian nicotinic responses. We set out here to quantify responses of human nAChRs to DN-IMI and an alternative metabolite, IMI-olefin. To evaluate toxicological hazards, these data were then compared to those of IMI and nicotine. Ca2+-imaging experiments on human neurons showed that DN-IMI exhibits an agonistic effect on nAChRs at sub-micromolar concentrations (equipotent with nicotine) while IMI-olefin activated the receptors less potently (in a similar range as IMI). Direct experimental data on the interaction with defined receptor subtypes were obtained by heterologous expression of various human nAChR subtypes in Xenopus laevis oocytes and measurement of the transmembrane currents evoked by exposure to putative ligands. DN-IMI acted on the physiologically important human nAChR subtypes α7, α3β4, and α4β2 (high-sensitivity variant) with similar potency as nicotine. IMI and IMI-olefin were confirmed as nAChR agonists, although with 2–3 orders of magnitude lower potency. Molecular docking studies, using receptor models for the α7 and α4β2 nAChR subtypes supported an activity of DN-IMI similar to that of nicotine. In summary, these data suggest that DN-IMI functionally affects human neurons similar to the well-established neurotoxicant nicotine by triggering α7 and several non-α7 nAChRs.

Detection of Neonicotinoid Insecticides and Their Metabolites in Human Cerebrospinal Fluid

“…Studies done using in vitro models have reported that some metabolites are more potent than the corresponding parent NEO because of their higher affinity to nicotinic nicotinic acetylcholine receptors. 8 A recent study reported that N-dm-ACE concentrations in 93% of CSF samples (13/14) collected from children treated for leukemia and lymphomas were within an order of magnitude ( ) 9 of the concentrations detected in our study. The potential neurotoxic effects of N-dm-ACE to the human CNS should be considered comprehensively.…”

Molecular Physicochemical Properties of Selected Pesticides as Predictive Factors for Oxidative Stress and Apoptosis-Dependent Cell Death in Caco-2 and HepG2 Cells

“…IMD belongs to the neonicotinoid insecticide class, with a chemical structure similar to nicotine it is selective for nicotinic acetylcholine receptor (nAChR), showing higher affinity for insect nAChR than for vertebrate nAChR [ 23 , 24 ]. Although developed to target insects nAChR, adverse effects on vertebrate cell and in vivo animal models were reported, taken together with the fact that high levels of IMD and of its metabolites have been detected in several food products, such as honey, fruits, and vegetables [ 25 ]. IMZ (or enilconazole) is a broad spectrum systemic fungicide that blocks ergosterol biosynthesis by targeting cytochrome P450-dependent sterol 14α-demethylase (Cyp51; EC 1.14.13.70) and blocking the production of C14-demethylation of lanosterol, a precursor of ergosterol, [ 26 ].…”

Low doses of imidacloprid induce neurotoxic effects in adult marsh frogs: GFAP, NfL, and angiostatin as biomarkers

“…This neonicotinoid is known to be an agonist of animal nicotinic acetylcholine receptors (nAChRs). This indicates neurotoxic properties of this insecticide (Loser, et al, 2021).…”