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

Autor: Loser D; NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770, Reutlingen, Germany.; In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457, Konstanz, Germany., Grillberger K; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria., Hinojosa MG; Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden., Blum J; In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457, Konstanz, Germany., Haufe Y; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, 80336, Munich, Germany., Danker T; NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770, Reutlingen, Germany., Johansson Y; Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden., Möller C; Life Sciences Faculty, Albstadt-Sigmaringen University, 72488, Sigmaringen, Germany., Nicke A; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, 80336, Munich, Germany., Bennekou SH; Technical University of Denmark, Kongens Lyngby, Denmark., Gardner I; CERTARA UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK., Bauch C; Cyprotex Discovery Ltd, No. 24 Mereside, Alderley Park, Cheshire, SK10 4TG, UK., Walker P; Cyprotex Discovery Ltd, No. 24 Mereside, Alderley Park, Cheshire, SK10 4TG, UK., Forsby A; Department of Biochemistry and Biophysics, Stockholm University, 106 91, Stockholm, Sweden., Ecker GF; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria., Kraushaar U; NMI Natural and Medical Sciences Institute at the University of Tübingen, 72770, Reutlingen, Germany., Leist M; In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457, Konstanz, Germany. marcel.leist@uni-konstanz.de.
Jazyk: angličtina
Zdroj: Archives of toxicology [Arch Toxicol] 2021 Dec; Vol. 95 (12), pp. 3695-3716. Date of Electronic Publication: 2021 Oct 10.
DOI: 10.1007/s00204-021-03168-z
Abstrakt: 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. Ca 2+ -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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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