Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

Loser, Dominik; Hinojosa, Maria G.; Blum, Jonathan; Schaefer, Jasmin; Brüll, Markus; Johansson, Ylva; Suciu, Ilinca; Grillberger, Karin; Danker, Timm; Leist, Marcel

Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

Dateien

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Datum

2021

Autor:innen

Loser, Dominik

Hinojosa, Maria G.

Blum, Jonathan

Schaefer, Jasmin

Brüll, Markus

Johansson, Ylva

Suciu, Ilinca

Grillberger, Karin

Danker, Timm

Leist, Marcel

et al.

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Archives of toxicology. Springer. 2021, 95(6), pp. 2081-2107. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-021-03031-1

Zusammenfassung

Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human neurons, and thus, affect the human adult or developing nervous system. We used SH-SY5Y neuroblastoma cells as established model of nicotinic acetylcholine receptor (nAChR) signaling. In parallel, we profiled dopaminergic neurons, generated from LUHMES neuronal precursor cells, as novel system to study nAChR activation in human post-mitotic neurons. Changes of the free intracellular Ca²⁺ concentration ([Ca²⁺]_i) were used as readout, and key findings were confirmed by patch clamp recordings. Nicotine triggered typical neuronal signaling responses that were blocked by antagonists, such as tubocurarine and mecamylamine. Pharmacological approaches suggested a functional expression of α7 and non-α7 nAChRs on LUHMES cells. In this novel test system, the neonicotinoids acetamiprid, imidacloprid, clothianidin and thiacloprid, but not thiamethoxam and dinotefuran, triggered [Ca²⁺]_i signaling at 10-100 µM. Strong synergy of the active neonicotinoids (at low micromolar concentrations) with the α7 nAChR-positive allosteric modulator PNU-120596 was observed in LUHMES and SH-SY5Y cells, and specific antagonists fully inhibited such signaling. To provide a third line of evidence for neonicotinoid signaling via nAChR, we studied cross-desensitization: pretreatment of LUHMES and SH-SY5Y cells with active neonicotinoids (at 1-10 µM) blunted the signaling response of nicotine. The pesticides (at 3-30 µM) also blunted the response to the non-α7 agonist ABT 594 in LUHMES cells. These data show that human neuronal cells are functionally affected by low micromolar concentrations of several neonicotinoids. An effect of such signals on nervous system development is a toxicological concern.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

Live-cell calcium imaging, Neurotoxicity, Nicotine, Desensitization, Molecular docking

Zitieren

ISO 690

LOSER, Dominik, Maria G. HINOJOSA, Jonathan BLUM, Jasmin SCHAEFER, Markus BRÜLL, Ylva JOHANSSON, Ilinca SUCIU, Karin GRILLBERGER, Timm DANKER, Marcel LEIST, 2021. Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons. In: Archives of toxicology. Springer. 2021, 95(6), pp. 2081-2107. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-021-03031-1

BibTex

@article{Loser2021-06Funct-53414,
  year={2021},
  doi={10.1007/s00204-021-03031-1},
  title={Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons},
  number={6},
  volume={95},
  issn={0340-5761},
  journal={Archives of toxicology},
  pages={2081--2107},
  author={Loser, Dominik and Hinojosa, Maria G. and Blum, Jonathan and Schaefer, Jasmin and Brüll, Markus and Johansson, Ylva and Suciu, Ilinca and Grillberger, Karin and Danker, Timm and Leist, Marcel}
}

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