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

Dominik Loser, Maria G. Hinojosa, Jonathan Blum, Jasmin Schaefer, Markus Brüll, Ylva Johansson, Ilinca Suciu, Karin Grillberger, Timm Danker, Clemens Möller, Iain Gardner, Gerhard F. Ecker, Susanne Hougaard Bennekou, Anna Forsby, Udo Kraushaar, Marcel Leist*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

11 Downloads (Pure)

Abstract

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.
Original languageEnglish
JournalArchives of Toxicology
Number of pages27
ISSN0340-5761
DOIs
Publication statusAccepted/In press - 2021

Keywords

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

Fingerprint Dive into the research topics of 'Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons'. Together they form a unique fingerprint.

Cite this