Functional Expression of Nicotinic Receptors on iPSC-Derived Astrocytes and Signalling Disturbances by a Panel of Neonicotinoid Pesticides and Their Metabolites.

Overview

1. Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, 78464 Konstanz, Germany; (E.C.)
2. Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria
3. NMI Natural and Medical Sciences Institute, University of Tübingen, 72770 Reutlingen, Germany
4. Center for Alternatives to Animal Testing, Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
5. Center for Alternatives to Animal Testing in Europe (CAAT-Europe), University of Konstanz, 78457 Konstanz, Germany

Abstract

Little is known about how nicotinic signalling in human astrocytes may contribute to the functional neurotoxicity of compounds related to tobacco alkaloids and neonicotinoid pesticides. We generated a single-cell Ca2+-imaging assay in induced pluripotent stem cell (iPSC)-derived astrocytes, and profiled functional expressions of some neurotoxicologically relevant receptors. Responses to pharmacological tool compounds indicated the expression of nicotinic, muscarinic, purinergic, glutamatergic receptors and voltage-gated Na+/Ca2+ channels. Closer investigation of the nicotinic system, e.g., using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective positive allosteric modulator PNU-120596 and alpha7-preferring agonist (AR-R17779) demonstrated that Ca2+ signals elicited by nicotine and neonicotinoids are dominated by alpha7 nAChRs and depend on the downstream activation of L-type Ca2+ channels and tetrodotoxin-sensitive Na+ channels. Crosstalk of nAChR activation/desensitization was not observed for the inflammatory response elicited by TNF or for activation of glutamatergic or purinergic signalling. However, pre-stimulation of nAChR by neonicotinoids significantly blunted the response to the neurotransmitter acetylcholine. Comparative experiments in the human neuronal cultures (LUHMES cells) revealed similar potency ranges and pharmacological fingerprints for several neonicotinoids and their human-relevant metabolites descyanothiacloprid and desnitroimidacloprid. The pesticide metabolites showed a high potency, compared with their respective parent compounds. After this basic system characterization, the hitherto data-poor pesticides cycloxaprid and flupyradifurone were comparatively profiled in astrocytic and neuronal test systems. They showed the typical features of alpha7 nAChR agonists. The disruption of cholinergic signalling in astrocytes suggests that neonicotinoids affect not only neurons in human brains. Therefore, future neurotoxicity screening approaches may need to consider astrocyte toxicity.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• zenodo:20840279 — at Zenodo; found in “Supplementary Materials”

Data Availability Statement

All data presented in manuscript figures are available in Excel files, so that other displays or statistical approaches may be applied to them. These data have been uploaded on Zenodo and can be accessed through the following link https://zenodo.org/records/20840279, accessed on 25 June 2026.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 6 keywords, 10 MeSH terms, 3 funders, 207 references.

Cite

This paper

Cöllen, E., Wolfbeisz, C., Leisner, H., Grillberger, K., Kormann, J., Tanaskov, Y., Dreser, N., Karreman, C., Hartung, T., Ecker, G., Kraushaar, U., & Leist, M. (2026). Functional Expression of Nicotinic Receptors on iPSC-Derived Astrocytes and Signalling Disturbances by a Panel of Neonicotinoid Pesticides and Their Metabolites. International journal of molecular sciences, 27(13), 5902. https://doi.org/10.3390/ijms27135902

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