Cited by 128Pluripotent Stem Cells ResearchAnimal testing and alternativesImmunotoxicology and immune responses

Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes

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Pei, Ying, Peng, Jun, Behl, Mamta, Sipes, Nisha S., Shockley, Keith R., Rao, Mahendra S., Tice, Raymond R., Zeng, Xianmin·2016·Brain Research

Abstract

Induced pluripotent stem cells (iPSC) and their differentiated derivatives offer a unique source of human primary cells for toxicity screens. Here, we report on the comparative cytotoxicity of 80 compounds (neurotoxicants, developmental neurotoxicants, and environmental compounds) in iPSC as well as isogenic iPSC-derived neural stem cells (NSC), neurons, and astrocytes. All compounds were tested over a 24-h period at 10 and 100 μM, in duplicate, with cytotoxicity measured using the MTT assay. Of the 80 compounds tested, 50 induced significant cytotoxicity in at least one cell type; per cell type, 32, 38, 46, and 41 induced significant cytotoxicity in iPSC, NSC, neurons, and astrocytes, respectively. Four compounds (valinomycin, 3,3',5,5'-tetrabromobisphenol, deltamethrin, and triphenyl phosphate) were cytotoxic in all four cell types. Retesting these compounds at 1, 10, and 100 μM using the same exposure protocol yielded consistent results as compared with the primary screen. Using rotenone, we extended the testing to seven additional iPSC lines of both genders; no substantial difference in the extent of cytotoxicity was detected among the cell lines. Finally, the cytotoxicity assay was simplified by measuring luciferase activity using lineage-specific luciferase reporter iPSC lines which were generated from the parental iPSC line. This article is part of a Special Issue entitled SI: PSC and the brain.

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Crossref · 10.1016/j.brainres.2015.07.048

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  • An acute inflammatory response might be triggered, activating microglia to produce cytokines and free radicals that could further harm neural cells.

    “Additionally, an acute inflammatory response might be triggered, activating microglia, the resident immune cells in the brain, to produce cytokines and free radicals that could further harm neural cells (Pei et al., 2016).”

    From Comparative analysis of energy transfer mechanisms for neural implants (2024) · cites this paper as Pei et al., 2016

    The Introduction discusses susceptibility to environmental influences, and the Results report cytotoxicity in iPSC-derived neural cells, but neither addresses an acute inflammatory response. Searches of our copy for microglia, cytokines, and inflammation found no passage describing microglial activation or release of cytokines and free radicals. (LLM, conf=0.76)

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  1. Wood PL Alexander RS Felty CC 2014 Disulfiram Neurotoxicity: Decrements in Ethanolamine, Serine, and Inositol Glycerophospholipids Journal of Molecular Pathophysiology 3 33 37

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Authors
Pei, Y., Peng, J., Behl, M., Sipes, N. S., Shockley, K. R., Rao, M. S., Tice, R. R., & Zeng, X.
Affiliations
  • XCell Science (United States) (US)
  • Buck Institute for Research on Aging (US)
  • National Institutes of Health (US)
Corresponding author
Zeng, Xianmin
Venue
Brain Research
Publisher
Elsevier BV
Published
2016-05
Volume
1638
Issue
Pt A
Pages
57-73
ISSN
0006-8993 (ISSN-L)
OpenAlex
W1055875683
Cited by
128
References
131
Citations by year
2026: 6 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 8 · 2021: 14 · 2020: 14 · 2019: 12 · 2018: 21 · 2017: 13 · 2016: 11 · 2015: 3 · 2014: 1
FWCI
6.95
Type
journal article
Language
en
Open access
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIEHS (1R43ES023522-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
neurotoxicity screening, induced pluripotent stem cells, iPSC-derived neurons, iPSC-derived astrocytes, cytotoxicity, environmental chemicals, valinomycin, deltamethrin, triphenyl phosphate, rotenone, sex differences, MTT assay
MeSH terms
Astrocytes, Cell Differentiation, Cell Line, Cells, Cultured, Drug Evaluation, Preclinical, Humans, Neurons, Neurotoxicity Syndromes, Induced Pluripotent Stem Cells, Neural Stem Cells

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