High-throughput assessment of metabolism-mediated neurotoxicity by combining 3D-cultured neural stem cells and liver cell spheroids
Despite the fact that biotransformation in the liver plays an important role in the augmented toxicity and detoxification of chemicals, relatively little efforts have been made to incorporate biotransformation into in vitro neurotoxicity testing. Conventional in vitro systems for neurotoxicity tests...
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| Published in: | Toxicology in vitro Vol. 93; p. 105688 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Elsevier Ltd
01-12-2023
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Despite the fact that biotransformation in the liver plays an important role in the augmented toxicity and detoxification of chemicals, relatively little efforts have been made to incorporate biotransformation into in vitro neurotoxicity testing. Conventional in vitro systems for neurotoxicity tests lack the capability of investigating the qualitative and quantitative differences between parent chemicals and their metabolites in the human body. Therefore, there is a need for an in vitro toxicity screening system that can incorporate hepatic biotransformation of chemicals and predict the susceptibility of their metabolites to induce neurotoxicity. To address this need, we adopted 3D cultures of metabolically competent HepaRG cell line with ReNcell VM and established a high-throughput, metabolism-mediated neurotoxicity testing system. Briefly, spheroids of HepaRG cells were generated in an ultralow attachment (ULA) 384-well plate while 3D-cultured ReNcell VM was established on a 384-pillar plate with sidewalls and slits (384PillarPlate). Metabolically sensitive test compounds were added in the ULA 384-well plate with HepaRG spheroids and coupled with 3D-cultured ReNcell VM on the 384PillarPlate, which allowed us to generate metabolites in situ by HepaRG cells and test them against neural stem cells. We envision that this approach could be potentially adopted in pharmaceutical and chemical industries when high-throughput screening (HTS) is necessary to assess neurotoxicity of compounds and their metabolites.
•Metabolism-mediated neurotoxicity has been assessed by combining 3D-cultured neural stem cells and liver cell spheroids.•Neural stem cells in 3D have been established with ReNcell VM in the mixture of alginate and Geltrex on a 384PillarPlate.•Metabolically active HepaRG cell spheroids have been cultured in the ULA 384-well plate to generate drug metabolites in situ.•Our system could incorporate hepatic biotransformation of compounds to predict metabolite-induced neurotoxicity. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0887-2333 1879-3177 1879-3177 |
| DOI: | 10.1016/j.tiv.2023.105688 |