Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone
For ethical, economical, and scientific reasons, animal experimentation, used to evaluate the potential neurotoxicity of chemicals before their release in the market, needs to be replaced by new approach methodologies. To illustrate the use of new approach methodologies, the human induced pluripoten...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1248882/full |
| _version_ | 1797691047860502528 |
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| author | Carolina Nunes Carolina Nunes Susana Proença Susana Proença Giovanna Ambrosini Giovanna Ambrosini David Pamies David Pamies Aurélien Thomas Aurélien Thomas Nynke I. Kramer Nynke I. Kramer Marie-Gabrielle Zurich Marie-Gabrielle Zurich |
| author_facet | Carolina Nunes Carolina Nunes Susana Proença Susana Proença Giovanna Ambrosini Giovanna Ambrosini David Pamies David Pamies Aurélien Thomas Aurélien Thomas Nynke I. Kramer Nynke I. Kramer Marie-Gabrielle Zurich Marie-Gabrielle Zurich |
| author_sort | Carolina Nunes |
| collection | DOAJ |
| description | For ethical, economical, and scientific reasons, animal experimentation, used to evaluate the potential neurotoxicity of chemicals before their release in the market, needs to be replaced by new approach methodologies. To illustrate the use of new approach methodologies, the human induced pluripotent stem cell-derived 3D model BrainSpheres was acutely (48 h) or repeatedly (7 days) exposed to amiodarone (0.625–15 µM), a lipophilic antiarrhythmic drug reported to have deleterious effects on the nervous system. Neurotoxicity was assessed using transcriptomics, the immunohistochemistry of cell type-specific markers, and real-time reverse transcription–polymerase chain reaction for various genes involved in the lipid metabolism. By integrating distribution kinetics modeling with neurotoxicity readouts, we show that the observed time- and concentration-dependent increase in the neurotoxic effects of amiodarone is driven by the cellular accumulation of amiodarone after repeated dosing. The development of a compartmental in vitro distribution kinetics model allowed us to predict the change in cell-associated concentrations in BrainSpheres with time and for different exposure scenarios. The results suggest that human cells are intrinsically more sensitive to amiodarone than rodent cells. Amiodarone-induced regulation of lipid metabolism genes was observed in brain cells for the first time. Astrocytes appeared to be the most sensitive human brain cell type in vitro. In conclusion, assessing readouts at different molecular levels after the repeat dosing of human induced pluripotent stem cell-derived BrainSpheres in combination with the compartmental modeling of in vitro kinetics provides a mechanistic means to assess neurotoxicity pathways and refine chemical safety assessment for humans. |
| first_indexed | 2024-03-12T02:08:49Z |
| format | Article |
| id | doaj.art-0fbfdfac356046d09b4a042507af3896 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-12T02:08:49Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-0fbfdfac356046d09b4a042507af38962023-09-06T17:44:14ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-09-011410.3389/fphar.2023.12488821248882Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodaroneCarolina Nunes0Carolina Nunes1Susana Proença2Susana Proença3Giovanna Ambrosini4Giovanna Ambrosini5David Pamies6David Pamies7Aurélien Thomas8Aurélien Thomas9Nynke I. Kramer10Nynke I. Kramer11Marie-Gabrielle Zurich12Marie-Gabrielle Zurich13Department of Biomedical Sciences, University of Lausanne, Lausanne, SwitzerlandSwiss Centre for Applied Human Toxicology (SCAHT), Basel, SwitzerlandInstitute for Risk Assessment Sciences, Utrecht University, Utrecht, NetherlandsToxicology Division, Wageningen University, Wageningen, NetherlandsBioinformatics Competence Center, Ecole Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandBioinformatics Competence Center, University of Lausanne, Lausanne, SwitzerlandDepartment of Biomedical Sciences, University of Lausanne, Lausanne, SwitzerlandSwiss Centre for Applied Human Toxicology (SCAHT), Basel, SwitzerlandUnit of Forensic Toxicology and Chemistry, CURML, Lausanne and Geneva University Hospitals, Geneva, SwitzerlandFaculty Unit of Toxicology, CURML, Faculty of Biology and Medicine, University of Lausanne, Lausanne, SwitzerlandInstitute for Risk Assessment Sciences, Utrecht University, Utrecht, NetherlandsToxicology Division, Wageningen University, Wageningen, NetherlandsDepartment of Biomedical Sciences, University of Lausanne, Lausanne, SwitzerlandSwiss Centre for Applied Human Toxicology (SCAHT), Basel, SwitzerlandFor ethical, economical, and scientific reasons, animal experimentation, used to evaluate the potential neurotoxicity of chemicals before their release in the market, needs to be replaced by new approach methodologies. To illustrate the use of new approach methodologies, the human induced pluripotent stem cell-derived 3D model BrainSpheres was acutely (48 h) or repeatedly (7 days) exposed to amiodarone (0.625–15 µM), a lipophilic antiarrhythmic drug reported to have deleterious effects on the nervous system. Neurotoxicity was assessed using transcriptomics, the immunohistochemistry of cell type-specific markers, and real-time reverse transcription–polymerase chain reaction for various genes involved in the lipid metabolism. By integrating distribution kinetics modeling with neurotoxicity readouts, we show that the observed time- and concentration-dependent increase in the neurotoxic effects of amiodarone is driven by the cellular accumulation of amiodarone after repeated dosing. The development of a compartmental in vitro distribution kinetics model allowed us to predict the change in cell-associated concentrations in BrainSpheres with time and for different exposure scenarios. The results suggest that human cells are intrinsically more sensitive to amiodarone than rodent cells. Amiodarone-induced regulation of lipid metabolism genes was observed in brain cells for the first time. Astrocytes appeared to be the most sensitive human brain cell type in vitro. In conclusion, assessing readouts at different molecular levels after the repeat dosing of human induced pluripotent stem cell-derived BrainSpheres in combination with the compartmental modeling of in vitro kinetics provides a mechanistic means to assess neurotoxicity pathways and refine chemical safety assessment for humans.https://www.frontiersin.org/articles/10.3389/fphar.2023.1248882/fullneurotoxicityin vitro distribution kineticshiPSClipid metabolismspheroidin silico modeling |
| spellingShingle | Carolina Nunes Carolina Nunes Susana Proença Susana Proença Giovanna Ambrosini Giovanna Ambrosini David Pamies David Pamies Aurélien Thomas Aurélien Thomas Nynke I. Kramer Nynke I. Kramer Marie-Gabrielle Zurich Marie-Gabrielle Zurich Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone Frontiers in Pharmacology neurotoxicity in vitro distribution kinetics hiPSC lipid metabolism spheroid in silico modeling |
| title | Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone |
| title_full | Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone |
| title_fullStr | Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone |
| title_full_unstemmed | Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone |
| title_short | Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone |
| title_sort | integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human brainspheres a case study on amiodarone |
| topic | neurotoxicity in vitro distribution kinetics hiPSC lipid metabolism spheroid in silico modeling |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1248882/full |
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