Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro.
3D neurosphere assay
Adverse outcome pathways
Chinese herbal medicines
Developmental neurotoxicity
Human neural progenitor cells in vitro
New approach methodologies
Journal
Cell biology and toxicology
ISSN: 1573-6822
Titre abrégé: Cell Biol Toxicol
Pays: Switzerland
ID NLM: 8506639
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
23
07
2021
accepted:
10
05
2022
medline:
29
3
2023
pubmed:
15
6
2022
entrez:
14
6
2022
Statut:
ppublish
Résumé
Adverse outcome pathways (AOPs) are organized sequences of key events (KEs) that are triggered by a xenobiotic-induced molecular initiating event (MIE) and summit in an adverse outcome (AO) relevant to human or ecological health. The AOP framework causally connects toxicological mechanistic information with apical endpoints for application in regulatory sciences. AOPs are very useful to link endophenotypic, cellular endpoints in vitro to adverse health effects in vivo. In the field of in vitro developmental neurotoxicity (DNT), such cellular endpoints can be assessed using the human "Neurosphere Assay," which depicts different endophenotypes for a broad variety of neurodevelopmental KEs. Combining this model with large-scale transcriptomics, we evaluated DNT hazards of two selected Chinese herbal medicines (CHMs) Lei Gong Teng (LGT) and Tian Ma (TM), and provided further insight into their modes-of-action (MoA). LGT disrupted hNPC migration eliciting an exceptional migration endophenotype. Time-lapse microscopy and intervention studies indicated that LGT disturbs laminin-dependent cell adhesion. TM impaired oligodendrocyte differentiation in human but not rat NPCs and activated a gene expression network related to oxidative stress. The LGT results supported a previously published AOP on radial glia cell adhesion due to interference with integrin-laminin binding, while the results of TM exposure were incorporated into a novel putative, stressor-based AOP. This study demonstrates that the combination of phenotypic and transcriptomic analyses is a powerful tool to elucidate compounds' MoA and incorporate the results into novel or existing AOPs for a better perception of the DNT hazard in a regulatory context.
Identifiants
pubmed: 35701726
doi: 10.1007/s10565-022-09730-4
pii: 10.1007/s10565-022-09730-4
pmc: PMC10042984
doi:
Substances chimiques
Laminin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
319-343Informations de copyright
© 2022. The Author(s).
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