Integrating biokinetics and in vitro studies to evaluate developmental neurotoxicity induced by chlorpyrifos in human iPSC-derived neural stem cells undergoing differentiation towards neuronal and glial cells.
Biological Assay
Brain-Derived Neurotrophic Factor
/ metabolism
Cell Differentiation
/ drug effects
Cells, Cultured
Chlorpyrifos
/ pharmacokinetics
Coculture Techniques
Cytochrome P-450 Enzyme System
/ genetics
Humans
Induced Pluripotent Stem Cells
/ cytology
Insecticides
/ pharmacokinetics
Neural Stem Cells
/ cytology
Neuroglia
/ cytology
Neurons
/ cytology
Neurotoxicity Syndromes
Biokinetics
Chlorpyrifos
Developmental neurotoxicity
Human iPSC-derived neural stem cells
Repeated exposure
Journal
Reproductive toxicology (Elmsford, N.Y.)
ISSN: 1873-1708
Titre abrégé: Reprod Toxicol
Pays: United States
ID NLM: 8803591
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
06
08
2020
revised:
17
09
2020
accepted:
24
09
2020
pubmed:
5
10
2020
medline:
21
10
2021
entrez:
4
10
2020
Statut:
ppublish
Résumé
For some complex toxicological endpoints, chemical safety assessment has conventionally relied on animal testing. Apart from the ethical issues, also scientific considerations have been raised concerning the traditional approach, highlighting the importance for considering real life exposure scenario. Implementation of flexible testing strategies, integrating multiple sources of information, including in vitro reliable test methods and in vitro biokinetics, would enhance the relevance of the obtained results. Such an approach could be pivotal in the evaluation of developmental neurotoxicity (DNT), especially when applied to human cell-based models, mimicking key neurodevelopmental processes, relevant to human brain development. Here, we integrated the kinetic behaviour with the toxicodynamic alterations of chlorpyrifos (CPF), such as in vitro endpoints specific for DNT evaluation, after repeated exposure during differentiation of human neural stem cells into a mixed culture of neurons and astrocytes. The upregulation of some cytochrome P450 and glutathione S-transferase genes during neuronal differentiation and the formation of the two major CPF metabolites (due to bioactivation and detoxification) supported the metabolic competence of the used in vitro model. The alterations in the number of synapses, neurite outgrowth, brain derived neurotrophic factor, the proportion of neurons and astrocytes, as well as spontaneous electrical activity correlated well with the CPF ability to enter the cells and be bioactivated to CPF-oxon. Overall, our results confirm that combining in vitro biokinetics and assays to evaluate effects on neurodevelopmental endpoints in human cells should be regarded as a key strategy for a quantitative characterization of DNT effects.
Identifiants
pubmed: 33011216
pii: S0890-6238(20)30214-8
doi: 10.1016/j.reprotox.2020.09.010
pmc: PMC7772889
pii:
doi:
Substances chimiques
Brain-Derived Neurotrophic Factor
0
Insecticides
0
BDNF protein, human
7171WSG8A2
Cytochrome P-450 Enzyme System
9035-51-2
Chlorpyrifos
JCS58I644W
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
174-188Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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