In vitro to in vivo extrapolation and high-content imaging for simultaneous characterization of chemically induced liver steatosis and markers of hepatotoxicity.
Hepatotoxicity
High-content imaging
In vitro to in vivo extrapolation
New approach method
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
21
01
2023
accepted:
21
03
2023
medline:
15
5
2023
pubmed:
13
4
2023
entrez:
12
4
2023
Statut:
ppublish
Résumé
Chemically induced steatosis is characterized by lipid accumulation associated with mitochondrial dysfunction, oxidative stress and nucleus distortion. New approach methods integrating in vitro and in silico models are needed to identify chemicals that may induce these cellular events as potential risk factors for steatosis and associated hepatotoxicity. In this study we used high-content imaging for the simultaneous quantification of four cellular markers as sentinels for hepatotoxicity and steatosis in chemically exposed human liver cells in vitro. Furthermore, we evaluated the results with a computational model for the extrapolation of human oral equivalent doses (OED). First, we tested 16 reference chemicals with known capacities to induce cellular alterations in nuclear morphology, lipid accumulation, mitochondrial membrane potential and oxidative stress. Then, using physiologically based pharmacokinetic modeling and reverse dosimetry, OEDs were extrapolated from data of any stimulated individual sentinel response. The extrapolated OEDs were confirmed to be within biologically relevant exposure ranges for the reference chemicals. Next, we tested 14 chemicals found in food, selected from thousands of putative chemicals on the basis of structure-based prediction for nuclear receptor activation. Amongst these, orotic acid had an extrapolated OED overlapping with realistic exposure ranges. Thus, we were able to characterize known steatosis-inducing chemicals as well as data-scarce food-related chemicals, amongst which we confirmed orotic acid to induce hepatotoxicity. This strategy addresses needs of next generation risk assessment and can be used as a first chemical prioritization hazard screening step in a tiered approach to identify chemical risk factors for steatosis and hepatotoxicity-associated events.
Identifiants
pubmed: 37046073
doi: 10.1007/s00204-023-03490-8
pii: 10.1007/s00204-023-03490-8
pmc: PMC10182956
doi:
Substances chimiques
Orotic Acid
61H4T033E5
Lipids
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1701-1721Subventions
Organisme : Bundesamt für Lebensmittelsicherheit und Veterinärwesen
ID : 4.17.01
Informations de copyright
© 2023. The Author(s).
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