In vitro to in vivo extrapolation and high-content imaging for simultaneous characterization of chemically induced liver steatosis and markers of hepatotoxicity
Author (Corporation)
Publication date
12.04.2023
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Type
01A - Journal article
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Parent work
Archives of Toxicology
Special issue
DOI of the original publication
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Series
Series number
Volume
97
Issue / Number
6
Pages / Duration
1701–1721
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Publisher / Publishing institution
Springer
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Abstract
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.
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Subject (DDC)
500 - Naturwissenschaften und Mathematik
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ISBN
ISSN
0340-5761
1432-0738
1432-0738
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
Open access category
Hybrid
License
Citation
MÜLLER, Fabrice A., Marianna STAMOU, Felix H. ENGLERT, Ole FRENZEL, Sabine DIEDRICH, Laura SUTER-DICK, John F. WAMBAUGH und Shana J. STURLA, 2023. In vitro to in vivo extrapolation and high-content imaging for simultaneous characterization of chemically induced liver steatosis and markers of hepatotoxicity. Archives of Toxicology. 12 April 2023. Bd. 97, Nr. 6, S. 1701–1721. DOI 10.1007/s00204-023-03490-8. Verfügbar unter: https://doi.org/10.26041/fhnw-5271