In vitro to in vivo extrapolation and high-content imaging for simultaneous characterization of chemically induced liver steatosis and markers of hepatotoxicity.

Autor: Müller FA; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland., Stamou M; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland., Englert FH; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland., Frenzel O; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland., Diedrich S; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland., Suter-Dick L; School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, 4132, Muttenz, Switzerland.; Swiss Centre for Applied Human Toxicology (SCAHT), 4001, Basel, Switzerland., Wambaugh JF; Center for Computational Toxicology and Exposure, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, Durham, NC, 27711, USA., Sturla SJ; Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland. sturlas@ethz.ch.
Jazyk: angličtina
Zdroj: Archives of toxicology [Arch Toxicol] 2023 Jun; Vol. 97 (6), pp. 1701-1721. Date of Electronic Publication: 2023 Apr 12.
DOI: 10.1007/s00204-023-03490-8
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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