Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury.

Archives of Toxicology
Eva GijbelsMathieu Vinken

Abstract

Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum...Continue Reading

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Citations

Sep 11, 2020·International Journal of Molecular Sciences·Axelle CooremanMathieu Vinken
Mar 13, 2021·Biomarkers in Medicine·Alanah PietersMathieu Vinken
Apr 6, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Eva GijbelsMathieu Vinken
Jun 3, 2021·International Journal of Molecular Sciences·Andrés TabernillaMathieu Vinken

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Methods Mentioned

BETA
chips
reductase assay
protein folding

Software Mentioned

IPA
Affymetrix Transcriptome Analysis Console
Affymetrix GCOS
Ingenuity Pathway Analysis ( IPA
Ingenuity Pathway Analysis ( IPA )
QIAGEN
Ingenuity Pathway Analysis
GraphPad Prism7
Transcriptome Analysis Console

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