Derivation of an adverse outcome pathway network for in vitro hepatotoxicity predictive testing

Scriptie/Masterproef: Master's Thesis

Samenvatting

The liver has a central role in the metabolization and degradation of xenobiotics, which makes it
vulnerable to exogenous compounds,such as chemicals. Concern for animal welfare and the European
regulation becoming stringent regarding the use of animals for the purpose of regulatory safety
evaluation of chemicals, necessitate the development of new testing strategies for the identification
of hepatotoxic compounds. Here, adverse outcome pathways (AOPs), which are pragmatic tools used
to portray and organize knowledge regarding the linkage between a molecular initiating event (MIE)
and an adverse outcome (AO), play a pivotal role. However, linear AOPs fail to portray the complexity
of human biology and the possible interaction of toxicological processes. As such, AOP networks,
consisting of two or more AOPs that share at least on key event (KE), can be used to increase the
understanding of the interplay between two or more toxicological processes. In this project, a
qualitative AOP network including 14 AOPs relevant to hepatotoxicity was derived and subsequently
analyzed. Cell injury/death, increased production of reactive oxygen species, mitochondrial
dysfunction and accumulation of fatty acids were identified as the most highly connected and central
KEs based on multiple topological parameters. These KEs may serve as a basis for the development of
test batteriesto be used in animal-free chemical safety assessment. Further focus was put on steatosis
and cholestasis, for which robust AOPs exist. KEs for these adversities were selected and tested in vitro
on human hepatoma HepaRG cells to compare the transcriptomic response to higher biological level
events in time and concentration.
Datum prijs15 jun 2021
Originele taalEnglish
BegeleiderEmma Arnesdotter (Advisor), Mathieu Vinken (Promotor) & Tamara Vanhaecke (Co-promotor)

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