Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-11-15

AUTHORS

Jimmy Alarcan, Georges de Sousa, Efrosini S. Katsanou, Anastasia Spyropoulou, Petros Batakis, Kyriaki Machera, Roger Rahmani, Alfonso Lampen, Albert Braeuning, Dajana Lichtenstein

ABSTRACT

Within the EuroMix project, we have previously developed an adverse outcome pathway (AOP)-based in vitro assay toolbox to investigate the combined effects of liver steatosis-inducing compounds in human HepaRG hepatocarcinoma cells. In this study, we applied the toolbox to further investigate mixture effects of combinations, featuring either similarly acting or dissimilarly acting substances. The valproic acid structural analogs 2-propylheptanoic acid (PHP) and 2-propylhexanoic acid (PHX) were chosen for establishing mixtures of similarly acting substances, while a combination with the pesticidal active substance clothianidin (CTD) was chosen for establishing mixtures of dissimilarly acting compounds. We first determined relative potency factors (RPFs) for each compound based on triglyceride accumulation results. Thereafter, equipotent mixtures were tested for nuclear receptor activation in transfected HepG2 cells, while gene expression and triglyceride accumulation were investigated in HepaRG cells, following the proposed AOP for liver steatosis. Dose addition was observed for all combinations and endpoints tested, indicating the validity of the additivity assumption also in the case of the tested mixtures of dissimilarly acting substances. Gene expression results indicate that the existing steatosis AOP can still be refined with respect to the early key event (KE) of gene expression, in order to reflect the diversity of molecular mechanisms underlying the adverse outcome. More... »

PAGES

211-229

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00204-021-03182-1

DOI

http://dx.doi.org/10.1007/s00204-021-03182-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1142587141

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/34778935


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