ArticleArchives of toxicology2022
Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach.
Article in Archives of toxicology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Mechanism-based new approach methodologies for in vitro detection of chemical-induced liver steatosis.Archives of toxicology · 2026Review
- Relevance of kinetic interactions and co-formulants for plant protection product liver toxicity in vitro.Archives of toxicology · 2025Article
- Adverse Outcome Pathways Mechanistically Describing Hepatotoxicity.Methods in molecular biology (Clifton, N.J.) · 2025Article
- A simple, reliable and easily generalizable cell-based assay for screening potential drugs that inhibit lipid accumulation.Current research in toxicology · 2025Article
- Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways.International journal of molecular sciences · 2024Review
- Wrangling Whole Mixtures Risk Assessment: Recent Advances in Determining Sufficient Similarity.Current opinion in toxicology · 2023Article
- An approach for mixture testing and prioritization based on common kinetic groups.Archives of toxicology · 2022Article
- Article title: Transcriptional profiling efficacy to define biological activity similarity for cosmetic ingredients' safety assessment based on next-generation read-across.Frontiers in toxicology · 2022Article
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Authors and funding
10 authors.
Funding
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.
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