Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach.
AOP-wise testing
Hepatotoxicity
Mixtures
Relative potency factors
Steatosis
Triglyceride accumulation
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
26
07
2021
accepted:
21
10
2021
pubmed:
16
11
2021
medline:
5
4
2022
entrez:
15
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34778935
doi: 10.1007/s00204-021-03182-1
pii: 10.1007/s00204-021-03182-1
pmc: PMC8748329
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
211-229Subventions
Organisme : h2020 food
ID : 633172
Informations de copyright
© 2021. The Author(s).
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