An adverse outcome pathway-based approach to assess steatotic mixture effects of hepatotoxic pesticides in vitro

Dajana Lichtenstein, Claudia Luckert, Jimmy Alarcan, Georges de Sousa, Michail Gioutlakis, Efrosini S. Katsanou, Parthena Konstantinidou, Kyriaki Machera, Emanuela S. Milani, Ad Peijnenburg, Roger Rahmani, Deborah Rijkers, Anastasia Spyropoulou, Marianna Stamou, Geert Stoopen, Shana J. Sturla, Bernd Wollscheid, Nathalie Zucchini-Pascal, Albert Braeuning*, Alfonso Lampen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

Exposure to complex chemical mixtures requires a tiered strategy for efficient mixture risk assessment. As a part of the EuroMix project we developed an adverse outcome pathway (AOP)-based assay toolbox to investigate the combined effects of the liver steatosis-inducing compounds imazalil, thiacloprid, and clothianidin in human HepaRG hepatocarcinoma cells. Compound-specific relative potency factors were determined using a benchmark dose approach. Equipotent mixtures were tested for nuclear receptor activation, gene and protein expression, and triglyceride accumulation, according to the molecular initiating events and key events proposed in the steatosis AOP. All three compounds affected the activity of nuclear receptors, but not key genes/proteins as proposed. Triglyceride accumulation was observed with three different methods. Mixture effects were in agreement with the assumption of dose additivity for all the combinations and endpoints tested. Compound-specific RPFs remained similar over the different endpoints studied downstream the AOP. Therefore, it might be possible to reduce testing to a smaller battery of key tests. The results demonstrate the suitability of our in vitro assay toolbox, integrated within an AOP framework and combined with the RPF approach, for the analysis of steatotic effects of chemical mixtures. However, mRNA results suggest that the steatosis AOP still needs improvement.

Original languageEnglish
Article number111283
JournalFood and Chemical Toxicology
Volume139
DOIs
Publication statusPublished - May 2020

Keywords

  • AOP-Wise testing
  • Liver
  • Pesticide mixtures
  • Relative potency factors
  • Triglyceride accumulation

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  • Projects

    EuroMix: EuroMix

    15/05/1514/05/19

    Project: EU research project

    Cite this

    Lichtenstein, D., Luckert, C., Alarcan, J., de Sousa, G., Gioutlakis, M., Katsanou, E. S., ... Lampen, A. (2020). An adverse outcome pathway-based approach to assess steatotic mixture effects of hepatotoxic pesticides in vitro. Food and Chemical Toxicology, 139, [111283]. https://doi.org/10.1016/j.fct.2020.111283