Fate and PPARγ and STATs-driven effects of the mitochondrial complex I inhibitor tebufenpyrad in liver cells revealed with multi-omics - Archive ouverte HAL Access content directly
Journal Articles Journal of Hazardous Materials Year : 2023

Fate and PPARγ and STATs-driven effects of the mitochondrial complex I inhibitor tebufenpyrad in liver cells revealed with multi-omics

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Abstract

The biological effects of the pesticide and mitochondrial complex I inhibitor tebufenpyrad (TEBU) on liver cells were investigated by combining proteomics and metabolomics. Both cell culture media and cellular lysates were analyzed in dose-response and kinetic experiments on the HepaRG cell line. Responses were compared with those obtained on primary human and rat hepatocytes. A multitude of phase I and II metabolites (>80) mainly common to HepaRG cells and primary hepatocytes and an increase in metabolization enzymes were observed. Synthesis of mitochondrion and oxidative phosphorylation complex constituents, fatty acid oxidation, and cellular uptake of lipids were induced to compensate for complex I inhibition and the decrease in ATP intracellular contents caused by TEBU. Secretion of the 20 S circulating proteasome and overall inhibition of acute inflammation followed by IL-6 secretion in later stages were observed in HepaRG cells. These effects were associated with a decrease in STAT1 and STAT3 transcription factor abundances, but with different kinetics. Based on identified TEBU targets, docking experiments, and nuclear receptor reporter assays, we concluded that liver cell response to TEBU is mediated by its interaction with the PPARγ transcription factor.
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anses-03933720 , version 1 (10-01-2023)

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Thibaut Léger, Patrick Balaguer, Ludovic Le Hégarat, Valérie Fessard. Fate and PPARγ and STATs-driven effects of the mitochondrial complex I inhibitor tebufenpyrad in liver cells revealed with multi-omics. Journal of Hazardous Materials, 2023, 442, pp.130083. ⟨10.1016/j.jhazmat.2022.130083⟩. ⟨anses-03933720⟩
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