SAT006 Activation Of The CAR/RXR Heterodimer By Pesticides And Induced Metabolic Effects

Abstract

Abstract Disclosure: Y. Dauwe: None. L. Lakhal: None. The nuclear receptor Constitutive Androstane Receptor (CAR or NR1I3) was initially reported as a transcription factor regulating the hepatic genes involved in detoxication function. Thereby CAR protects against xenobiotics but also endogenous molecules such as biliary acid, bilirubin, thyroids and steroids hormones. Different studies showed that CAR activation results in metabolic disorders including Non-Alcoholic Fatty Liver Disease (NAFLD) by promoting lipogenesis in the liver. Environmental contaminants referred to as endocrine disrupting chemicals are suspected to be involved in the increased incidence of metabolic disorders through the activation of nuclear receptors such as CAR and PXR. Previous in vitro studies have shown that the synergistic activation of the Pregnane X Receptor (PXR) by two PXR ligands is potentiated in presence of a Retinoid X Receptor (RXR) environmental ligand, tributyltin (TBT). The objective of our study was to determine whether the synergic activation of PXR/RXR observed in vitro could be transposed in vivo with environmental chemicals on the PXR/RXR and CAR/RXR heterodimers. But also, to asses if this activation could exacerbate the metabolic effects. In that aim, binary mixtures of six, CAR and PXR ligands, pesticides and TBT were first orally administrated to C57BL/6 mice for 3 days, each close to the minimal dose able to activate CAR which was determined in a previous dose response study. A synergistic activation of the CAR/RXR heterodimer by pesticides in combination with TBT was observed on the expression of prototypical CAR target gene Cyp2b10 and on genes involved in lipid metabolism. Combined effects where observed on lipid accumulation in the liver. A synergic elevation of plasma cholesterol was observed and decreased free fatty acid levels were also evidenced for some pesticides in combination with TBT. Two mixtures of five pesticides ligand of CAR and PXR with or without TBT, each at the No Observed Adverse Effect Level (NOAEL), were then administered for 120 days to determine if these threshold safe doses are underestimated in the context of human chronic exposure to a mixture of endocrine disrupting chemicals. The experiment was performed with wild type, CAR null and PXR null mice to check the involvement of nuclear receptors in the measured effects. We observed an activation of CAR by the pesticide cocktail alone or in combination with TBT. The cocktail effect is now tested on the expression of genes involved in lipid metabolism, circulating plasma lipids, lipid accumulation in the liver as well as inflammation and fibrosis. Our first results show an increased transcription of lipogenic genes but no significant effects on lipid plasma levels. Considering these cooperative effects of pesticides may help refine risk assessment, which could lead to a better prevention policy. Presentation: Saturday, June 17, 2023