Synergistic Steatosis Induction in Mice: Exploring the Interactions and Underlying Mechanisms between PFOA and Tributyltin

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 11; p. 940
• Main Authors: Dauwe, Yannick, Mary, Lucile, Oliviero, Fabiana, Dubois, Louise, Rousseau-Bacquie, Elodie, Gomez, Jelskey, Gayrard, Véronique, Mselli-Lakhal, Laïla
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.05.2024; MDPI
• Subjects: Ammonium perfluorooctanoate; Animals; Blood lipids; Caprylates; Caprylates - pharmacology; Cholesterol; Contaminants; Diabetes; Epidemiology; Ethylenediaminetetraacetic acid; Fatty acids; Fatty Liver; Fatty Liver - chemically induced; Fatty Liver - metabolism; Fatty Liver - pathology; Fibrosis; Fluorocarbons; Fluorocarbons - pharmacology; Fluorocarbons - toxicity; Gene expression; Genes; Laboratory animals; Life Sciences; Ligands; Lipid Metabolism; Lipid Metabolism - drug effects; Lipids; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver diseases; Liver X Receptors; Liver X Receptors - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; NAFLD; Non-alcoholic Fatty Liver Disease; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; nuclear receptor; Nuclear receptors; Perfluoroalkyl & polyfluoroalkyl substances; Perfluorooctanoic acid; Peroxisome proliferator-activated receptors; PFAS; Physiological aspects; Pregnane X receptors; Receptors, Cytoplasmic and Nuclear; Receptors, Cytoplasmic and Nuclear - metabolism; Retinoid X Receptors; Retinoid X Receptors - metabolism; Santé publique et épidémiologie; Steatosis; synergism; TBT; Trialkyltin Compounds; Trialkyltin Compounds - pharmacology; Tributylin; Tributyltin; Type 2 diabetes; France; synergism; nuclear receptor; NAFLD; metabolism; PFAS; TBT
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13110940

This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.