In vitro PPARγ agonistic potential of chitin synthesis inhibitors and their energy metabolism-related hepatotoxicity

Abstract

The extensive use of chitin synthesis inhibitors (CSIs) in integrated pest management programs has a detrimental effect on the surrounding environment. Recent studies reveal that CSIs may affect non-target organisms at sublethal concentrations, highlighting the need for further ecological and health risk investigations of these compounds. In this study, we characterized the peroxisome proliferator-activated receptor γ (PPARγ) agonistic activity of fourteen CSIs in HepG2 cells using an in vitro reporter gene assay. Five of the tested CSIs showed remarkable PPARγ-mediated transactivation, and the relative agonistic potencies were diflubenzuron>chlorfluazuron>flucycloxuron>noviflumuron>flufenoxuron based on REC20 values. In addition, molecular docking indicated that different interactions may stabilize ligand binding to PPARγ. Next, we clarified that sublethal concentration of diflubenzuron caused a shift in cellular energy metabolism from the aerobic tricarboxylic acid (TCA) cycle to anaerobic glycolysis and this process was associated with the activation of PPARγ. These findings suggest that CSIs act as PPARγ agonists and exert diverse hepatotoxic effects by disrupting energy metabolism at sublethal concentrations.