Metformin-Induced Epigenetic Toxicity in Zebrafish: Experimental and Molecular Dynamics Simulation Studies.

ABSTRACT

The increased detection of many prescription drugs in aquatic environments has heightened concerns of their potential ecotoxicological effects. In this study, the effects of metformin (MEF) exposure on tissue accumulation, gene expression, and global DNA methylation (GDM) in zebrafish were investigated. The toxic mechanism of MEF exposure was simulated by molecular dynamics (MD) to reveal any conformational changes to DNA methyltransferase 1 (DNMT1). The results showed MEF accumulation in the gills, gut, and liver of zebrafish after 30 days of exposure, and the bioaccumulation capacity was in the order of gut > liver > gills. After a 30 day recovery period, MEF could still be detected in zebrafish tissues in groups exposed to MEF concentrations ≥ 10 µg/L. Moreover, the liver was the main site of GDM, and the restoration of GDM in the liver was slower than that in the gut and gills during the recovery period. Furthermore, MEF could induce the abnormal expression of CYP3A65, GSTM1, p53, and DNMT1 genes in the liver due to the formation of hydrogen bonds between MEF and the protein residues of those genes. The MD simulation allowed for the mechanistic determination of MEF-induced three-dimensional (3D) conformational changes and changes to the catalytic activity of DNMT1.