Co-Exposure to Polystyrene Microplastics and Bisphenol A Contributes to the Formation of Liver Fibrosis in Mice through Inhibition of the BMAL1/E-Cad Signaling Pathway

The food safety risks posed by exposure to polystyrene microplastics (PS-MPs) and bisphenol A (BPA) have become an issue worldwide. However, the toxic effects of PS-MPs and BPA coexposure on the mammalian liver remain elusive. In this study, we found that PS-MPs and BPA coexposure have synergistic toxic effects on AML12 cells and the mouse liver. Histopathological staining revealed excessive accumulation of the extracellular matrix in the coexposure liver. Co-exposure to PS-MPs and BPA downregulated Bmal1 and E-cad both in vitro and in vivo. Additionally, Bmal1^-/- AML12 cells and liver-specific Bmal1^-/- mice exhibited significantly reduced E-cad levels, with no significant reduction under PS-MPs and BPA coexposure. Notably, overexpression of BMAL1 and CLOCK significantly enhanced luciferase activity driven by the E-cad gene intron region (containing an E-box cis-element). These results demonstrated that coexposure to PS-MPs and BPA contributed to the development of liver fibrosis by inhibiting the BMAL1/E-cad signaling pathway.