Bisphenol M Induces Dose-Dependent Hepatic Injury and Fibrotic Remodeling in Female Mice

The safety of bisphenol analogs as alternatives to bisphenol A (BPA) is increasingly concerning. This study investigated the hepatotoxic effects of bisphenol M (BPM), a widely used BPA substitute, in 6-week-old female BALB/c mice exposed to 2.5, 5, and 10 mg/kg/day intraperitoneally for 14 days. Hepatic changes were assessed via histopathology, ultrastructure, biochemistry, and molecular analyses. BPM caused dose-dependent liver damage, including hydropic degeneration, necrosis, apoptosis, sinusoidal dilatation, and fibrotic remodeling. Masson's trichrome staining indicated increased collagen deposition, especially in medium- and high-dose groups. TUNEL assay confirmed elevated hepatocyte apoptosis, and immunohistochemistry showed dose-dependent TGF-β1 upregulation in hepatocytes, portal areas, and inflammatory regions. Transmission electron microscopy identified mitochondria and endoplasmic reticulum as primary targets, showing mitochondrial swelling, cristae disruption, membrane rupture, myelin figure formation, ribosomal loss, and rough ER disorganization. Biochemically, TNF-α and IL-6 increased significantly, while tissue sspartate aminotransferase (AST) and alanine aminotransferase (ALT) remained unchanged. Molecular analysis revealed upregulation of p53, Bax, caspase-3, and cytochrome c, indicating activation of the intrinsic mitochondrial apoptotic pathway. Concurrent Bcl-2 upregulation suggested compensatory anti-apoptotic responses under severe stress. In summary, BPM induces dose-dependent hepatotoxicity associated with mitochondrial, inflammatory, and apoptotic alterations, which may not be reflected by changes in conventional liver enzyme markers, including AST and ALT. These findings raise concerns regarding the safety of BPA alternatives and emphasize the need for careful evaluation of BPM-related health risks.