Hepatotoxic effects of bisphenols A, S, and F and their mixtures: An integrative in silico and in vivo study

Abstract

Bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF) are endocrine and reproductive-disrupting chemicals that may induce liver injury. The aim of this study was to compare the toxicity of individual bisphenols and their mixtures using an integrative in silico and in vivo approach. Common genes associated with bisphenols and liver injury were identified using the Comparative Toxicogenomics Database (CTD). Biomarkers selected using the CytoHubba algorithm were determined in female Wistar rats subacutely exposed orally to BPA (0.26 μg/kg bw/day), BPS (0.60 μg/kg bw/day), and BPF (0.68 μg/kg bw/day), individually and in mixtures, at doses calculated based on human exposure. Liver biomarker levels were determined by ELISA. CTD analysis identified 192 common genes, including IL6, TNF, IL1B, MMP9, and MCP1. In vivo results showed significantly increased IL1B levels in the BPF, BPA+BPS, and MIX groups, with IL1B in the MIX group being 1.65-fold higher than in controls (p<0.0001). TNF showed the most pronounced increase in the MIX group (54% higher than controls, p<0.01), with elevated levels in other groups. IL6 showed an opposite pattern, decreasing in the BPA+BPS group and increasing in the MIX group (p<0.05). MMP9 and MCP1 were altered after bisphenol exposure, with the most pronounced effects in the BPF and BPA+BPF groups. These changes indicate disturbances in inflammation and liver remodeling. Integrative analysis demonstrated that bisphenols and their mixtures affect liver injury-related genes/proteins, with stronger effects of mixtures, particularly the ternary mixture, while BPF showed the highest potential among individual bisphenols.