Integrated multi-omics analyses reveal potential inflammatory, hepatic, and endocrine risks of the overlooked BPA isomer o,p’-BPA

2,4’-Isopropylidenediphenol ( o,p’ -BPA), a structural isomer and byproduct of bisphenol A (BPA) synthesis, is frequently detected in food and human samples, yet its toxicological effects remain insufficiently characterized. In this study, the toxicological profiles of BPA and o,p’ -BPA were systematically compared in male Sprague-Dawley rats exposed to 50 μg/kg/day for 28 days. Hematological parameters, metabolomic profiles, and gut microbiota composition were integrated to construct a microbiota-metabolite-host interaction framework. Both compounds significantly elevated inflammation-related markers (e.g., white blood cell count) and liver function indicators (e.g., alanine aminotransferase) by 11–42% (ANOVA, p = 0.0018–0.037). Multi-omics analysis revealed that BPA toxicity involved Romboutsia dysbiosis and disruptions in purine metabolism, lipid metabolism, and pantothenate/CoA biosynthesis. In contrast, o,p’ -BPA exposure was associated with changes in both Romboutsia and Escherichia_Shigella populations and with alterations in glutathione metabolism and steroid hormone biosynthesis-related pathways. These findings suggest that o,p’ -BPA may induce a distinct pattern of microbiota and metabolic perturbations compared with BPA, highlighting the importance of considering potential isomer-specific responses in chemical safety evaluations.