Bisphenol A disrupts renal metabolism via MAPK-mediated steroid hormone dysregulation identified by transcriptomic and metabolomic analyses

Bisphenol A (BPA) continuously leaches from consumer products and accumulates in the human body, with detectable levels in urine. Emerging evidence suggests potential associations between prolonged BPA exposure and subclinical nephrotoxicity accompanied by metabolic dysregulation, though the gene regulatory mechanisms underlying these associations remain insufficiently characterized. In this study, bioinformatics analyses were employed to systematically reveal the potential transcriptional regulation of chronic renal injury due to BPA exposure. Complementary positron emission tomography/computed tomography (PET/CT) imaging revealed pronounced renal inflammatory responses and localized tissue damage in murine models following 6-week oral BPA administration. Histopathological examination of the kidney revealed exfoliation of renal tubular epithelial cells, with collagen fibers and mucus deposits. Further multi-omics integration (transcriptomic-metabolomic) analysis identified significant perturbations in cortisol biosynthesis, aldosterone regulation, and MAPK signaling cascades induced by BPA exposure. These findings were further validated through molecular docking studies and MAPK inhibitor intervention studies in cellular models. In summary, a critical pathway in BPA-induced renal injury involves the modulation of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression, which is mediated by p38 MAPK. This process impacts cortisol metabolism and aldosterone synthesis, suggesting that the biosynthesis of renal steroid hormones is intricately linked to MAPK regulation in renal injury following BPA exposure. Our findings furnish a theoretical foundation for elucidating the mechanisms underlying BPA-induced nephrotoxicity and contribute a holistic viewpoint to environmental health risk assessments.