Integrated metabolomic and histopathological analysis reveals mitochondrial-driven renal metabolic reprogramming in vivo in mice following chronic bisphenol A exposure

Bisphenol A (BPA) is a widely used industrial chemical and endocrine-disrupting compound associated with metabolic and toxic effects in multiple organs. Although BPA-induced transcriptional alterations in renal tissue have been previously reported, the extent to which these changes translate into functional metabolic remodeling remains incompletely understood. This study aimed to characterize metabolomic alterations in mouse kidney following chronic exposure to BPA at the lowest observed adverse effect level (LOAEL) and to integrate these findings with histopathological observations and previously reported transcriptomic changes.Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was performed on kidney samples obtained from BPA-exposed (50 mg/kg body weight/day, LOAEL, for 3 months; n = 8) and control (n = 6) mice. Differentially abundant metabolites were identified and subjected to pathway enrichment analysis using KEGG annotations. Histopathological examination of renal tissue was conducted using hematoxylin and eosin staining. BPA exposure induced pronounced metabolic remodeling in the kidney, with significant alterations in lipid metabolism, mitochondrial fatty acid oxidation, steroid hormone metabolism, and xenobiotic detoxification pathways. Several omega-3 polyunsaturated fatty acids, including alpha-linolenic acid, eicosapentaenoic acid, and 18-HEPE, were markedly decreased, whereas long-chain fatty acids such as adrenic acid and docosapentaenoic acid were increased, indicating disrupted fatty acid homeostasis. Alterations in lysophospholipid species suggested substantial remodeling of membrane phospholipid composition. Decreased levels of multiple acylcarnitines indicated impaired mitochondrial β-oxidation and energy metabolism. Steroid hormone metabolism was also significantly affected, with reduced levels of pregnenolone and 20α-dihydroprogesterone. In addition, increased levels of sulfated and glucuronidated metabolites suggested activation of phase II detoxification pathways. Histopathological analysis revealed structural renal damage, including necrosis of tubular epithelial cells, mitochondrial swelling, endoplasmic reticulum alterations, and glomerular structural disorganization. Chronic BPA exposure at a LOAEL dose induces coordinated metabolic and structural remodeling in mouse kidney characterized by lipid metabolic disruption, mitochondrial dysfunction, steroidogenic imbalance, and activation of detoxification pathways. Integration of metabolomic and histopathological findings provides comprehensive evidence that BPA exposure promotes renal metabolic dysregulation and tissue injury, highlighting potential mechanisms underlying BPA-associated nephrotoxicity. These findings provide mechanistic evidence linking BPA exposure to mitochondrial dysfunction–driven renal metabolic reprogramming.