Transcriptomic- and metabolomic-based elucidation of macrophage inflammatory response in gestational bisphenol A (BPA)-induced cholesterol metabolic reprogramming.

Accumulating evidence reveals that bisphenol A (BPA) exposure triggered maternal lipid metabolism disorders and pregnancy complications, but the molecular regulatory networks driving metabolic reprogramming remain to be fully elucidated. This study employed an integrated multi-omics approach based on BPA-exposed animal and cell models to systematically explore the molecular mechanisms underlying gestational BPA-induced metabolic dysfunction and macrophage inflammatory activation. Untargeted metabolomics revealed elevated cholesterol abundance in gestational BPA-exposed mice, indicating that gestational BPA exposure induced synergistic abnormalities in aromatic amino acid and lipid metabolism. The molecular regulatory mechanisms of BPA toxicity during pregnancy were investigated via transcriptomic analysis. Interestingly, the multifunctional lipid receptor CD36 has been regarded as the sole key gene at the intersection of macrophage inflammation and cholesterol metabolism. Gestational BPA-induced downregulation of CD36 impairs tissue repair and disrupts anti-inflammatory negative feedback loops in macrophages. Conclusion Gestational BPA exposure induces chronic inflammation accompanied by CD36 downregulation and abnormal cholesterol metabolism, revealing an inflammation-metabolic disorder axis in macrophage reprogramming. This study provides evidence for the role of BPA in the pathogenesis of cholesterol metabolic reprogramming, and illustrates the advantages of integrative analysis for investigating the mechanisms of pregnancy complications triggered by gestational BPA exposure.