Peroxisome Proliferator-activated Receptor Gamma (PPARγ) Activation And Metabolism Disturbance Induced By Bisphenol A And Its Replacement Analog Bisphenol S

As one of the highest volume industrial chemicals,bisphenol A（BPA）is primarily used to manufacture consumer products,leading to its widespread and continuous exposure to human beings.Accumulating studies have reported that BPA has endocrine-disrupting effects which is associated with metabolic disorders.Due to the adverse effects associated with BPA exposure,some countries have banned the use of BPA and replaced it with structural analogues such as bisphenol S（BPS）.Recently,BPA and BPS have been proposed as environmental obesogen to disrupt the lipid metabolism through regulating peroxisome proliferator-activated receptor gamma（PPARγ）.However,there is a dearth of information on whether this biological effect can occur in human macrophage,a cell type which closely interacts with adipocytes and hepatocytes to control lipid metabolism.Here,we for the first time investigate the activity of BPA and BPS on PPARγpathway in human macrophages.The results demonstrated that BPA and BPS served as activators of PPARγin human macrophage cell line,and significantly induced the expression of lipid metabolism-related genes,including fatty acid binding protein 4（FABP4）,cluster of differentiation 36（CD36）and nuclear receptor subfamily 1 group H member 3（NR₁H₃）.In PPARγknockout cells,expression of these genes was down-regulated,suggesting that these genes are dependent on PPARγ.The underlying mechanisms were further investigated using an in vivo mouse model,and the results confirmed the induction of PPARγand its respective target genes in mice following exposure to BPA or BPS.Moreover,the observed alteration of PPARγexpression highly correlated with the disturbance of metabolism profiles in liver tissues as detected by¹H Nuclear Magnetic Resonance（NMR）-based metabonomics.Overall,this study provided the first evidence that BPA and BPS,as an activator,regulated PPARγand its target genes in human macrophages,and provided comprehensive information to confirm that BPA and BPS disturb the metabolism through targeting PPARγvia both in vitro assays and in vivo animal models.