Peroxisome proliferator-activated receptor gamma (PPARγ) activation and metabolism disturbance induced by bisphenol A and its replacement analog bisphenol S using in vitro macrophages and in vivo mouse models

Bisphenol A (BPA) and its replacement analog, bisphenol S (BPS), have been proposed as environmental obesogen to disrupt the lipid metabolism through regulating peroxisome proliferator-activated receptor gamma (PPAR gamma) receptor. 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 PPAR gamma pathway in human macrophages. The results demonstrated that BPA and BPS served as activators of PPAR gamma in 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 PPAR gamma knockout cells, expression of these genes was down-regulated, suggesting that these genes are dependent on PPAR gamma. The underlying mechanisms were further investigated using an in vivo mouse model, and the results confirmed the induction of PPAR gamma and its respective target genes in mice following exposure to BPA or BPS. Moreover, the observed alteration of PPAR gamma expression highly correlated with the disturbance of metabolism profiles in liver tissues as detected by H-1 Nuclear Magnetic Resonance (NMR)-based metabonomics. Overall, this study provided the first evidence that BPA and BPS activated PPAR gamma and its target genes in human macrophages, and provided comprehensive information to confirm that BPA and BPS disturb the metabolism through targeting PPAR gamma via both in vitro assays and in vivo animal models.