G protein-coupled estrogen receptor activation by bisphenol-A disrupts lipid metabolism and induces ferroptosis in the liver

As a metabolic disruptor, bisphenol A (BPA) has been widely reported to disrupt lipid balance. Moreover, BPA has gained significant attention due to its estrogenic activity. While both ferroptosis and the G-protein-coupled estrogen receptor (GPER) have been implicated in lipid metabolism, their link to BPA-induced lipid accumulation remains unclear. In this study, chickens were randomly assigned to three groups and housed them for 4 weeks: a control group (0 & mu;g/L BPA), a low dose group (50 & mu;g/L BPA) and a high dose group (5000 & mu;g/L BPA) to investigate the underlying mechanism of BPA-induced hepatotoxicity. Our results showed that BPA exposure significantly increased the contents of TG, TC, and LDL-C while decreasing HDL-C levels. We also found that BPA treatment altered the levels of genes involved in fatty acid 13-oxidation (ampk & alpha;, cpt-1, and ppa & alpha;), synthesis (acc, fas, scd-1, and srebp-1) and absorption (lpl and cd36). Moreover, the results showed that the BPA group had higher levels of IL-113, IL-18 and TNF-& alpha;. These results indicated that BPA exposure disrupted lipid metabolism and induced inflammation in the liver. We also demonstrated that BPA caused hepatic ferroptosis by raising iron content and the expression of genes related to lipid peroxidation (lpcat3, acsl4 and alox15), while reducing the expression of antioxidant system-associated genes (gpx4, slc7a11 and slc3a2). Importantly, BPA remarkably activated GPER expression in the liver. Interestingly, inhibition of GPER remarkably ameliorated BPA-induced lipid metabolism disorder, inflammatory response, and ferroptosis, indicating the crucial role of GPER in BPAinduced liver abnormalities. These findings highlight the link between GPER and ferroptosis in BPA-induced hepatotoxicity, providing new insights into the potential hazard of BPA.