Binding of Bisphenol S to Hemoglobin Exacerbated Hemin Release: New Insight into the Mechanism of Toxicity

Bisphenol S (BPS), a common replacement for bisphenol A (BPA) in packaging and food containers, has posed a threat to human health through dietary consumption. In this study, the effects of BPS binding on the redox states and stabilities of hemeproteins were investigated. Spectroscopy and molecular docking indicated that BPS could cause conformational alterations of hemoglobin (Hb) and the conversion of ferrous Hb to ferric Hb, which subsequently led to increased liberation of free hemin. Next, free hemin significantly caused cell membrane damage, reactive oxygen species formation, lipid peroxidation, and a decline of cell viability in endothelial cells. The selective inhibitors of ferroptosis significantly suppressed hemin-induced toxicity, indicating a hemin-mediated ferroptotic cell death mechanism. Our findings illustrate the binding mechanism of BPS with the hemeprotein as well as the cytotoxicity, which have important implications for the environmental and human health impacts of BPA replacements.