Exposure to Bisphenol A induces abnormal fetal heart development by promoting ferroptosis

Background: Bisphenol A (BPA), a common endocrine-disrupting chemical (EDC), has been revealed to be closely associated with the induction of abnormal heart development, obesity, prediabetes, and other metabolic disor-ders. However, the underlying mechanism of maternal BPA exposure on fetal heart development abnormalities is not clear.Methods: To explore the adverse effects of BPA and its potential mechanism on heart development, C57BL/6 J mice and human cardiac AC-16 cells were used to conduct in vivo and in vitro studies. For the in vivo study, mice were exposed to low-dose BPA (40 mg/(kg center dot bw)) and high-dose BPA (120 mg/(kg center dot bw)) for 18 d during preg-nancy. In vitro study, human cardiac AC-16 cells were exposed to BPA of various concentrations (0.01, 0.1, 1, 10, and 100 mu M) for 24 h. Cell viability and ferroptosis were evaluated using 2,5-diphenyl-2 H-tetrazolium bromide (MTT), immunofluorescence staining, and western blotting.Results: In BPA-treated mice, the alterations of fetal cardiac structure were observed. Increased NK2 homeobox 5 (Nkx2.5) was detected in vivo with the induction of ferroptosis, revealing that BPA induced abnormal fetal heart development. Furthermore, the results showed that SLC7A11 and SLC3A2 decreased in low-and high-dose BPA-treated groups, suggesting that system Xc-mediated BPA-induced abnormal fetal heart development via inhib-iting the expression of GPX4. Observing AC-16 cells confirmed that cell viability declined significantly with various concentrations of BPA. Moreover, BPA exposure suppressed GPX4 expression by inhibiting System Xc-(the decrease of SLC3A2 and SLC7A11). Collectively, system Xc-modulating cell ferroptosis might play important in abnormal fetal heart development induced by BPA exposure.