Arsenic induces ferroptosis in HTR-8/SVneo cells and placental damage.

Placenta ferroptosis has been proven to be associated with a variety of adverse pregnancy outcomes. Arsenic, a conventional metal noxious substance, has garnered considerable attention due to traversing the placental barrier. How arsenic induces placental ferroptosis and reproductive developmental toxicities remains largely unknown. Herein, we investigated the impact of sodium arsenite (As (III)) on iron homeostasis in the placenta through both in vivo and in vitro experiments by using HTR-8/SVneo cells and ICR pregnant mice. As (III) up-regulated the expression of genes or proteins associated with iron uptake (TFRC, DMT1), iron storage (FTH, FTL), ferritin autophagy (NCOA4), and heme degradation (HO-1), and induced cell iron overload. Additionally, accumulation of the lipid hydroperoxide malondialdehyde within cells was triggered by As (III) through inhibition of the Nrf2/GPX4 signal pathway, which resulted in cellular ferroptosis. Fer-1 effectively alleviated the suppression of GPX4 induced by As (III), reduced the accumulation of intracellular lipid peroxidation product MDA, and mitigated cellular ferroptosis. As (III) affected the iron homeostasis, as evidenced by the abnormal iron accumulation in the placenta. Placental structural abnormalities and hemorrhage may be the reason for As (III) causing placental injury and subsequent poor pregnancy outcomes. This study provides new insights into understanding the mechanisms by which As (III) produces placental damage and possible fetal developmental toxicity.