Sulfur quantum dots cause ferroptosis in human placental trophoblast and ovarian granulosa cells and induce mouse adverse pregnancy outcomes.

Sulfur quantum dots (SQDs) possess heavy metal-free and unique optical properties and have been widely applied in various fields. SQDs unavoidably enter human body from environments. However, their transportation and accumulation in organs and potential toxicity are completely unknown. Using a mouse model, we find that SQDs by oral gavage could pass and transport from gastrointestinal tract to bloodstream, then to placenta and ovaries, and finally to fetus. Oral gavage of ≥ 20 mg/kg/d SQDs disrupts the structure and functions of mouse placenta and ovaries, and induces mouse miscarriage and suppresses fetal growth and development. Furthermore, a comprehensive study shows that exposure to SQDs causes ferroptosis at mouse, human cellular, and molecular levels and also at the levels of proteins and metabolites. In mouse models, oral gavage of ≥ 20 mg/kg/d SQDs causes ferroptosis in both placental and ovarian tissues. In human cell models, exposure to ≥ 25 μg/mL SQDs also causes ferroptosis in placental trophoblast Swan 71 cells and ovarian granulosa KGN cells. Co-treatment with ferroptosis inhibitor (Fer-1) alleviates ferroptosis in SQDs-exposed cells and also suppresses placental and ovarian ferroptosis and reduces miscarriage in SQDs-exposed mice. Moreover, SQDs exposure down-regulates GPX4 protein levels (a key suppressor of ferroptosis) by suppressing its mRNA level and promoting its protein ubiquitination degradation in both cells. At molecular levels, SQDs can also directly interact with free Fe2+ ions, which also contributed to ferroptosis. All these studies give a consistent conclusion that exposure to higher doses of SQDs cause ferroptosis to induce adverse pregnant outcomes. Collectively, this study identify that SQDs is a new risk factor for female reproductive health, which deserves high attention by governments, businesses, and hospitals.