Gestational exposure to nanoplastics disrupts fetal development by promoting the placental aging via ferroptosis of syncytiotrophoblast

• Gestational nanoplastics (NPs) exposure induced intrauterine growth restriction and fetal resorption in mice. • Exposure to NPs during pregnancy caused placental ferroptosis and accelerated placental aging in mice. • NPs induced ferroptosis and senescence in human placental syncytiotrophoblast (STB) cells. • Inhibition of ferroptosis in human placental STB cells alleviated NPs-induced cellular senescence. • Ferrostatin-1 treatment alleviated mice intrauterine growth restriction caused by NPs exposure during pregnancy. Micro(nano)plastics (MNPs), are emerging environmental pollutants that have garnered widespread attention. Epidemiological and animal studies have shown that MNPs exposure during pregnancy is associated with adverse pregnancy outcomes, such as intrauterine growth restriction (IUGR) and miscarriage. However, the underlying mechanisms remain poorly understood. In this study, we found that exposure to a high dose (1 μg·mL −1 ) of 100 nm polystyrene nanoparticles (NPs) from gestational day (GD) 0 to GD17 significantly decreased fetal weight and increased the number of resorptions compared to the control group. Moreover, fetal weight was significantly lower in the high-dose group than in the low-dose (0.1 μg·mL −1 ) group. Meanwhile, ferroptosis and senescence were observed in placentas from mice exposed to high dose of NPs. In vitro experiments using human syncytiotrophoblast (STB) cells differentiated from BeWo cells, we found that NPs caused ferroptosis and senescence in STB cells. Subsequent investigations revealed that the inhibition of the ferroptosis signaling by ferrostain-1 (Fer-1) or deferiprone (DFP) ameliorated senescence induced by NPs in human STB cells. Furthermore, alleviating placental senescence using Fer-1 significantly improves fetal weight loss caused by NPs exposure during pregnancy in mice. Taken together, our results demonstrated that NPs exposure during pregnancy activated the ferroptosis pathway in placental STB, resulting in senescence of STB, which may attribute to the NPs-induced IUGR. This study not only elucidated the mechanistic link between NPs exposure and adverse pregnancy outcomes but also highlighted the necessity for targeted interventions to protect fetal health, underscoring the broader implications for environmental and public health policy.