Subchronic Exposure to Polystyrene Nanoplastics Disrupts Placental Development and Calcium Homeostasis: Insights from <i>In Vivo</i> and <i>In Vitro</i> Models

Nanoplastics have recently emerged as persistent pollutants of global concern that pose substantial risks to human health. However, the long-term adverse effects of nanoplastics on the female reproductive system remain unclear. Polystyrene nanoplastics (PS-NPs; 50 nm diameter) were selected as representative nanosized plastic particles to investigate the potential effects of subchronic prenatal and gestational exposure <i>via</i> drinking water on placental development in ICR (CD-1) mice. Maternal exposure to 10 mg/L PS-NPs induced an increase in fetal resorption rate and significantly increased fetal weight. Further observation of the placental morphology showed that PS-NPs exposure led to an aberrant placental structure and damaged the trophoblast cells. At the cellular level, PS-NPs exposure promoted the proliferation, migration, and invasion of HTR-8/SVneo cells. Mechanistically, transcriptomic and proteomic analyses revealed that PS-NPs triggered placental calcium disturbances and upregulated the Stam2 expression in mice. STAM2 induced by PS-NPs mediates the disruption of trophoblastic calcium homeostasis and regulates cell functions by disturbing the lysosomal degradation of the calcium channel protein IP3R3 and promoting intracellular calcium inflow by increasing the level of TRPV6 in HTR-8/SVneo cells. Therefore, our results indicated that trophoblastic calcium dyshomeostasis is the main mechanism by which subchronic PS-NPs exposure induces abnormal placental development. These findings reveal a link between subchronic PS-NPs exposure and placental damage and elucidate the underlying molecular mechanism, providing evidence for environmental triggers of adverse pregnancy and highlighting the risk of plastic products to pregnant women.