Gestational Exposure to Black Phosphorus Nanoparticles Induces Placental Trophoblast Dysfunction by Triggering Reactive Oxygen Species-Regulated Mitophagy.

Abstract

As a type of two-dimensional nanomaterial, black phosphorus (BP) has attracted considerable interest for applications in various fields. Despite its advantages, including biodegradability and biocompatibility, recent studies have shown that BP exhibits cytotoxicity in different types of cells. However, no studies have investigated the effects of BP exposure during pregnancy. Herein, we first investigated the effect of gestational exposure to BP nanoparticles (BPNPs) in a mouse model. Our findings indicated that BPNPs exposure restricted fetal growth and hindered placental development. In HTR8/SVneo trophoblast cells, BPNPs inhibited cell proliferation, migration, and invasion and caused apoptosis in a dose-dependent manner. Furthermore, BPNPs induced intracellular reactive oxygen species (ROS) overproduction and extensive mitochondrial damage. We further demonstrated that BPNPs promoted mitophagy via the PINK1/Parkin signaling pathway. Parkin siRNA knockdown rescued BPNPs-induced trophoblast dysfunction, while ROS inhibition attenuated BPNPs-induced cytotoxicity by reducing mitochondrial damage. Finally, treatment with mdivi-1, a mitophagy inhibitor, mitigated mitochondrial membrane potential reduction, excessive mtROS production, and the resulting trophoblast dysfunction. <i>In vivo</i> model investigation indicated that the application of mdivi-1 ameliorated embryonic resorption and fetal growth by alleviating placental damage. In summary, gestational exposure to BPNPs impairs fetal growth by inducing placental trophoblast dysfunction through ROS-regulated, PINK1/Parkin-dependent mitophagy.