Mechanistic toxicity assessment of differently sized and charged polystyrene nanoparticles based on human placental cells

• PS-NPs had size- and surface charge-specific toxicity pattern. • NH2-labeled PS-NPs caused greater toxicity than COOH-labeled and unlabeled PS-NPs. • PS-NPs induced endocrine system-disrupting effects by inhibiting PKA activity. • PS-NPs induced size- and surface charge-depended expression profiles of toxicity-related genes. • Differently sized and charged PS-NPs induced reproductive toxicity via different mechanisms. Nanoplastics, as emerging contaminants, may be degraded from microplastics and released into aquatic systems globally, which pose threats to human health via ingestion with food or water. Although plastic fragments have been isolated from placental tissues in pregnant women, little is known about the direct toxicity of nanoplastics on human placental cells that plays a critical role in maintaining healthy growth of fetus. This study explored the mechanistic toxicity of polystyrene nanoplastics (PS-NPs) with different sizes (25, 50, 100 and 500 nm) and surface charges (-NH 2 , -COOH and unlabeled) on human placental cells. Results showed that PS-NPs had size- and surface charge-specific toxicity pattern. The smaller the PS-NP size was, the greater the toxicity induced on human placental cells. In terms of surface charges, NH 2 -labeled PS-NPs caused greater effects on cytotoxicity, inhibition of protein kinase A (PKA) activity, oxidative stress, and cell cycle arrest compared to COOH-labeled and unmodified PS-NPs. PS-NPs also induced size- and surface charge-dependent expression profiles of genes involved in various and interrelated toxicity pathways. In particular, PS-NPs increased intracellular reactive oxygen species in human placental cells, which can induce DNA damage and lead to cell cycle arrest in G1or G2 phase, inflammation and apoptosis. Our findings provide empirical evidences that the negative effects of nanoplastics on human placental cells, and highlight the necessity to conduct risk assessment of nanoplastics on female reproduction and fetal development.