Nanoplastic Particle Exposure Induces Toxicity and Amplifies Cellular Stress in THP-1 Macrophages: Insights on Molecular Pathways and Circulating Proteome Interaction.

The widespread accumulation of polystyrene nanoplastic particles (NPPs) in the environment has raised significant human health concerns, specifically on immune function. However, the underlying molecular mechanisms behind NPP induced immune cell (monocyte/macrophage) toxicity and their relationship with existing pathological conditions remain largely unexplored. The current study explored the interaction of NPPs with serum proteins and composition of protein corona through proteomic analysis (LC-HRMS/MS). Further, we investigated the immunotoxic effects on THP-1 macrophage cells via various cellular and molecular assays, including cytotoxicity, oxidative stress, mitochondrial function, intracellular calcium homeostasis, apoptosis and stress signaling pathway assessment. This study further assessed the amplification potential of NPPs on inflammatory (TNF α and lipopolysaccharide), atherogenic (ox-LDL) and environmental (polycyclic aromatic hydrocarbons (PAH)) stress conditions. The findings demonstrated that NPPs triggered cytotoxicity in a dose dependent manner along with excessive ROS generation, mitochondrial impairment, elevated intracellular calcium levels and apoptosis by altering BAX and BCL2 expression. We also found that NPPs activated stress signaling pathways through modulating HSP27, SAPK/JNK, p38 MAPK and c-Jun phosphorylation. Interestingly, pathway inhibition studies confirmed the involvement of p38 MAPK, ERK and mitochondrial ROS signaling in NPP-associated toxicity. In addition, NPPs exposure augmented inflammatory response, promoted atherogenesis (foam cell formation), amplified PAH induced toxicity. Together, these observations revealed precise adverse outcome pathways (AoP) and stress amplification effects of NPPs on macrophages and consequent toxic effects on the immune system.