Polystyrene Micro(nano)plastic-Induced Ca²⁺ Disorder Activates Endoplasmic Reticulum and Mitochondrial Signaling Pathways to Synergistically Promote Apoptosis in Human Lung Cells

Micro(nano)plastics (MNPs) are a global environmental issue that threatens human health. As a representative class of MNP, polystyrene (PS) has been widely detected in the atmosphere. However, study on its toxicity toward the human respiratory system remains incomplete. Previous works have investigated toxicological mechanisms of PS in human normal lung (BEAS-2B) cells based on a single signaling pathway, which is partial and inadequate. In this work, by analyzing key protein level changes, fluorescence colocalization, and pathway inhibition, PS exposure-induced Ca²⁺ disorder was found to simultaneously activate endoplasmic reticulum (ER) (IRE1α-XBP 1s-Chop and caspase 12) and mitochondrial signaling pathways to promote BEAS-2B cell apoptosis. By exposing these cells to different particle sizes (20, 100, and 1000 nm) and concentrations (100, 250, and 500 μg mL^-1) of PS, the rule of different signaling pathways that synergistically induce toxicity in BEAS-2B cells was discerned. Conditional appearance of caspase 12 pathway and sustained coactivation of IRE1α-XBP 1s-Chop and mitochondrial pathways were proved to be related to effective PS deposition and mitochondria-associated ER membrane mediation, respectively. The synergistic signaling pathways causing aberrant BEAS-2B cell apoptosis under environmentally relevant dosages highlight the complexity of PS toxicity in the respiratory system. These results provide a new insight into the toxicological mechanisms of MNP in the human body.