Dose-Dependent Responses to Polystyrene Nanoplastics in SH-SY5Y Cells: Bioaccumulation, Antioxidant Adaptation, and Modulation of UPR Activation/ER Stress and Mitochondrial Oxidative Stress

Polystyrene nanoplastics (PS-NPs) are increasingly recognized as environmental contaminants with potential implications for human health. However, the changes that polystyrene undergoes under environmental conditions, as well as the cellular stress responses and adaptive processes induced by these particles in human neuronal cell models, have not yet been fully characterized. In this study, we investigated the effects of 100 nm polystyrene nanoplastics functionalized with carboxyl groups (PS-NPs-COOH) on SH-SY5Y cells after 24 h of exposure, focusing on cell viability, intracellular particle accumulation, oxidative stress, antioxidant responses, and endoplasmic reticulum (ER) stress-associated signaling. Cell viability decreased significantly (p < 0.0001) to 68% at a concentration of 500 µg/mL, compared to 96.14% in the control group. Holotomographic microscopy showed concentration-dependent intracellular accumulation and aggregation of PS-NPs-COOH. Exposure was also associated with increased dihydroethidium-derived fluorescence, consistent with an alteration in cellular oxidative status. The increased expression of NRF2 and antioxidant response-related genes suggested a compensatory transcriptional response to the oxidative stress generated. In parallel, changes in ER stress-associated markers, including components of the unfolded protein response (UPR), together with alterations in apoptosis-related transcripts, indicated the involvement of interconnected cellular stress response pathways. These responses varied according to the exposure concentration of PS-NPs-COOH, possibly suggesting an adaptive process in response to cellular stress. Further studies are needed to clarify this proposed adaptive response and determine the balance between cellular dysfunction and survival mechanisms.