Polystyrene microplastics-triggered mitophagy and oxidative burst via activation of PERK pathway

Worldwide annual production of plastics is estimated to be >300 million tons. Plastic debris in aquatic environment can degrade into micro/nanoplastics, leading to biopersistence, bioaccumulation, and toxicity. Here, we determined the potential hepatotoxicity of polystyrene (PS) microplastics at an environmental relevant level. The results reveal that oral administration of PS (diameter 5 μm, exposure doses of 0.1 mg/day) notably triggered endoplasmic reticulum (ER) stress in the liver as evidence by activation of the eIF2α-ATF4-C/EBP homologous protein (CHOP) axis. Moreover, relief of ER stress by 4-phenylbutyric acid (4pba) effectively inhibited PS (0.5 mg/mL)-induced apoptosis in L02 hepatocytes, and similar results were in cells with protein kinase RNA-like ER kinase (PERK) gene silencing. After PS treatment, PERK knockdown positively regulated Bcl2 expression, accompanied with decreased expression of Bax and Cytochrome C (Cyt C). Furthermore, we also found that PS significantly induced excessive reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) and these effects were significantly suppressed by PERK gene silencing. Meanwhile, the results showed that suppression of PERK hyperactivation could improve cell survival, accompanied by inhibition of parkin-mediated mitophagy induced by PS in vitro. Overall, these data demonstrated that ER stress induced by PS is the cause of hepatocyte mitophagy and oxidative stress. Additionally, the regulation of PERK signaling may be crucial in PS exposure-induced hepatotoxicity. This investigation provided basic toxicological data toward elucidating the impacts of microplastics on mammals.