Polystyrene microplastics induce hepatotoxicity and disrupt lipid metabolism in the liver organoids

Microplastic particles (MP) has been detected in the environment widespread. Human beings are inevitably exposed to MP via multiple routines. However, the hazard identifications, as direct evidence of exposure and health risk, have not been fully characterized in human beings. Many studies suggest the liver is a potential target organ, but currently no study regarding the MP on human liver has been reported. In this study, we used a novel in vitro 3D model, the liver organoids (LOs) generated from human pluripotent stem cells, as an alternative model to the human liver, to explore the adverse biological effect of 1 μm polystyrene-MP (PS-MP) microbeads applying a non-static exposure approach. When the LOs were exposed to 0.25, 2.5 and 25 μg/mL PS-MP (the lowest one was relevant to the environmental concentrations, calculated to be 102 ± 7 items/mL). The potential mechanisms of PS-MP induced hepatotoxicity and lipotoxicity, in aspects of cytotoxicity, levels of key molecular markers, ATP production, alteration in lipid metabolism, ROS generation, oxidative stress and inflammation response, were determined. Specifically, it has been firstly observed that PS-MP could increase the expression of hepatic HNF4A and CYP2E1. Based on these findings, the potential adverse outcome pathways (AOPs) relevant to PS-MP were proposed, and the potential risks of PS-MP on liver steatosis, fibrosis and cancer were implicated. The combined application of novel LOs model and AOPs framework provides a new insight into the risk assessment of MP. Further studies are anticipated to validate the hepatotoxic molecular mechanism of PS-MP based on HNF4A or CYP2E1, and to investigate the MP-induced physical damage and its relationship to hepatic adverse effect for human beings. Microplastics cause hepatotoxicity and disrupt lipid metabolism in the human pluripotent stem cells-derived liver organoids, providing evidence for human implication.