Toxicity of microplastics and plastic additive co-exposure in liver Disse organoids from healthy donors and patient-derived induced pluripotent stem cells

Abstract The ubiquitous microplastics (MPs) and plastic additives in the environment usually form complexes, enter human blood circulation, and increase the risk of steatohepatitis. The liver Disse space plays a vital role in corresponding hepatic pathological processes. However, due to the limited understanding of the regulatory cues in multilineage maturation, the generation of large-scale Disse-like organoids (DOs) mirroring the comprehensive toxicity responses of MPs is challenging. Here, using human-induced pluripotent stem cells (hiPSCs), we biofabricated healthy donors and patient-derived DOs containing hepatocytes, endothelial cells, and hepatic stellate cells, resembling the features of Disse space. These organoids revealed that polystyrene MPs preferentially entered endothelial cells and then dispersed throughout the organoids, similar to reported studies in zebrafish. Co-exposure to MPs and tetrabromobisphenol A (TBBPA), a common plastic additive, showed enhanced accumulation of contamination in the organoids. We also biofabricated alcoholic liver disease (ALD) patient-derived DOs representing the specific disease transcriptional profiles. We found that co-exposure to MPs and TBBPA at environmental-related dosages significantly elevated the pathological transcriptional expression and biochemical profiles in patient-derived DOs but not in healthy organoids, suggesting that both hereditary factors and pollutants contribute to susceptibility to environmental toxicants. This study exemplified the value of biofabricated hiPSC-derived organoids in environmental toxicology and offered a powerful strategy for personalized toxicology evaluation.