Distinct toxicity of microplastics/TBBPA co-exposure to bioprinted liver organoids derived from hiPSCs of healthy and patient donors

Abstract

Bioprinted tissues derived from human-induced pluripotent stem cells (hiPSCs) can provide precise information on disease mechanisms and toxicity. The detection of microplastics (MPs) in the liver tissues of patients with liver cirrhosis has raised concerns about their hepatotoxicity. MPs could absorb endocrine disruptors, such as tetrabromobisphenol A (TBBPA) that is widely present in the environment, thereby complicating their toxic behaviors. To investigate their toxic mechanisms in liver tissues, we used the electro-assisted inkjet printing technology to fabricate healthy donor or patient-sourced hiPSC-derived Disse space organoids (DOs) that resembled the cell types and transcriptional features of Disse space. We observed an accumulation of polystyrene MP microbeads in the DOs, and TBBPA exacerbated the process. Neither MPs and TBBPA alone nor the co-exposure at non-cytotoxicity dosages could affect the liver functions of healthy donor hiPSC-derived DOs, as revealed by transcriptomic and biochemical analyses, whereas alcoholic liver disease (ALD) patient hiPSC-derived DOs exhibited the ALD disease transcriptional profiles. We found that MPs/TBBPA co-exposure significantly influenced the patient organoids in terms of the pathological transcription expression and biochemical profiles. These results suggested that both hereditary factors and pollutants contribute to susceptibility to environmental toxicants. This study exemplified the value of bioprinting hiPSC-derived organoids in environmental toxicology, offering a powerful strategy to advance the personalized environmental toxicology paradigm.