A human-relevant and AOP-driven in vitro approach for studying the cholestatic potential of micro- and nanoplastics

Plastics are versatile materials with a myriad of applications in daily life and degrade in the environment to smaller fragments called micro- and nanoplastics (MNPs). Although still controversial, MNPs have been associated with a variety of adverse health effects. Recent animal studies showed alteration of bile acid homeostasis in the liver induced by MNPs, which suggests cholestatic potential. However, animal testing in the MNP field raises serious ethical questions and has been frequently criticized because of the lack of human relevance. This defines the scope of the present project, in which it will be investigated if MNPs not only induce bile accumulation, but also exacerbate pre-existing cholestasis in human liver. For this purpose, a human-centric in vitro setting will be set up consisting of liver-based cell culture systems linked with a series of assays, each that monitor one or more mechanistic key events in the adverse outcome pathway network of cholestatic liver injury at the transcriptional, translational or functional level. Cell culture systems allowing prediction of cholestatic adversity at the personalized and general population level will be used, and will be exposed to MNPs in in vivo-like and human-relevant conditions. Overall, this project will shed more light onto the liver toxic potential of MNPs and will demonstrate the power of animal-free and human-based in vitro experimentation for hazard identification purposes.