Dietary coexposure to micro- and nano-plastics and metabolism-disrupting chemicals: Combined hepatotoxicity - insights from mammalian and cellular models.

Micro- and nano-plastics (MNPs), omnipresent in the environment, can act as carriers of metabolism-disrupting chemicals (MDCs) and can enter the human body through the food web, thereby increasing coexposure risk. Although the combined hepatotoxicity has been reported, the underlying mechanism has not yet been well understood. Given the limited evidence from the human aspect, this review is mainly based on the evidence from mammalian and in vitro studies. We reviewed articles published in PubMed, Web of science and Scopus related to this topic (singular hepatotoxicity, interaction, and combined toxicity) and conducted a classified summary analysis. Our analysis summarized that the interactions between MNPs and the four main types of MDCs (per- and polyfluoroalkyl substances, bisphenol A, phthalates, and heavy metals), especially in the gastrointestinal environment, are regulated by factors such as pH, the biomolecular corona, and physiological state. Current research indicates that the combined liver toxicity of MNPs and MDCs is primarily synergistic under most tested conditions, with antagonistic effects observed only in a few specific circumstances (such as protein corona formation and high concentration of polystyrene microplastics). Mechanistically, coexposure induces multilevel perturbations, from initial physicochemical interactions such as carrier effects and corona formation to cellular dysfunction, and further to systemic effects mediated by the gut-liver axis. We distinguish the differences in the contaminant interactions and transport mechanisms of microplastics and nanoplastics, and explore the regulatory conditions for the combined effects. Finally, we analyze environmental realism and research limitations, proposing future directions for subsequent research on the impacts of dietary coexposure on the environment and human health.