Combined Enterohepatic Toxicity of Polystyrene Microplastics and Di(2-ethylhexyl) Phthalate in Mice: Gut Microbiota-Dependent Synergistic Effects

With growing toxicological research on microplastics (MPs), scientific attention has shifted from their single toxicity to their combined toxicity with other pollutants. Di(2-ethylhexyl) phthalate (DEHP), a common synthetic plasticizer, may co-occur with MPs through intrinsic association during production or through exogenous environmental pathways, posing the significant risk of co-exposure to organism. Oral exposure represents the primary route for MPs and DEHP, which traverse the gastrointestinal tract and target the enterohepatic system through direct intestinal interaction and systemic circulation. However, their combined toxicity, especially enterohepatic, remains poorly studied in the mammals. In this study, adult C57/BL6J mice were employed and exposed to polystyrene MPs (PS-MPs), DEHP or both for eight weeks. It was revealed that co-exposure to PS-MPs and DEHP induced more significant enterohepatic toxicity than the single exposures, involving enhanced enterohepatic inflammatory response and oxidative stress, as well as intestinal microbial disturbance. Furthermore, after fecal microbiota transplantation, the recipient mice developed similar trends of enterohepatic toxicity to those observed in the corresponding donor mice, revealing the key function played by intestinal microbiota. This study highlighted the crucial link of the gut-liver axis in the combined effects of PS-MPs and DEHP-induced enterohepatic toxicity in mammals and provided a mechanism insight of co-exposure to MPs and other environmental pollutants.