Co-exposure to polystyrene nanoplastics and di(2-ethylhexyl) phthalate: Effects and mechanistic insights into hepatic lipid metabolism in mice

Recent environmental health studies have indicated that co-exposure to nanoplastics (NPs) and di(2-ethylhexyl) phthalate (DEHP) is closely associated with synergistic hepatotoxicity. However, the effects of co-exposure on hepatic lipid metabolism and the underlying mechanisms remain elusive. In this study, we found that co-exposure to polystyrene NPs (1 μg·mL⁻¹) and DEHP (50 mg·kg⁻¹) elevated the serum levels of hepatic functional enzymes and aggravated hepatic lipid metabolic dysregulation, eventually triggered excessive lipid accumulation in liver tissue and hepatocyte. The hepatic transcriptomic results showed that the differentially expressed genes (DEGs) in the co-exposure group were significantly enriched in lipid metabolism. In addition, the DEGs in the co-exposure group were specifically enriched in the response to unfolded protein, and mechanistic exploration further revealed that co-exposure uniquely activated the IRE1α-XBP1s pathway, without affecting the PERK or ATF6 branches. In vitro experiments using AML12 cells, we found that co-exposure to 10 μg·mL-1 NPs and 50 µM mono(2-ethylhexyl) phthalate (MEHP) also promoted lipid accumulation, and subsequent investigations revealed that the inhibition of the IRE1α signaling by Kira6 ameliorated lipid deposition induced by co-exposure. Collectively, our results demonstrate that co-exposure to NPs and DEHP induces hepatic lipid deposition and liver dysfunction in mice, and the IRE1α-XBP1s signaling pathway is involved in regulating co-exposure induced lipid accumulation in hepatocytes. This study provides novel insights into the potential mechanism underlying the co-exposure-induced hepatotoxicity of NPs and DEHP co-exposure.