Proteomics reveals that nanoplastics with different sizes induce hepatocyte apoptosis in mice through distinct mechanisms involving mitophagy dysregulation and cell cycle arrest.

Abstract

Nanoplastics (NPs) can penetrate the intestinal barrier of organisms and accumulate in the liver, thereby inducing hepatocyte apoptosis. However, the underlying mechanisms remain incompletely elucidated. This study examined the effects of PS-NPs exposure on hepatocyte apoptosis and revealed the role of cell cycle arrest and mitophagy. The C57BL/6 mice were administered a diet containing 100 nm and 500 nm PS-NPs at a concentration of 0.1 g/kg for 180 days, respectively. TUNEL staining confirmed that 100 nm PS-NPs induced more pronounced apoptosis compared to 500 nm PS-NPs in mouse liver. Mechanistically, proteomic analysis revealed that Pdcd2l, associated with the S phase of cell cycle and apoptosis, exhibited the highest fold changes among all detected proteins in 100 nm and 500 nm PS-NPs exposure groups. Notably, the expression of Tbc1d17, Bcl2l13, and Pgam5 involved in mitophagosome formation in mouse liver was upregulated by 100 nm PS-NPs but not by 500 nm PS-NPs; moreover, mitophagosomes were observed in HepG2 cells exposed to 100 nm PS-NPs. Additionally, 100 nm PS-NPs internalized by HepG2 cells could penetrate lysosomes. The protein levels of Igf2r and Rab7a were altered, and p62 mRNA expression was increased in mouse liver, suggesting 100 nm PS-NPs, but not 500 nm PS-NPs, impaired lysosomal function and subsequently inhibited mitophagy degradation. Collectively, 500 nm PS-NPs induced Pdcd2l-mediated cell cycle arrest, thereby exacerbating hepatocyte apoptosis; while 100 nm PS-NPs not only triggered similar levels of cell cycle arrest as 500 nm PS-NPs, but also disrupted mitophagy, which was also associated with hepatocyte apoptosis.