背景:塑料材料的全球使用经历了快速扩展,导致大量产生降解和合成的微塑料和纳米塑料(MNPs),它们有可能带来巨大的环境负担,并对生物体造成有害影响。尽管如此,尚未彻底表征MNPs暴露对宿主细胞和组织的有害影响。
结果:在本研究中,我们已经阐明了20nm合成聚苯乙烯纳米颗粒(PSNP)的先前未被发现的肝毒性作用,而不是更大的PS珠,通过选择性诱导巨噬细胞坏死。机械上,20nmPSNPs被巨噬细胞迅速内化并在线粒体中积累,它们破坏了线粒体的完整性,导致线粒体活性氧(mtROS)的产生增加。这种升高的mtROS产生基本上触发了巨噬细胞的坏死性凋亡,导致与肝细胞的串扰增强,最终导致肝细胞损伤。此外,已证明PSNPs可诱导小鼠坏死并促进急性肝损伤。通过在PSNP注射之前施用坏死性凋亡抑制剂或巨噬细胞的全身性消耗,显著减轻了这种有害作用。
结论:总的来说,我们的研究表明,通过触发巨噬细胞坏死性凋亡,环境PSNP暴露具有深远的毒性,进而通过肝微环境中巨噬细胞和肝细胞之间的细胞间串扰诱导肝毒性。
BACKGROUND: The global use of plastic materials has undergone rapid expansion, resulting in the substantial generation of degraded and synthetic microplastics and nanoplastics (MNPs), which have the potential to impose significant environmental burdens and cause harmful effects on living organisms. Despite this, the detrimental impacts of MNPs exposure towards host cells and tissues have not been thoroughly characterized.
RESULTS: In the present study, we have elucidated a previously unidentified hepatotoxic effect of 20 nm synthetic polystyrene nanoparticles (PSNPs), rather than larger PS beads, by selectively inducing necroptosis in macrophages. Mechanistically, 20 nm PSNPs were rapidly internalized by macrophages and accumulated in the mitochondria, where they disrupted mitochondrial integrity, leading to heightened production of mitochondrial reactive oxygen species (mtROS). This elevated mtROS generation essentially triggered necroptosis in macrophages, resulting in enhanced crosstalk with hepatocytes, ultimately leading to hepatocyte damage. Additionally, it was demonstrated that PSNPs induced necroptosis and promoted acute liver injury in mice. This harmful effect was significantly mitigated by the administration of a necroptosis inhibitor or systemic depletion of macrophages prior to PSNPs injection.
CONCLUSIONS: Collectively, our study suggests a profound toxicity of environmental PSNP exposure by triggering macrophage necroptosis, which in turn induces hepatotoxicity via intercellular crosstalk between macrophages and hepatocytes in the hepatic microenvironment.