Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China.
College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
Environ Int. 2024 Mar;185:108532. doi: 10.1016/j.envint.2024.108532. Epub 2024 Feb 24.
Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.
纳米塑料（NPs）持续在全球水生和陆地系统中积累，通过食物链和/或其他途径对人类健康构成潜在威胁。体内和体外研究都证实，肝脏是生物体中 NPs 蓄积的主要靶器官之一。然而，暴露于 NPs 是否会引起与 NPs 大小相关的肝脂质代谢紊乱仍存在争议，而且 NPs 诱导的肝毒性的可逆性在很大程度上尚不清楚。在这项研究中，从自噬和溶酶体机制方面研究了长期暴露于环境相关剂量的聚苯乙烯纳米塑料（PS-NPs）对脂质积累的影响。结果表明，与 500nm PS-NPs 相比，100nm PS-NPs 暴露的小鼠肝脂质积累更为明显。100nm 和 500nm PS-NPs 暴露后 50 天的自我恢复有效地缓解了这种效应。从机制上讲，尽管 PS-NPs 暴露通过 ERK（丝裂原活化蛋白激酶 1）/mTOR（雷帕霉素靶蛋白激酶）信号通路激活自噬体形成，但 Rab7（RAB7，RAS 癌基因家族成员）、CTSB（组织蛋白酶 B）和 CTSD（组织蛋白酶 D）表达的抑制会损害溶酶体功能，从而阻断自噬流并导致肝脂质积累。PS-NPs 暴露终止后，溶酶体胞吐作用负责清除积累在溶酶体中的 PS-NPs。此外，溶酶体功能障碍和自噬流抑制得到有效缓解。这可能是恢复后缓解 PS-NPs 诱导的脂质积累的主要原因。总的来说，我们首次证明溶酶体在环境相关剂量的 NPs 诱导的肝毒性的持久性和可逆性中起双重作用，为预防和干预与纳米塑料暴露相关的肝损伤提供了新的证据。
