School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China; Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China.
Pestic Biochem Physiol. 2024 Sep;204:106030. doi: 10.1016/j.pestbp.2024.106030. Epub 2024 Jul 15.
There have been persistent concerns about the safety risks associated with DDT residues in the environment. Studies have shown that exposure to DDT or its metabolites can cause various liver diseases. However, the mechanisms of liver toxicity haven't been well studied. In our current investigation, we observed that DDT triggers pyroptosis in human liver cells (HL-7702), representing a novel form of programmed cell death. Our results delineated DDT (0-100 μM) induced pyroptosis in HL-7702 cells, which was confirmed through morphological changes, lactate dehydrogenase (LDH) release, gasdermin E (GSDME) cleavage and Annexin-V/PI staining. Knockdown of GSDME reduced cell death and transferred the mode of cell death from pyroptosis to apoptosis. Notably, DDT exposure markedly increased reactive oxygen species (ROS) production, concurrent with c-Jun N-terminal kinase (JNK) phosphorylation. Intervention with a ROS inhibitor or JNK inhibitor SP600125 restored cell viability and hindered GSDME-mediated pyroptosis. Our results firstly demonstrate that DDT suppresses HL-7702 cells growth by inducing pyroptosis mainly through the ROS/JNK/GSDME pathway. These findings not only contribute to an in-depth understanding of DDT toxicity but also open avenues for gaining valuable insights into potential mitigation strategies and therapeutic interventions.
一直以来，人们都对环境中滴滴涕残留所带来的安全风险感到担忧。研究表明，接触滴滴涕或其代谢物会导致各种肝脏疾病。然而，其肝毒性的作用机制尚未得到充分研究。在我们目前的研究中，我们观察到滴滴涕（0-100 μM）在人肝细胞（HL-7702）中引发细胞焦亡，这代表了一种新型的程序性细胞死亡形式。我们的结果表明，滴滴涕（0-100 μM）在 HL-7702 细胞中诱导细胞焦亡，这可以通过形态变化、乳酸脱氢酶（LDH）释放、Gasdermin E（GSDME）裂解和 Annexin-V/PI 染色来证实。敲低 GSDME 可减少细胞死亡，并将细胞死亡模式从细胞焦亡转变为细胞凋亡。值得注意的是，滴滴涕暴露显著增加了活性氧（ROS）的产生，同时伴随着 c-Jun N 端激酶（JNK）的磷酸化。用 ROS 抑制剂或 JNK 抑制剂 SP600125 干预可恢复细胞活力并抑制 GSDME 介导的细胞焦亡。我们的研究结果首次表明，滴滴涕主要通过 ROS/JNK/GSDME 途径诱导细胞焦亡来抑制 HL-7702 细胞的生长。这些发现不仅有助于深入了解滴滴涕的毒性，还为探索潜在的缓解策略和治疗干预措施提供了有价值的见解。
