3-Acetyldeoxynivalenol induces lysosomal membrane permeabilization-mediated apoptosis and inhibits autophagic flux in macrophages. (October 2020)

• Record Type: Journal Article
• Authors: Liu, Ning; Yang, Ying; Chen, Jingqing; Jia, Hai; Zhang, Yunchang; Jiang, Da; Wu, Guoyao; Wu, Zhenlong
• Is Part Of: Environmental pollution. Volume 265(2020)Part B
• Publication Date: 2020-10
• Subjects: 3-Acetyldeoxynivalenol -- Apoptosis -- Autophagy -- Cathepsin -- Lysosomal membrane permeabilization; Pollution -- Periodicals; Pollution -- Environmental aspects -- Periodicals; Environmental Pollution -- Periodicals; Pollution -- Périodiques; Pollution -- Aspect de l'environnement -- Périodiques; Pollution -- Effets physiologiques -- Périodiques; Pollution; Pollution -- Environmental aspects; Periodicals; Electronic journals; 363.73
• DOI: 10.1016/j.envpol.2020.114697
• Languages: English
• ISSNs: 0269-7491

Abstract

Abstract: 3-Acetyldeoxynivalenol (3-Ac-DON), the acetylated derivative of deoxynivalenol (DON), has been reported to be coexisted with DON in various cereal grains. Ingestion of grain-based food products contaminated by 3-Ac-DON might exert deleterious effects on the health of both humans and animals. However, the biological toxicity of 3-Ac-DON on macrophages and the underlying mechanisms remain largely unknown. In the present study, we showed that RAW 264.7 macrophages treated with 0.75 or 1.50 μg/mL of 3-Ac-DON resulted in DNA damage and the related cell cycle arrest at G1 phase and cell death, activation of the ribotoxic stress and the endoplasmic reticulum (ER) stress responses. The 3-Ac-DON-induced cell death was accompanied by a protective autophagy, because gene silencing of Atg5 using the small interfering RNA enhanced cell death. Results of further experiments revealed a role for lysosomal membrane permeabilization in the 3-Ac-DON triggered inhibition of autophagic flux. Additional work also showed that increased lysosomal biogenesis and leakage of cathepsin B (CTSB) from lysosomes to cytosol was critical for the 3-Ac-DON-induced cell death. Importantly, 3-Ac-DON-induced DNA damage and cell death were rescued by CA-074-me, a CTSB inhibitor. Collectively, these results indicated a critical role of lysosomal membrane permeabilization in the 3-Ac-DON-induced apoptosis of RAW 264.7 macrophages. Graphical abstract: Image 1 Highlights: 3-Acetyldeoxynivalenol is one of the most prevalent mycotoxins associated with grain-related products contamination. 3-Acetyldeoxynivalenol induces DNA damage, cell cycle arrest, apoptosis, and autophagy in macrophages. 3-Acetyldeoxynivalenol induces cell death is mediated by the lysosomal membrane permeabilization. 3-Acetyldeoxynivalenol administration-triggered autophagy is a protective response.