Journal
ENVIRONMENTAL POLLUTION
Volume 265, Issue -, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.envpol.2020.114697
Keywords
3-Acetyldeoxynivalenol; Apoptosis; Autophagy; Cathepsin; Lysosomal membrane permeabilization
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Funding
- National Natural Science Foundation of China [31625025, 31572410, 31572412, 31272450, 31272451]
- State Key Laboratory of Animal Nutrition [2004DA125184F1909]
- 111 Project [B16044]
- Texas A&M AgriLife Research [H-8200]
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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 mu g/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. (C) 2020 Elsevier Ltd. All rights reserved.
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