3-Acetyldeoxynivalenol induces cell death through endoplasmic reticulum stress in mouse liver.

Abstract

Ingestion of food or cereal products contaminated by deoxynivalenol (DON) and related derivatives poses a threat to the health of humans and animals. However, the toxicity and underlying mechanisms of 3-acetyldeoxynivalenol (3-Ac-DON), an acetylated form of deoxynivalenol, have not been fully elucidated. In the present study, we showed that 3-Ac-DON caused significant oxidative damage, as shown by elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH) in serum, increased lipid peroxidation products, such as hydrogen peroxide (H2O2) and malondialdehyde (MDA), decreased activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). In addition, 3-Ac-DON exposure led to elevated infiltrations of immune cell, increased apoptosis and autophagy in the liver. Interestingly, 3-Ac-DON-resulted apoptosis and liver injury were partially reduced by autophagy inhibitors. Further study showed that 3-Ac-DON-treated mice had altered ultrastructural changes of endoplasmic reticulum (ER), as well as enhanced protein levels of p-IRE1α, p-PERK, and downstream targets, indicating activation of unfolded protein response (UPR) in the liver. Importantly, 3-Ac-DON induced ER stress, oxidative damage, cell death, infiltration of immune cells, and increased mRNA levels of inflammatory cytokines were significantly abolished by 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, indicating a critical role of UPR signaling for the cellular damage of the liver in response to 3-Ac-DON exposure. In conclusion, using mice as an animal model, we showed that 3-Ac-DON exposure impaired the function of liver, as shown by oxidative damage, cell death, and infiltration of immune cell, in which ER stress played an important role. Restoration of the ER function might be a preventive strategy to reduce the deleterious effect of 3-Ac-DON on the liver of animals.