Accurate evaluation of cytotoxicity in human cells are more promising as valuable references with great potential for toxicological assessment, in replacement of laborious, unaffordable and controversial animal-based experiments. However, Molecular mechanism and key factors responsible for cytotoxicity against mycotoxin deoxynivalenol (DON) from Fusarium pathogens are rarely elucidated. 

As newly published on Toxicological Sciences, August 30, 2018, WU Aibo's group from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences reported  "Transcription factor FOXO3a is a negative regulator of cytotoxicity of Fusarium mycotoxin in GES-1 cells". It demonstrated that deoxynivalenol (DON) exposure caused cell oxidative stress induced the GES-1 cell death, mitochondrial dysfunction, activated the ROS-JNK-FOXO3a signaling pathway. As resulted, the transcription factor FOXO3a plays a transcriptional regulatory role, affected cell antioxidant, cycle arrest and apoptosis. 

In this study, the interaction platform of DON and GES-1 cells was well-established. Rapid increases of ROS, mitochondrial DNA damage, impaired respiratory chain and decreased oxygen consumption rate(OCR) values, as well as G2/M cell cycle arrest and apoptosis were first observed. More interestingly, a transcription factor of Forkhead box O3 (FOXO3a) was found with crucial functionalities, downregulated some apoptotic genes associated with mitochondrial toxicity and cell death after activation by nuclear translocation. in vivo and in vitro knockdown of FOXO3a and DAF16 (the FOXO ortholog) decreased the cytotoxicity of DON to GES-1 cells and worms, respectively. As concluded, the transcription factor FOXO3a as negative regulator for DON-induced cytotoxicity and proposed signaling pathway of ROS/JNK/FOXO3a would contribute a lot as potential calibrator for stable, simplified and accurate toxicological evaluation on cytotoxicity of target Fusarium mycotoxin, providing valuable references as novel strategies for compulsory toxicological data of other substances. 

This work was mainly supported by The National Key Research and Development Program of China and National Natural Science Foundation of China.  

Transcription factor FOXO3a as a negative regulator of cytotoxicity of DON in GES-1 cells
(Image by Prof Wu Aibo's Group)