Revealing High-Efficiency Natural Mycotoxin Antidotes in Zebrafish Model Screening Against Zearalenone-Induced Toxicity
Hong-Yun Zhang,
Wei-Dan Jiang,
Pei Wu,
Yang Liu,
Hong-Mei Ren,
Xiao-Wan Jin,
Xiao-Qiu Zhou,
Lin Feng
Affiliations
Hong-Yun Zhang
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China
Wei-Dan Jiang
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Animal Disease-Resistant Nutrition (Ministry of Education of the People's Republic of China), Sichuan Agricultural University, Chengdu 611130, China
Pei Wu
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Animal Disease-Resistant Nutrition (Ministry of Education of the People's Republic of China), Sichuan Agricultural University, Chengdu 611130, China
Yang Liu
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Animal Disease-Resistant Nutrition (Ministry of Education of the People's Republic of China), Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Animal Disease-Resistance Nutrition and Feed (Ministry of Agriculture and Rural Affairs of the People's Republic of China), Sichuan Agricultural University, Chengdu 611130, China
Hong-Mei Ren
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China
Xiao-Wan Jin
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China
Xiao-Qiu Zhou
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Animal Disease-Resistant Nutrition (Ministry of Education of the People's Republic of China), Sichuan Agricultural University, Chengdu 611130, China; Corresponding authors.
Lin Feng
Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China; Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Animal Disease-Resistant Nutrition (Ministry of Education of the People's Republic of China), Sichuan Agricultural University, Chengdu 611130, China; Corresponding authors.
Zearalenone (ZEA), a mycotoxin, poses a significant global hazard to human and animal health. Natural products (NPs) have shown promise for mitigating the adverse effects of ZEA owing to their diverse functional activities. However, the current challenge lies in the absence of an efficient strategy for systematic screening and identification of NPs that can effectively protect against ZEA-induced toxicity. This study describes a phenotype-based screening strategy for screening NP libraries and discovering more effective compounds to mitigate or counteract the adverse consequences of ZEA exposure in animals. Using this strategy, we initially identified 96 NPs and evaluated the potency and efficacy of two effective candidate compounds, fraxetin, and hydroxytyrosol, based on embryonic phenotype and locomotor activity using a scoring system and the TCMacro method. Furthermore, we performed transcriptome and protein−protein interaction (PPI) network analyses to extract two mRNA signatures to query the Connectivity Map (CMap) database and predict NPs. The predicted NPs showed the potential to reverse the gene expression profiles associated with ZEA toxicity. Consequently, we further screened these compounds using our model, which indicated that hispidin, daphnetin, and riboflavin exhibit promising in vivo efficacy in zebrafish. Notably, throughout the process, fraxetin consistently stood out as the most promising NP. Biological pathway analysis and functional verification revealed that fraxetin completely reversed the toxic effects of ZEA at very low doses. This was achieved by repairing damaged cell apoptosis, modifying the cell cycle pathway, and preventing senescence induction, indicating good application potential. Overall, we demonstrated that this integration strategy can be successfully applied to effectively discover potential antidotes.
