Zearalenone accelerates aging and mitochondrial dysfunction: Evidence from network toxicology and zebrafish models.

Rong Li, Ziyuan Zhang, Yu Xu

Department of Endocrine and Metabolic Diseases, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.Department of Endocrine and Metabolic Diseases, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China. · pubmed

Paper

Abstract

Zearalenone (ZEN), a ubiquitous mycotoxin contaminating cereals and feed, is best known for reproductive toxicity. It remains unclear whether chronic, low-level exposure contributes to aging and mitochondrial decline. Here, we combine network toxicology, molecular docking, transcriptomics and zebrafish (Danio rerio) models to address this question. In silico analyses identified 30 high-confidence ZEN targets linked to aging or mitochondrial biology; AKT1, MAPK3, TP53 and NFKB1 emerged as the central hubs. Docking predicted strong binding afﬁnities (-6.2 to -8.3 kcal/mol) and 100 ns molecular-dynamics simulations confirmed stable complex formation. Translating these predictions to a living system, we exposed zebrafish larvae to 2 μM ZEN. Within 72 h this produced overt developmental toxicity (delayed hatching, bradycardia, skeletal malformations) and sarcopenia-like muscle degeneration. Transmission-electron microscopy revealed disorganised sarcomeres; immunostaining showed reduced myosin heavy-chain expression. Oxidative stress (DCF fluorescence) rose markedly, while ATP-synthase transcripts were down-regulated. Locomotor assays at 96 h revealed a selective loss of high-speed swimming bouts. RNA-seq corroborated dysregulation of MAPK, PI3K-AKT and apoptosis pathways; longevity-linked genes (igf1, sirt1, nfkb2) were significantly downregulated. Collectively, our work provides the first integrated evidence that ZEN exposure accelerates organismal aging through mitochondrial dysfunction and suggests that tighter mycotoxin surveillance is warranted as populations grow older.

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Research summary

Zearalenone exposure accelerates aging through mitochondrial dysfunction in zebrafish models. The study addresses the potential root causes of aging by linking a mycotoxin to mitochondrial decline and organismal aging, which is relevant to longevity research.

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