Isavuconazole induces neurodevelopment defects and motor behaviour impairment in zebrafish embryos

Abstract

Isavuconazole is a broad-spectrum antifungal drug used for the treatment of serious infections caused by invasive aspergillosis and mucormycosis in adults. With the continuous use of this drug, its safety and environmental impact have received increasing attention. However, information on the adverse effects of the drug is very limited. Fish is a particularly important model for assessing environmental risks. In this study, the aquatic vertebrate zebrafish was used as a model to study the toxic effects and mechanisms of isavuconazole. We exposed zebrafish embryos to 0.25, 0.5, and 1 mg/L of isavuconazole 6 hours after fertilization. The results showed that at 72 hpf, isavuconazole exposure reduced heart rate, body length, and survival of zebrafish embryos compared to controls. Secondly, when isavuconazole reached a certain dose level, it caused morphological changes in the Tg(elavl3:eGFP) transgenic fish line, with the head shrunk, the body bent, and the fluorescence intensity becoming weaker, etc. At the same time, exposure of zebrafish embryos to isavuconazole down-regulated acetylcholinesterase (AchE) and adenosine triphosphate (ATPase) activities but up-regulated oxidative stress, thereby disrupting neural development and gene expression of neurotransmitter pathways. In addition, astaxanthin partially rescued the neurodevelopmental defects of zebrafish embryos by down-regulating oxidative stress. Thus, our study suggests that isavuconazole exposure may induce neurodevelopment defects and behavioural disturbances in larval zebrafish.