Developmental disorders caused by cefixime in the otic vesicles of zebrafish embryos or larvae

Chaobao Chen; Xuan Ni; Xiaoyu Yin; Hao Chen; Yini Zhou; Huiying Sun; Chelimuge Qi; Nini Bu; Shuaiyu Wang; Jianhua Yu; Jingfeng Yang; Wuliji Ao; Baoquan Zhao; Wu Dong

doi:10.1016/j.cbpc.2022.109295

Developmental disorders caused by cefixime in the otic vesicles of zebrafish embryos or larvae

Comp Biochem Physiol C Toxicol Pharmacol. 2022 May:255:109295. doi: 10.1016/j.cbpc.2022.109295. Epub 2022 Feb 6.

Authors

Chaobao Chen¹, Xuan Ni¹, Xiaoyu Yin¹, Hao Chen¹, Yini Zhou¹, Huiying Sun¹, Chelimuge Qi¹, Nini Bu¹, Shuaiyu Wang¹, Jianhua Yu¹, Jingfeng Yang¹, Wuliji Ao², Baoquan Zhao³, Wu Dong⁴

Affiliations

¹ Inner Mongolia Key Laboratory of Toxicant Monitoring and Toxicology, Collage of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao 028000, China.
² Inner Mongolia Research Institute of Traditional Mongolian Medicine Engineering Technology/College of Mongolian Medicine and Pharmacy, Inner Mongolia Minzu University, Tongliao 028000, China.
³ State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
⁴ Inner Mongolia Key Laboratory of Toxicant Monitoring and Toxicology, Collage of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao 028000, China. Electronic address: dongwu@imun.edu.cn.

PMID: 35134541
DOI: 10.1016/j.cbpc.2022.109295

Abstract

To explore the developmental toxicity of cefixime (CE) in the developmental disorder and toxicity mechanism of CE on otic vesicles, zebrafish embryos were used as an animal model. The results showed that CE increased mortality in a dose-dependent manner and decreased the hatching rate of zebrafish larva at 96 hpf. Interestingly, CE significantly reduced the area of the saccule and utricle, as well as the area of otic vesicles in zebrafish larvae (p < 0.001). Fibroblast growth factor 8a (Fgf8a) inhibitors and bone morphogenetic protein (BMP) inhibitors caused similar morphological changes. CE decreased the lateral hair cells of zebrafish larvae in a dose-dependent manner. Furthermore, CE caused the downregulation of cartilage and bone-related genes and Na⁺/K⁺-ATPase-related genes of zebrafish larvae at 72 hpf and 120 hpf according to RT-qPCR. A comparison with the control group revealed that 100 μg/mL CE also caused a decrease in Na⁺/K⁺-ATPase activity (p < 0.01). In addition, antibody staining verified that CE inhibited the expression of Na⁺/K⁺-ATPase in the otic vesicles and the nephridium of zebrafish larvae. The data obtained in this study suggested that CE has significant ototoxicity during embryonic development of zebrafish, which is closely related to Na⁺/K⁺-ATPase and the regulation of the Fgf8a/BMP signaling pathways. The effects and toxicity of CE on ear development in other animal models need to be further explored.

Keywords: Cefixime; Fgf8a; Na(+)/K(+)-ATPase; Ototoxicity; Zebrafish embryo.

MeSH terms

Animals
Anti-Bacterial Agents / toxicity
Cefixime / toxicity*
Embryo, Nonmammalian / drug effects*
Embryonic Development / drug effects*
Gene Expression Regulation, Developmental / drug effects*
Larva / drug effects
Organogenesis / drug effects*
Zebrafish

Substances

Anti-Bacterial Agents
Cefixime