Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress

Due to the widely application of Cyclosporine A (CsA) as an immunosuppressant in clinic, it is necessary to study its potential toxicity. Therefore, we used zebrafish as a model animal to evaluate the toxicity of CsA on embryonic development. Exposure of zebrafish embryos to CsA at concentrations of...

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Autores principales:	Mengqi Wan, Ling Huang, Jieping Liu, Fasheng Liu, Guilan Chen, Huiwen Ni, Guanghua Xiong, Xinjun Liao, Huiqiang Lu, Juhua Xiao, Qiang Tao, Zigang Cao
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	cyclosporine a cardiac toxicity oxidative stress wnt signaling apoptosis Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/7655dadcd85841d0a724e67bbafe2ed6
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spelling	oai:doaj.org-article:7655dadcd85841d0a724e67bbafe2ed62021-11-12T05:41:18ZCyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress1663-981210.3389/fphar.2021.747991https://doaj.org/article/7655dadcd85841d0a724e67bbafe2ed62021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.747991/fullhttps://doaj.org/toc/1663-9812Due to the widely application of Cyclosporine A (CsA) as an immunosuppressant in clinic, it is necessary to study its potential toxicity. Therefore, we used zebrafish as a model animal to evaluate the toxicity of CsA on embryonic development. Exposure of zebrafish embryos to CsA at concentrations of 5 mg/L, 10 mg/L, and 15 mg/L from 12 hpf to 72 hpf resulted in abnormal embryonic development, including cardiac malformation, pericardial edema, decreased heart rate, decreased blood flow velocity, deposition at yolk sac, shortened body length, and increased distance between venous sinus and arterial bulb (SV-BA). The expression of genes related to cardiac development was disordered, and the apoptotic genes were up-regulated. Oxidative stress level was up-regulated and accumulated in pericardium in a dose-dependent manner. Astaxanthin (ATX) treatment could significantly alleviate zebrafish heart defects. CsA induced up-regulation of Wnt signaling in zebrafish, and IWR-1, an inhibitor of Wnt signaling pathway, could effectively rescue the heart defects induced by CsA. Together, our study indicated that CsA induced cardiac developmental toxicity in zebrafish larvae through up-regulating oxidative stress and Wnt signaling, contributing to a more comprehensive evaluation of the safety of the drug.Mengqi WanLing HuangJieping LiuFasheng LiuGuilan ChenHuiwen NiGuanghua XiongXinjun LiaoHuiqiang LuJuhua XiaoQiang TaoZigang CaoFrontiers Media S.A.articlecyclosporine acardiac toxicityoxidative stresswnt signalingapoptosisTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cyclosporine a cardiac toxicity oxidative stress wnt signaling apoptosis Therapeutics. Pharmacology RM1-950
spellingShingle	cyclosporine a cardiac toxicity oxidative stress wnt signaling apoptosis Therapeutics. Pharmacology RM1-950 Mengqi Wan Ling Huang Jieping Liu Fasheng Liu Guilan Chen Huiwen Ni Guanghua Xiong Xinjun Liao Huiqiang Lu Juhua Xiao Qiang Tao Zigang Cao Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress
description	Due to the widely application of Cyclosporine A (CsA) as an immunosuppressant in clinic, it is necessary to study its potential toxicity. Therefore, we used zebrafish as a model animal to evaluate the toxicity of CsA on embryonic development. Exposure of zebrafish embryos to CsA at concentrations of 5 mg/L, 10 mg/L, and 15 mg/L from 12 hpf to 72 hpf resulted in abnormal embryonic development, including cardiac malformation, pericardial edema, decreased heart rate, decreased blood flow velocity, deposition at yolk sac, shortened body length, and increased distance between venous sinus and arterial bulb (SV-BA). The expression of genes related to cardiac development was disordered, and the apoptotic genes were up-regulated. Oxidative stress level was up-regulated and accumulated in pericardium in a dose-dependent manner. Astaxanthin (ATX) treatment could significantly alleviate zebrafish heart defects. CsA induced up-regulation of Wnt signaling in zebrafish, and IWR-1, an inhibitor of Wnt signaling pathway, could effectively rescue the heart defects induced by CsA. Together, our study indicated that CsA induced cardiac developmental toxicity in zebrafish larvae through up-regulating oxidative stress and Wnt signaling, contributing to a more comprehensive evaluation of the safety of the drug.
format	article
author	Mengqi Wan Ling Huang Jieping Liu Fasheng Liu Guilan Chen Huiwen Ni Guanghua Xiong Xinjun Liao Huiqiang Lu Juhua Xiao Qiang Tao Zigang Cao
author_facet	Mengqi Wan Ling Huang Jieping Liu Fasheng Liu Guilan Chen Huiwen Ni Guanghua Xiong Xinjun Liao Huiqiang Lu Juhua Xiao Qiang Tao Zigang Cao
author_sort	Mengqi Wan
title	Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress
title_short	Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress
title_full	Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress
title_fullStr	Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress
title_full_unstemmed	Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress
title_sort	cyclosporine a induces cardiac developmental toxicity in zebrafish by up-regulation of wnt signaling and oxidative stress
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/7655dadcd85841d0a724e67bbafe2ed6
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Cyclosporine A Induces Cardiac Developmental Toxicity in Zebrafish by Up-Regulation of Wnt Signaling and Oxidative Stress

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