Publication List English

2024/08/06
Validation of a new protocol for a zebrafish MEFL (malformation or embryo-fetal lethality) test method that conforms to the ICH S5 (R3) guideline.

2024/05/21
In vivo assessment of individual and total proteinuria in zebrafish larvae using the solvatochromic compound ZMB741

2021/10/31
Generation of a Transgenic Zebrafish Line for In Vivo Assessment of Hepatic Apoptosis

2021/08/19
Patient-Derived Cancer Xenograft Zebrafish Model (PDXZ) for Drug Discovery Screening and Personalized Medicine

2021/07/09
Quality Control Protocol for Zebrafish Developmental Toxicity Studies

tIncreased susceptibility to oxidative stress-induced toxicological evaluation by genetically modified nrf2a-deficient zebrafish.

                     
2018/12/27

J Pharmacol Toxicol Methods. 2018 Dec 27;96:34-45. doi: 10.1016/j.vascn.2018.12.006. [Epub ahead of print]
Increased susceptibility to oxidative stress-induced toxicological evaluation by genetically modified nrf2a-deficient zebrafish.
Yamashita A1, Deguchi J2, Honda Y2, Yamada T2, Miyawaki I2, Nishimura Y3, Tanaka T4.
Author information
Abstract
INTRODUCTION:
Oxidative stress plays an important role in drug-induced toxicity. Oxidative stress-mediated toxicities can be detected using conventional animal models but their sensitivity is insufficient, and novel models to improve susceptibility to oxidative stress have been researched. In recent years, gene targeting methods in zebrafish have been developed, making it possible to generate homozygous null mutants. In this study, we established zebrafish deficient in the nuclear factor erythroid 2-related factor 2a (nrf2a), a key antioxidant-responsive gene, and its potential to detect oxidative stress-mediated toxicity was examined.

METHODS:
Nrf2a-deficient zebrafish were generated using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 technique. The loss of nrf2a function was confirmed by the tolerability to hydrogen peroxide and hydrogen peroxide-induced gene expression profiles being related to antioxidant response element (ARE)-dependent signaling. Subsequently, vulnerability of nrf2a-deficient zebrafish to acetaminophen (APAP)- or doxorubicin (DOX)-induced toxicity was investigated.

RESULTS:
Nrf2a-deficient zebrafish showed higher mortality than wild type accompanied by less induction of ARE-dependent genes with hydrogen peroxide treatment. Subsequently, this model showed increased severity and incidence of APAP-induced hepatotoxicity or DOX-induced cardiotoxicity than wild type.

DISCUSSION:
Our results demonstrated that anti-oxidative response might not fully function in this model, and resulted in higher sensitivity to drug-induced oxidative stress. Our data support the usefulness of nrf2a-deficient model as a tool for evaluation of oxidative stress-related toxicity in drug discovery research.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS:
Acetaminophen; Doxorubicin; Nrf2a-deficiency; Oxidative stress; Toxicity evaluation; Zebrafish

PMID: 30594530 DOI: 10.1016/j.vascn.2018.12.006

ŠΦ˜AƒŠƒ“ƒN

ŽOd‘εŠw‘εŠw‰@ˆγŠwŒnŒ€‹†‰ΘƒVƒXƒeƒ€ƒY–ς—Šw

PubMed

ŠΦ˜Aƒtƒ@ƒCƒ‹

J Pharmacol Toxicol Methods. 2018 Dec 27;96:34-45. doi: 10.1016/j.vascn.2018.12.006. [Epub ahead of print]