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Int. J. Mol. Sci. 2018, 19(11), 3516; https://doi.org/10.3390/ijms19113516

Toxicity Evaluation and Biomarker Selection with Validated Reference Gene in Embryonic Zebrafish Exposed to Mitoxantrone

1,2
,
1
,
2,* , 2
and
2
1
Beijing Key Laboratory of Fishery Biotechnology, Beijing Fisheries Research Institute, Beijing 100068, China
2
Graduate School, Chinese Academy of Agricultural Sciences, Beijing 100081, China
*
Author to whom correspondence should be addressed.
Received: 22 October 2018 / Revised: 3 November 2018 / Accepted: 6 November 2018 / Published: 8 November 2018
(This article belongs to the Section Molecular Toxicology)
Full-Text   |   PDF [2796 KB, uploaded 8 November 2018]   |  

Abstract

Notwithstanding the widespread use and promising clinical value of chemotherapy, the pharmacokinetics, toxicology, and mechanism of mitoxantrone remains unclear. To promote the clinical value in the treatment of human diseases and the exploration of potential subtle effects of mitoxantrone, zebrafish embryos were employed to evaluate toxicity with validated reference genes based on independent stability evaluation programs. The most stable and recommended reference gene was gapdh, followed by tubα1b, for the 48 h post fertilization (hpf) zebrafish embryo mitoxantrone test, while both eef1a1l1 and rpl13α were recommended as reference genes for the 96 hpf zebrafish embryo mitoxantrone test. With gapdh as an internal control, we analyzed the mRNA levels of representative hepatotoxicity biomarkers, including fabp10a, gclc, gsr, nqo1, cardiotoxicity biomarker erg, and neurotoxicity biomarker gfap in the 48 hpf embryo mitoxantrone test. The mRNA levels of gclc, gsr, and gfap increased significantly in 10 and 50 μg/L mitoxantrone-treated 48 hpf embryos, while the transcript levels of fabp10a decreased in a dose-dependent manner, indicating that mitoxantrone induced hepatotoxicity and neurotoxicity. Liver hematoxylin–eosin staining and the spontaneous movement of embryos confirmed the results. Thus, the present research suggests that mitoxantrone induces toxicity during the development of the liver and nervous system in zebrafish embryos and that fabp10a is recommended as a potential biomarker for hepatotoxicity in zebrafish embryos. Additionally, gapdh is proposed as a reference gene for the 48 hpf zebrafish embryo mitoxantrone toxicity test, while eef1a1l1 and rpl13α are proposed as that for the 96 hpf test. View Full-Text
Keywords: reference genes; stability evaluation; zebrafish embryos; mitoxantrone; toxicity evaluation; biomarker selection reference genes; stability evaluation; zebrafish embryos; mitoxantrone; toxicity evaluation; biomarker selection
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Liu, L.; Zhu, H.; Yan, Y.; Lv, P.; Wu, W. Toxicity Evaluation and Biomarker Selection with Validated Reference Gene in Embryonic Zebrafish Exposed to Mitoxantrone. Int. J. Mol. Sci. 2018, 19, 3516.

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