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Chemosphere. 2019 Dec 24;246:125727. doi: 10.1016/j.chemosphere.2019.125727. [Epub ahead of print]

Isoliquiritigenin triggers developmental toxicity and oxidative stress-mediated apoptosis in zebrafish embryos/larvae via Nrf2-HO1/JNK-ERK/mitochondrion pathway.

Author information

1
School of Pharmacy, Hebei University, Baoding, 071002, China; Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan, 250103, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, 250103, China.
2
Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan, 250103, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, 250103, China.
3
Shandong Academy of Chinese Medicine, Jinan, 250014, China.
4
Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li, 32023, China.
5
School of Pharmacy, Hebei University, Baoding, 071002, China. Electronic address: lijianheng@hbu.cn.
6
Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan, 250103, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, 250103, China. Electronic address: sdxq1021@163.com.
7
Biology Institute, Qilu University of Technology, Shandong Academy of Sciences, Jinan, 250103, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, 250103, China. Electronic address: hliukch@sdas.org.

Abstract

Isoliquiritigenin (ISL) is an emerging natural flavonoid found in the roots of licorice, exhibits antioxidant, anti-cancer, anti-inflammatory, anti-allergic, cardioprotective, hepatoprotective and neuroprotective properties. However, the effect of ISL in embryonic development is yet to be elucidated, and the mechanisms underlying its target-organ toxicity and harmful side effects are still unclear. In the present study, we employed zebrafish embryos to study the developmental toxicity effect of ISL and its underlying mechanisms. Zebrafish embryos upon treatment with either vehicle control (0.1% DMSO) or ISL solutions for 4-96 h post fertilization (hpf) showed that ISL exposure instigated severe developmental toxicity in heart, liver, and nervous system. Mortality and morphological abnormalities were also observed. High concentrations of ISL exposure resulted in abnormal phenotypes and embryonic malformations including pericardial edema, swim bladder defects, yolk retention, curved body shape and shortening of body length. Moreover, ISL exposure led to significant loss of dopaminergic neurons accompanied by reduced locomotor behaviour. Apoptotic cells were predominantly located in the heart area of 96 hpf embryo. Additionally, ISL significantly increased the levels of reactive oxygen species, lipid peroxidation content and decreased antioxidant enzyme activities. The expressions pattern of apoptosis-related genes Bad, Cyto c, Caspase-9, Caspase-3 and Bax/Bcl-2 indicated that the oxidative stress-induced apoptosis triggered by ISL suggest involvement of Nrf2-HO1/JNK-ERK/mitochondrion pathways. In conclusion, here we provide first evidence that demonstrate ISL-induced dose-dependent developmental toxicity in zebrafish embryos. Furthermore, gene expression patterns in the embryos correlate the above and reveal potential genetic mechanisms of developmental toxicity.

KEYWORDS:

Apoptosis; Developmental toxicity; Isoliquiritigenin; Oxidative stress; Zebrafish

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