Li Juanjuan, Zhang Yun, Liu Kechun, He Qiuxia, Sun Chen, Han Jian, Han Liwen, Tian Qingping
Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, China.
Front Pharmacol. 2018 Nov 6;9:1250. doi: 10.3389/fphar.2018.01250. eCollection 2018.
The aim of the study was to determine the developmental toxicity of the traditional Chinese medicine Xiaoaiping (XAP) and to investigate its underlying mechanism of action. Zebrafish embryos were incubated with 0.4, 0.8, 1.2, and 1.6 mg/mL XAP. Endpoints such as mortality, hatching rate, malformation, body length, morphology score, swimming behavior, histological changes, reactive oxygen species (ROS) production, total superoxide dismutase (T-SOD) activity, and the mRNA expression of genes related to oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and the Wnt pathway were evaluated. Our results demonstrated that XAP exposure increased mortality and malformation and reduced the hatching rate. XAP resulted in severe malformation, including swim bladder deficiency, yolk retention, pericardial edema, and tail curvature. Histopathological analysis showed that XAP induced liver, heart and muscle injury. High doses (≥1.2 mg/mL) of XAP notably decreased the locomotor capacity of zebrafish. ROS generation was remarkably increased and T-SOD activity was decreased, confirming that oxidative stress was induced by XAP. The mRNA expression levels of ER stress-related genes (), apoptosis-related genes (, , and ) and were significantly upregulated by XAP exposure. The expression levels of the oxidative stress-related genes (, , and ), Wnt pathway-related genes (β-, , and ) and initially increased and then decreased as the XAP exposure dose increased. In conclusion, we provide evidence for the first time that XAP can induce dose-related developmental toxicity, and ER stress, apoptosis and the Wnt pathway participate in the toxicity regulation.
本研究的目的是确定中药消癌平（XAP）的发育毒性，并探讨其潜在的作用机制。将斑马鱼胚胎与0.4、0.8、1.2和1.6mg/mL的XAP一起孵育。评估了死亡率、孵化率、畸形、体长、形态学评分、游泳行为、组织学变化、活性氧（ROS）产生、总超氧化物歧化酶（T-SOD）活性以及与氧化应激、内质网（ER）应激、细胞凋亡和Wnt信号通路相关基因的mRNA表达等终点指标。我们的结果表明，暴露于XAP会增加死亡率和畸形率，并降低孵化率。XAP导致严重畸形，包括鳔缺失、卵黄滞留、心包水肿和尾巴弯曲。组织病理学分析表明，XAP会诱导肝脏、心脏和肌肉损伤。高剂量（≥1.2mg/mL）的XAP显著降低斑马鱼的运动能力。ROS生成显著增加，T-SOD活性降低，证实XAP诱导了氧化应激。暴露于XAP后，ER应激相关基因（）、细胞凋亡相关基因（、和）以及的mRNA表达水平显著上调。随着XAP暴露剂量的增加，氧化应激相关基因（、和）、Wnt信号通路相关基因（β-、和）以及的表达水平最初升高，然后降低。总之，我们首次提供证据表明XAP可诱导剂量相关的发育毒性，并且ER应激、细胞凋亡和Wnt信号通路参与毒性调节。
