State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
National Demonstration Center for Experimental Biological Sciences Education, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Toxicol Appl Pharmacol. 2018 Feb 15;341:8-15. doi: 10.1016/j.taap.2018.01.002. Epub 2018 Jan 5.
Dihydroartemisinin (DHA), the main active metabolite of artemisinin, has been used to treat malaria and has anticancer activities. Previous work has shown that DHA has negative impacts on embryos in rodents and primates. However, whether DHA has adverse effects on oocyte maturation is unknown. In the present study, we evaluated the toxic effects and possible mechanisms of DHA on porcine oocyte maturation. The results showed that exposure to DHA inhibited porcine oocyte polar body extrusion, and blocked cell cycle progression. Meanwhile, early embryo development after parthenogenetic activation was also impaired. DHA disturbed spindle morphology and actin assembly in porcine oocytes by reducing phosphorylation levels of MAPK. Moreover, the ROS content was increased and the mitochondrial membrane potential decreased in oocytes treated with DHA. DHA also increased the levels of intracellular and mitochondrial calcium. Furthermore, Annexin V-FITC staining showed that early apoptosis occurred in DHA-treated oocytes. The mRNA levels of apoptosis-related genes BAX and CASP3 were increased, and the anti-apoptotic gene BCL2 was decreased in oocytes exposed to DHA. Taken together, these results indicate that DHA exposure impairs porcine oocyte maturation in vitro via mechanisms involved in cytoskeleton dynamics, oxidative stress, calcium homeostasis, and apoptosis.
二氢青蒿素（DHA）是青蒿素的主要活性代谢物，已被用于治疗疟疾，并具有抗癌活性。先前的工作表明，DHA 对啮齿动物和灵长类动物的胚胎有不良影响。然而，DHA 是否对卵母细胞成熟有不良影响尚不清楚。在本研究中，我们评估了 DHA 对猪卵母细胞成熟的毒性作用及其可能的机制。结果表明，暴露于 DHA 抑制猪卵母细胞极体排出，并阻断细胞周期进程。同时，孤雌激活后的早期胚胎发育也受到损害。DHA 通过降低 MAPK 的磷酸化水平来干扰猪卵母细胞中的纺锤体形态和肌动蛋白组装。此外，DHA 处理的卵母细胞中 ROS 含量增加，线粒体膜电位降低。DHA 还增加了细胞内和线粒体钙的水平。此外，Annexin V-FITC 染色显示 DHA 处理的卵母细胞发生早期凋亡。暴露于 DHA 的卵母细胞中凋亡相关基因 BAX 和 CASP3 的 mRNA 水平升高，而抗凋亡基因 BCL2 降低。综上所述，这些结果表明，DHA 暴露通过细胞骨架动态、氧化应激、钙稳态和细胞凋亡相关机制损害体外猪卵母细胞成熟。
