Department of Obstetrics and Gynecology, Tao-Yuan Hospital, Ministry of Health & Welfare, Taoyuan City 33004, Taiwan.
Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Taoyuan City 32023, Taiwan.
Int J Mol Sci. 2017 Sep 20;18(9):2018. doi: 10.3390/ijms18092018.
Rhein, a glucoside chemical compound found in a traditional Chinese medicine derived from the roots of rhubarb, induces cell apoptosis and is considered to have high potential as an antitumor drug. Several previous studies showed that rhein can inhibit cell proliferation and trigger mitochondria-related or endoplasmic reticulum (ER) stress-dependent apoptotic processes. However, the side effects of rhein on pre- and post-implantation embryonic development remain unclear. Here, we show that rhein has cytotoxic effects on blastocyst-stage mouse embryos and induces oxidative stress and immunotoxicity in mouse fetuses. Blastocysts incubated with 5-20 μM rhein showed significant cell apoptosis, as well as decreases in their inner cell mass cell numbers and total cell numbers. An in vitro development assay showed that rhein affected the developmental potentials of both pre- and post-implantation embryos. Incubation of blastocysts with 5-20 μM rhein was associated with increased resorption of post-implantation embryos and decreased fetal weight in an embryo transfer assay. Importantly, in an in vivo model, intravenous injection of dams with rhein (1, 3, and 5 mg/kg body weight/day) for four days resulted in apoptosis of blastocyst-stage embryos, early embryonic developmental injury, and decreased fetal weight. Intravenous injection of dams with 5 mg/kg body weight/day rhein significantly increased the total reactive oxygen species (ROS) content of fetuses and the transcription levels of antioxidant proteins in fetal livers. Additional work showed that rhein induced apoptosis through ROS generation, and that prevention of apoptotic processes effectively rescued the rhein-induced injury effects on embryonic development. Finally, the transcription levels of the innate-immunity related genes, , and , were down-regulated in the fetuses of dams that received intravenous injections of rhein. These results collectively show that rhein has the potential to induce embryonic cytotoxicity and induce oxidative stress and immunotoxicity during the development of mouse embryos.
大黄酸是一种来源于大黄根的中药中的糖苷类化合物，它能诱导细胞凋亡，被认为是一种很有前途的抗肿瘤药物。以前的几项研究表明，大黄酸可以抑制细胞增殖，并触发与线粒体或内质网（ER）应激相关的凋亡过程。然而，大黄酸对植入前和植入后胚胎发育的副作用尚不清楚。在这里，我们表明大黄酸对囊胚期的小鼠胚胎具有细胞毒性作用，并在小鼠胎儿中诱导氧化应激和免疫毒性。用 5-20μM 大黄酸孵育的囊胚表现出明显的细胞凋亡，以及其内细胞团细胞数量和总细胞数量减少。体外发育试验表明，大黄酸影响植入前和植入后胚胎的发育潜力。在胚胎移植试验中，用 5-20μM 大黄酸孵育囊胚与着床后胚胎的吸收率增加和胎儿体重下降有关。重要的是，在体内模型中，对母体静脉注射大黄酸（1、3 和 5mg/kg 体重/天）四天导致囊胚期胚胎凋亡、早期胚胎发育损伤和胎儿体重下降。静脉注射母体 5mg/kg 体重/天的大黄酸显著增加了胎儿的总活性氧（ROS）含量和胎肝中抗氧化蛋白的转录水平。进一步的研究表明，大黄酸通过 ROS 的产生诱导凋亡，而阻止凋亡过程能有效地挽救大黄酸对胚胎发育的损伤作用。最后，注射大黄酸的母体胎儿中先天免疫相关基因 、 和 的转录水平下调。这些结果表明，大黄酸有可能诱导胚胎细胞毒性，并在小鼠胚胎发育过程中诱导氧化应激和免疫毒性。
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