Tong Jun-Wei, Zhang Jing-Pu, Meng Jie
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Yao Xue Xue Bao. 2011 Jan;46(1):50-7.
The pharmaceutical ethynylestradiol (EE) is a potent endocrine modulator. Application enlargement of ethynylestradiol in clinics and abuse in livestock farming and fishing make it important to explore ethynylestradiol toxicological action on vertebrate embryonic development and to establish an in vivo method for EE toxicity detection efficiently and conveniently. In the present study, using a model animal zebrafish and 17alpha-ethynylestradiol as a representative compound, we have investigated EE2 teratogenicity, target tissues and target genes on zebrafish embryo. The results show that median teratogenesis concentration (TC50) of EE2 is 0.8 microg x mL(-1), and median lethal dose (LD50) is 3.3 microg x mL(-1). Targets of EE2 action were implicated in brain, eyes, heart, muscle, skeleton, pigment and viscera. Embryonic cardiac arrhythmia caused by EE2 is probably resulted from heart abnormal structure. The embryonic stage sensitive to EE2 mainly started at cleavage and last up to the organogenesis with time-accumulating effect. RT-PCR results indicate that EE2 treatment disturbed gene expression pattern at the early period of zebrafish embryonic development by suppressing transcription of gene boz that promotes brain development, upregulating genes for trunk and tail, such as ntl, spt, shh, and perturbing Nodal signal expression of TGFbeta superfamily, for example, cyc, sqt and oep. Using zebrafish, an efficient in vivo method for quick evaluation of EE toxicity on embryonic development has been developed.
药物乙炔雌二醇（EE）是一种强效内分泌调节剂。乙炔雌二醇在临床上的应用扩大以及在畜牧业和渔业中的滥用，使得探索其对脊椎动物胚胎发育的毒理作用并建立一种高效便捷的体内EE毒性检测方法变得尤为重要。在本研究中，我们以模式动物斑马鱼和17α - 乙炔雌二醇作为代表性化合物，研究了EE2对斑马鱼胚胎的致畸性、靶组织和靶基因。结果表明，EE2的致畸中浓度（TC50）为0.8μg·mL-1，致死中剂量（LD50）为3.3μg·mL-1。EE2的作用靶点涉及脑、眼、心脏、肌肉、骨骼、色素和内脏。EE2引起的胚胎心律失常可能是由心脏结构异常导致的。对EE2敏感的胚胎阶段主要从卵裂期开始，一直持续到器官形成期，具有时间累积效应。RT-PCR结果表明，EE2处理通过抑制促进脑发育的基因boz的转录、上调躯干和尾部相关基因（如ntl、spt、shh）以及干扰TGFβ超家族的Nodal信号表达（如cyc、sqt和oep），扰乱了斑马鱼胚胎发育早期的基因表达模式。利用斑马鱼，已开发出一种高效的体内方法，用于快速评估EE对胚胎发育的毒性。
