以正常动物为对象的毒性研究结果不能全面反映峻烈中药的发育毒性，限制了其临床应用，“有故无殒，亦无殒”是中医对妊娠期用药安全的权衡准则。本项目围绕“寒凝血瘀证是莪术神经发育毒性与活血化瘀功效选择性表达的决定性因素” 的科学假说，以妊娠禁忌中药莪术的子代脑组织氧化应激损伤为切入点，比较正常状态和寒凝血瘀证模型小鼠母体妊娠期莪术暴露对子代神经发育、脑组织氧化应激和凋亡影响的差异。观察寒邪（冷应激）对核因子E2相关因子2（Nrf2）介导的抗氧化应激通路信号分子的影响，并利用Nrf2基因敲除小鼠和Nrf2激动剂叔丁基对苯二酚（tBHQ）验证Nrf2在神经发育毒性选择性表达中的关键作用。丰富“有故无殒，亦无殒”的中药辨证减毒理论的科学内涵，对构建符合中医理论和临床实际的中药神经发育毒性研究体系具有重要的理论和现实意义。

Results obtained with normal animal could not completely demonstrate embryo-fetal developmental toxicity of Chinese medicine with drastic effect, which have restricted rational clinical applicability of it. The theory of “YOU-GU-WU-YUN” is criterion about safety of Chinese medicine during pregnancy. Therefore, we propose the working hypothesis that cold coagulation and blood stasis syndrome is determining factor for selective expression of developmental neurotoxicity of Rhizoma Curcumae or its therapentic effect of removing blood stasis and resolving static blood. To test this hypothesis, this project take brain tissue of offspring from oxidative stress injury and apoptosis induced by Rhizoma Curcumae, which is forbidden to take for pregnant women, as an entry point to evaluate the differences of developmental neurotoxicity, oxidative stress and apoptosis in offspring between normal and cold coagulation and blood stasis syndrome pregnant mice. Then, we investigate the effect of cold stress on the Nrf2-mediated anti-oxidative stress signaling pathway, and the important role played by Nrf2 in selective expression of developmental neurotoxicity of Rhizoma Curcumae was verified using Nrf2-deficient mice and tert-butylhydroquinone, Nrf2 pharmacological activators. This project will evidence the theory of toxicity-attenuating based on syndrome differentiation of Chinese medicine, and has the important theory and the practical significance for establishing research system of developmental neurotoxicity of traditional Chinese medicine.