National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS, USA.
Chem Res Toxicol. 2010 Aug 16;23(8):1405-16. doi: 10.1021/tx100205a.
Blue cohosh (Caulophyllum thalictroides) (BC) has been used widely to induce labor and to treat other uterine conditions. However, the safety and effectiveness of this herbal product has not yet been evaluated by the US Food and Drug Administration (FDA). Several conflicting reports indicated that the root extract of BC is a teratogen and, by some unknown mechanisms, is able to induce cardiovascular malfunctions in new-born babies. To understand the mechanism, we have used Japanese medaka (Oryzias latipes) embryo-larval development as the experimental model and the methanolic extract of BC root as the teratogen. The embryo mortality, hatching efficiency, and morphological abnormalities in craniofacial and cardiovascular systems are considered for the evaluation of BC toxicity. Our results indicate that BC is able to disrupt cardiovascular and craniofacial cartilage development in medaka embryo in a dose and developmental stage-specific manner. Moreover, embryos in precirculation are to some extent more resistant to BC than ones with circulation. By using subtractive hybridization, we have observed that gata2 mRNA was differentially expressed in the circulating embryos after BC treatment. As GATA-binding sequences are required for the expression of the endothelin1 (edn1) gene and edn1 expressed in blood vessels and craniofacial cartilages, we have extended our investigations to edn1 gene expression regulation by BC. We found that edn1, furin1, and endothelin receptor A (ednrA) genes are developmentally regulated; endothelin converting enzyme mRNA (ece1) maintained a steady-state level throughout development. Circulating medaka embryos (3 days post fertilization, dpf) exposed to BC (10 microg/mL) for 48 h have increased levels of gata2, ece1, and preproenodthelin (preproedn1) mRNA contents; however, other mRNAs (furin and ednrA) remained unaltered. Therefore, the enhanced expression of gata2 mRNA followed by ece1 and preproedn1 mRNA by BC might be able to induce vasoconstriction and cardiovascular defects and disrupt craniofacial cartilages in medaka embryos. We conclude that cardiovascular and craniofacial defects in medaka embryogenesis by BC are probably mediated through a GATA2-EDN1 signaling pathway.
升麻（Caulophyllum thalictroides）（BC）被广泛用于引产和治疗其他子宫疾病。然而，这种草药产品的安全性和有效性尚未得到美国食品和药物管理局（FDA）的评估。一些相互矛盾的报告表明，BC 的根提取物是一种致畸物，并通过一些未知的机制，能够在新生儿中引起心血管功能障碍。为了了解这种机制，我们使用日本青鳉（Oryzias latipes）胚胎-幼虫发育作为实验模型，用 BC 根的甲醇提取物作为致畸物。胚胎死亡率、孵化效率和颅面及心血管系统的形态异常被认为是评估 BC 毒性的指标。我们的结果表明，BC 能够以剂量和发育阶段特异性的方式破坏青鳉胚胎的心血管和颅面软骨发育。此外，在循环前的胚胎在某种程度上比有循环的胚胎更能抵抗 BC。通过使用消减杂交，我们观察到 gata2mRNA 在 BC 处理后的循环胚胎中差异表达。由于 GATA 结合序列是内皮素 1（edn1）基因表达所必需的，而 edn1 在血管和颅面软骨中表达，我们将研究扩展到 BC 对 edn1 基因表达的调控。我们发现，edn1、furin1 和内皮素受体 A（ednrA）基因是发育调控的；内皮素转换酶 mRNA（ece1）在整个发育过程中保持稳定水平。暴露于 BC（10μg/mL）48 小时的循环青鳉胚胎（受精后 3 天，dpf），gata2、ece1 和前内皮素原（preproedn1）mRNA 含量增加；然而，其他 mRNA（furin 和 ednrA）保持不变。因此，BC 诱导的 gata2mRNA 表达增加，随后是 ece1 和 preproedn1mRNA，可能能够诱导血管收缩和心血管缺陷，并破坏青鳉胚胎的颅面软骨。我们得出结论，BC 诱导的青鳉胚胎心血管和颅面缺陷可能是通过 GATA2-EDN1 信号通路介导的。
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