Alexander Peter G, Chau Lillian, Tuan Rocky S
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-8022, USA.
Birth Defects Res A Clin Mol Teratol. 2007 Aug;79(8):581-94. doi: 10.1002/bdra.20386.
Nitric oxide (NO), produced by the nitric oxide synthase family of enzymes, mediates multiple signaling functions, and when unchecked, NO causes pathological damage. Exposure of embryos to a variety of teratogens, including carbon monoxide (CO), has been shown to increase reactive intermediates, such as NO, and recent work showed that either the excess or absence of NO caused morphological defects. While endogenous NO is known to regulate many adult tissues, its role during embryonic organogenesis and/or in mediating responses to teratogen exposure has not been explored.
We have examined here the presence of NO during normal chick embryonic organogenesis, and investigated the teratogenicity of NO through the application of sodium nitroprusside (SNP), which mimics NO overproduction, and NG-monomethyl-L-arginine (L-NMMA), which inhibits endogenous NOS activity.
Topical treatment with SNP or L-NMMA for 18 h resulted in morphological defects, specifically in the neural tube and somites, which corresponded to sites of altered apoptosis. The location of NO was histochemically correlated with the observed morphological defects. Coadministration of SNP or L-NMMA with CO showed functional coregulation and interaction between NO and CO in chick embryonic development.
Our results showed that regulation of NO is essential for normal axial development, that sites of altered NO expression correlate to those of altered apoptosis and dysmorphogenesis, and that CO coadministration resulted in a rectification of normal NO expression. Collectively, these results suggest that alteration in endogenous NO/CO signaling is responsible, at least in part, for the observed NO-induced teratogenesis.
一氧化氮合酶家族的酶产生的一氧化氮（NO）介导多种信号功能，若不受控制，NO会导致病理损伤。已表明胚胎暴露于包括一氧化碳（CO）在内的多种致畸物会增加活性中间体，如NO，并且最近的研究表明，NO过量或缺乏都会导致形态缺陷。虽然已知内源性NO调节许多成年组织，但其在胚胎器官发生过程中的作用和/或在介导对致畸物暴露的反应方面尚未得到探索。
我们在此研究了正常鸡胚器官发生过程中NO的存在情况，并通过应用硝普钠（SNP）模拟NO过量产生，以及应用NG-甲基-L-精氨酸（L-NMMA）抑制内源性NOS活性来研究NO的致畸性。
用SNP或L-NMMA局部处理18小时会导致形态缺陷，特别是神经管和体节的缺陷，这与凋亡改变的部位相对应。NO的定位与观察到的形态缺陷在组织化学上相关。SNP或L-NMMA与CO共同给药显示在鸡胚发育中NO和CO之间存在功能协同调节和相互作用。
我们的结果表明，NO的调节对于正常的轴向发育至关重要，NO表达改变的部位与凋亡改变和畸形发生的部位相关，并且CO共同给药导致正常NO表达的纠正。总的来说，这些结果表明内源性NO/CO信号的改变至少部分地导致了观察到的NO诱导的致畸作用。
