Webster William S, Abela Dominique
Department of Anatomy and Histology, University of Sydney, Sydney, Australia.
Birth Defects Res C Embryo Today. 2007 Sep;81(3):215-28. doi: 10.1002/bdrc.20102.
There is increasing evidence that the oxygen supply to the human embryo in the first trimester is tightly controlled, suggesting that too much oxygen may interfere with development. The use of hypoxia probes in mammalian embryos during the organogenic period indicates that the embryo is normally in a state of partial hypoxia, and this may be essential to control cardiovascular development, perhaps under the control of hypoxia-inducible factor (HIF). A consequence of this state of partial hypoxia is that disturbances in the oxygen supply can more easily lead to a damaging degree of hypoxia. Experimental mammalian embryos show a surprising degree of resilience to hypoxia, with many organogenic stage embryos able to survive 30-60 min of anoxia. However, in some embryos this degree of hypoxia causes abnormal development, particularly transverse limb reduction defects. These abnormalities are preceded by hemorrhage/edema and tissue necrosis. Other parts of the embryo are also susceptible to this hypoxia-induced damage and include the genital tubercle, the developing nose, the tail, and the central nervous system. Other frequently observed defects in animal models of prenatal hypoxia include cleft lip, maxillary hypoplasia, and heart defects. Animal studies indicate that hypoxic episodes in the first trimester of human pregnancy could occur by temporary constriction of the uterine arteries. This could be a consequence of exposure to cocaine, misoprostol, or severe shock, and there is evidence that these exposures have resulted in hypoxia-related malformations in the human. Exposure to drugs that block the potassium current (IKr) can cause severe slowing and arrhythmia of the mammalian embryonic heart and consequently hypoxia in the embryo. These drugs are highly teratogenic in experimental animals. There is evidence that drugs with IKr blockade as a side effect, for example phenytoin, may cause birth defects in the human by causing periods of embryonic hypoxia. The strongest evidence of hypoxia causing birth defects in the human comes from studies of fetuses lacking hemoglobin (Hb) F. These fetuses are thought to be hypoxic from about the middle of the first trimester and show a range of birth defects, particularly transverse limb reduction defects.
越来越多的证据表明，孕早期人类胚胎的氧气供应受到严格控制，这表明过多的氧气可能会干扰发育。在器官形成期对哺乳动物胚胎使用缺氧探针表明，胚胎通常处于部分缺氧状态，这可能对控制心血管发育至关重要，或许是在缺氧诱导因子（HIF）的控制之下。这种部分缺氧状态的一个后果是，氧气供应的干扰更容易导致有害程度的缺氧。实验性哺乳动物胚胎对缺氧表现出惊人的恢复能力，许多器官形成期胚胎能够在缺氧30 - 60分钟后存活下来。然而，在一些胚胎中，这种程度的缺氧会导致异常发育，尤其是横向肢体减少缺陷。这些异常之前会出现出血/水肿和组织坏死。胚胎的其他部分也易受这种缺氧诱导的损伤，包括生殖结节、发育中的鼻子、尾巴和中枢神经系统。产前缺氧动物模型中其他常见的缺陷包括唇裂、上颌发育不全和心脏缺陷。动物研究表明，人类妊娠早期的缺氧事件可能是由于子宫动脉的暂时收缩引起的。这可能是接触可卡因、米索前列醇或严重休克的结果，并且有证据表明这些接触会导致人类出现与缺氧相关的畸形。接触阻断钾电流（IKr）的药物会导致哺乳动物胚胎心脏严重减慢和心律失常，从而导致胚胎缺氧。这些药物在实验动物中具有高度致畸性。有证据表明，具有IKr阻断副作用的药物，例如苯妥英，可能通过导致胚胎缺氧期而在人类中引起出生缺陷。缺氧导致人类出生缺陷的最有力证据来自对缺乏血红蛋白（Hb）F的胎儿的研究。这些胎儿被认为从孕早期中期左右开始缺氧，并表现出一系列出生缺陷，尤其是横向肢体减少缺陷。
