Sulik K K, Cook C S, Webster W S
Department of Anatomy, University of North Carolina, Chapel Hill 27514.
Development. 1988;103 Suppl:213-31. doi: 10.1242/dev.103.Supplement.213.
Environmental agents including ethanol, 13-cis retinoic acid (RA, Accutane), the antimetabolite methotrexate, periods of hypoxia, ionizing radiation or hyperthermic stress, when administered acutely to pregnant experimental animals, induce stage-dependent craniofacial malformations comparable to those in corresponding human teratogen syndromes. Acute treatment regimens have allowed analysis of cell populations initially affected and subsequent dysmorphogenetic sequences as well as speculation relative to mechanisms of teratogenesis. In rodent models, ethanol and RA appear to affect similar cell populations and comparable malformations can be induced by both agents. When administered during gastrulation they cause a major insult to the anterior neural plate which results in characteristic ocular, brain and facial malformations comparable to those seen in the fetal alcohol syndrome. Exposure to these drugs at a time just prior to and during neural crest cell migration into the craniofacial and cervical regions results in malformations comparable to those seen in the Di-George sequence and/or retinoic acid embryopathy. Slightly later, at the time that the epibranchial placodes are active, insult results in mandibulofacial dysostosis-like syndromes. We propose that the pattern of these malformations is related to the particular vulnerability of cells in the vicinity of normal programmed cell death. Cell death is also associated with ionizing radiation and hyperthermia-induced malformations. Both of these teratogens are particularly damaging to the early development of the eye and central nervous system. Teratogenic temperature elevations result in arrest of mitotic activity and death of cells in mitosis. Hypoxia is also associated with cell death in specific regions and subsequent malformation. For example, death of cells in the invaginating olfactory placode has recently been associated with cleft lip formation. The relationship of hypoxia-induced cell death to energy requirements is being explored. Acute treatment with methotrexate results in frontonasal dysplasia (median facial clefts). Combined effects of fluid imbalance, lack of proliferation or death of frontonasal mesenchyme appear to be involved. Although the mechanisms of craniofacial malformation are complex, a common feature for many is excessive cell death for which the embryo may be unable to compensate. Excessive cell death in regions of programmed cell death represents an important, yet little appreciated, mechanism of teratogenesis.
包括乙醇、13 - 顺式维甲酸（RA，异维甲酸）、抗代谢物甲氨蝶呤、缺氧期、电离辐射或热应激在内的环境因素，在对怀孕实验动物进行急性给药时，会诱发与相应人类致畸综合征中类似的、依赖发育阶段的颅面畸形。急性治疗方案有助于分析最初受影响的细胞群体以及随后的畸形发生序列，还能对致畸机制进行推测。在啮齿动物模型中，乙醇和RA似乎会影响相似的细胞群体，且两种药物均可诱发类似的畸形。在原肠胚形成期给药时，它们会对前神经板造成严重损伤，从而导致与胎儿酒精综合征中所见类似的典型眼部、脑部和面部畸形。在神经嵴细胞迁移至颅面和颈部区域之前及期间接触这些药物，会导致与Di-George序列和/或维甲酸胚胎病中所见类似的畸形。稍晚些时候，在外鳃板活跃时受到损伤会导致下颌面骨发育不全样综合征。我们认为，这些畸形的模式与正常程序性细胞死亡附近细胞的特殊易损性有关。细胞死亡也与电离辐射和热诱导的畸形有关。这两种致畸剂对眼睛和中枢神经系统的早期发育尤其具有破坏性。致畸性温度升高会导致有丝分裂活动停滞以及处于有丝分裂期的细胞死亡。缺氧也与特定区域的细胞死亡及随后的畸形有关。例如，最近发现内陷的嗅基板中的细胞死亡与唇裂形成有关。正在探索缺氧诱导的细胞死亡与能量需求之间的关系。甲氨蝶呤急性治疗会导致额鼻发育不全（正中面部裂）。似乎涉及液体失衡、额鼻间充质增殖不足或死亡的综合作用。尽管颅面畸形的机制很复杂，但许多畸形的一个共同特征是细胞过度死亡，而胚胎可能无法对此进行补偿。程序性细胞死亡区域的细胞过度死亡是致畸的一个重要但尚未得到充分认识的机制。
