Alexander Peter G, Tuan Rocky S
Department of Orthopaedic Surgery and Graduate Program of Developmental Biology and Teratology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Birth Defects Res A Clin Mol Teratol. 2003 Apr;67(4):219-30. doi: 10.1002/bdra.10041.
Congenital axial skeletal defects affect two to three individuals per 1,000 live births. Without strong evidence for heritability, the cause is assumed to be multi-factorial. Carbon monoxide (CO), an increasingly prevalent environmental toxicant, is a potential environmental component in the etiology of these defects. The chick embryo is a useful model for the characterization and assessment of the mechanism(s) of action of basic developmental mechanisms.
We have determined a critical period and dose for CO teratogenicity and established a model of CO-induced axial skeletal dysmorphogenesis in the chick embryo. The resulting phenotypes reveal a spectrum of axial skeletal defects ranging from minor defects of the vertebral canal and inter-vertebral discs, to thoraco-lumbar scoliosis, to a tailless phenotype reminiscent of caudal dysgenesis syndrome. These axial skeletal defects have been related to earlier developmental defects in somitogenesis, including errors in segmentation and epithehalization and the expression of the somitic epithelialization factor, Paraxis. We have examined patterns of cell death and apoptosis in CO exposed chick embryos to assess the target tissue(s) involved in the teratogenicity of CO.
With respect to the embryonic axis, the neural tube was found to be the most sensitive to CO-induced apoptosis, followed by the somitic mesoderm and Hensen's node.
We hypothesize that the somitic defects and the resulting axial skeletal dysmorphogenesis are caused by disrupted neural tube or ectoderm functions related to somite formation and maintenance. We also hypothesize that CO-induced dysmorphogenesis at this critical period of somitogenesis is caused by the overabundance of CO acting endogenously as a cellular signal, while coincidentally exerting its influence as a toxicant of oxygen delivery or utilization.
先天性轴骨骼缺陷在每1000例活产中影响2至3人。由于缺乏有力的遗传证据，其病因被认为是多因素的。一氧化碳（CO）作为一种日益普遍的环境毒物，是这些缺陷病因中潜在的环境因素。鸡胚是表征和评估基本发育机制作用机制的有用模型。
我们确定了CO致畸性的关键时期和剂量，并建立了鸡胚中CO诱导的轴骨骼畸形发生模型。所产生的表型揭示了一系列轴骨骼缺陷，范围从椎管和椎间盘的轻微缺陷到胸腰椎脊柱侧弯，再到类似尾发育不全综合征的无尾表型。这些轴骨骼缺陷与体节发生早期的发育缺陷有关，包括分割和上皮化错误以及体节上皮化因子Paraxis的表达。我们检查了暴露于CO的鸡胚中的细胞死亡和凋亡模式，以评估参与CO致畸性的靶组织。
就胚胎轴而言，发现神经管对CO诱导的凋亡最敏感，其次是体节中胚层和亨氏结。
我们假设体节缺陷及由此产生的轴骨骼畸形发生是由与体节形成和维持相关的神经管或外胚层功能紊乱引起的。我们还假设在体节发生的这个关键时期，CO诱导的畸形发生是由于内源性作为细胞信号的CO过量，同时作为氧输送或利用的毒物发挥其影响。
