Abbott B D, Birnbaum L S
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Teratology. 1990 Dec;42(6):597-610. doi: 10.1002/tera.1420420604.
Retinoic acid (RA) is teratogenic in many species, producing multiple malformations, including cleft palate. The effects of RA which lead to cleft palate vary depending on the stage of development exposed. After exposure of embryonic mice to RA on gestation day (GD) 10, abnormally small palatal shelves form. After exposure on GD 12 shelves of normal size form, but fail to fuse, as the medial cells proliferate and differentiate into a nasal-like epithelium. Growth factors and their receptors play an important role in regulating development, and the expression of EGF receptors, EGF, TGF-alpha, TFG-beta 1, and TGF-beta 2 has been reported in the mouse embryo. In a variety of cell types in culture, these growth factors are capable of regulating proliferation, differentiation, expression of matrix proteins, and other cellular events including epithelial-mesenchymal transformations. The present study examines immunohistochemically the expression of EGF, TGF-alpha, TGF-beta 1, and TGF-beta 2 in the control embryonic palatal shelves from GD 12 to 15 and the effects of RA treatment on GD 10 or 12 on their expression on GD 14 and 16. These growth factors were shown to have specific temporal and spatial expression in the palatal shelf. With advancing development the levels of TGF-alpha decreased while the expression of EGF increased. TGF-beta 2 localization became regional by GD 14-15, with higher levels found in epithelial cells and chondrogenic mesenchyme. TGF-beta 1 occurred in epithelial and mesenchymal cells and distribution did not change substantially with advancing development. RA exposure altered the expression of TFG-alpha, TGF-beta 1, and TGF-beta 2, but significant effects on EGF were not found. The effects on TGF-alpha and TGF-beta 1 expression were dependent on the gestational age exposed. Levels of TGF-alpha on GD 14 decreased after RA exposure on GD 10, but increased after GD 12 exposure. TGF-beta 1 expression in the mesenchyme was increased after exposure on GD 12, but was unaffected by RA on GD 10. After exposure on either day, the levels of TGF-beta 2 increased in GD 14 nasal epithelial cells. Acting in concert, growth factors could regulate events critical to formation of the secondary palate, including cessation of medial epithelial cell proliferation, synthesis of extracellular matrix proteins in the mesenchyme, programmed cell death of medial epithelial peridermal cells, and transformation of basal epithelial medial cells to mesenchymal cells.(ABSTRACT TRUNCATED AT 400 WORDS)
维甲酸（RA）在许多物种中具有致畸性，会导致多种畸形，包括腭裂。RA导致腭裂的影响因胚胎发育阶段不同而有所差异。在妊娠第10天（GD10）将胚胎小鼠暴露于RA后，腭突形成异常小。在GD12暴露后，腭突形成正常大小，但无法融合，因为内侧细胞增殖并分化为类似鼻的上皮。生长因子及其受体在调节发育中起重要作用，并且在小鼠胚胎中已报道了表皮生长因子（EGF）受体、EGF、转化生长因子-α（TGF-α）、转化生长因子-β1（TGF-β1）和转化生长因子-β2（TGF-β2）的表达。在培养的多种细胞类型中，这些生长因子能够调节增殖、分化、基质蛋白的表达以及其他细胞事件，包括上皮-间充质转化。本研究采用免疫组织化学方法检测了从GD12至15正常胚胎腭突中EGF、TGF-α、TGF-β1和TGF-β2的表达，以及在GD10或GD12给予RA处理后对其在GD14和GD16表达的影响。结果显示这些生长因子在腭突中有特定的时空表达。随着发育进程，TGF-α水平下降而EGF表达增加。到GD14 - 15时，TGF-β2的定位呈区域性，在上皮细胞和成软骨间充质中水平较高。TGF-β1出现在上皮和间充质细胞中，其分布随发育进程变化不大。RA暴露改变了TGF-α、TGF-β1和TGF-β2的表达，但未发现对EGF有显著影响。对TGF-α和TGF-β1表达的影响取决于暴露的胎龄。在GD10暴露RA后，GD14时TGF-α水平下降，但在GD12暴露后则升高。在GD12暴露后，间充质中TGF-β1的表达增加，但在GD10时不受RA影响。在任何一天暴露后，GD14鼻上皮细胞中TGF-β2水平均升高。生长因子协同作用，可调节对次生腭形成至关重要的事件，包括内侧上皮细胞增殖停止、间充质中细胞外基质蛋白的合成以及内侧上皮周皮细胞的程序性细胞死亡，以及基底上皮内侧细胞向间充质细胞的转化。（摘要截选至400字）
