Abbott B D, Birnbaum L S
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Toxicol Appl Pharmacol. 1989 Jun 15;99(2):287-301. doi: 10.1016/0041-008x(89)90011-2.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and retinoic acid (RA) are both teratogenic in mice. TCDD is a highly toxic, stable environmental contaminant, while RA is a naturally occurring form of vitamin A. Exposure to TCDD induces hydronephrosis and cleft palate, and exposure to RA induces limb defects and cleft palate. Teratology studies previously have shown that the incidence of clefting is higher after exposure to RA + TCDD than would be observed for the same doses of either compound given alone. This study examines the cellular effects which result in cleft palate, after po administration on gestation Day (GD) 10 or 12 of RA + TCDD in corn oil (10 ml/kg total volume). Exposure on GD 10 to 6 micrograms TCDD + 40 mg RA/kg inhibited early growth of the shelves and clefting was due to a failure of shelves to meet and fuse. This effect on mesenchyme was observed in previous studies to occur after exposure on GD 10 to 40 mg/kg RA alone, but not after TCDD alone. After exposure on GD 12 to 6 micrograms TCDD + 80 mg RA/kg, clefting was due to a failure of shelves to fuse after making contact, because the medial cells differentiated into an oral-like epithelium. This response was observed in previous studies to occur after exposure to TCDD alone, but RA alone on GD 12 resulted in differentiation toward nasal-like cells. The interaction between TCDD and RA results in RA-like clefting after exposure on GD 10 and TCDD-like clefting after exposure on GD 12, and this clefting occurs at higher incidences than would occur after the same levels of either agent alone. After exposure on either GD 10 or 12 to RA + TCDD, the programmed cell death of the medial cells does not occur, and these cells continue to express EGF receptors and to bind 125I-EGF. The effects of RA and TCDD may involve modulation of the cells responses to embryonic growth and differentiation factors.
2,3,7,8-四氯二苯并对二恶英（TCDD）和视黄酸（RA）对小鼠均具有致畸性。TCDD是一种剧毒、稳定的环境污染物，而RA是维生素A的天然存在形式。接触TCDD会诱发肾盂积水和腭裂，接触RA会诱发肢体缺陷和腭裂。此前的致畸学研究表明，相较于单独给予相同剂量的任何一种化合物，同时接触RA + TCDD后腭裂的发生率更高。本研究检测了在妊娠第10天或第12天经口给予玉米油（总体积10 ml/kg）中的RA + TCDD后，导致腭裂的细胞效应。在妊娠第10天接触6微克TCDD + 40毫克RA/千克会抑制腭板的早期生长，腭裂是由于腭板未能相遇并融合所致。此前的研究发现，单独在妊娠第10天接触40毫克/千克RA后会出现这种对间充质的影响，但单独接触TCDD后不会出现。在妊娠第12天接触6微克TCDD + 80毫克RA/千克后，腭裂是由于腭板接触后未能融合，因为内侧细胞分化为类似口腔的上皮。此前的研究发现，单独接触TCDD后会出现这种反应，但在妊娠第12天单独接触RA会导致细胞分化为类似鼻的细胞。TCDD和RA之间的相互作用导致在妊娠第10天接触后出现类似RA的腭裂，在妊娠第12天接触后出现类似TCDD的腭裂，并且这种腭裂的发生率高于单独接触相同水平的任何一种药物后的发生率。在妊娠第10天或第12天接触RA + TCDD后，内侧细胞不会发生程序性细胞死亡，这些细胞会继续表达表皮生长因子（EGF）受体并结合125I-EGF。RA和TCDD的作用可能涉及调节细胞对胚胎生长和分化因子的反应。
