Research concerning Effects of Endocrine Disrupters on Development of Cleft Lip and/or Palate

我们已经阐明了雌激素雌二醇和内分泌干扰物双酚A(BPA)对自发形成唇腭裂的A/J小鼠品系的唇腭裂发育具有抑制作用，并且它们的抑制作用呈倒U形剂量特性曲线。为了解双酚A抑制唇腭裂发育的作用机制，研究了雌激素受体和维甲酸受体(RAR)在骨髓间充质干细胞向骨分化过程中的相关性。(1)在利用成骨细胞MC3T3-E1细胞研究BPA对RAR发育的影响时，10-10M和10-5M的BPA对RAR的发育没有影响。(2)BPA上调RAR的靶基因骨桥蛋白的mRAN水平。BPA的作用在浓度为10-8M时达到最大，呈倒U形剂量特性曲线。结果表明，BPA的作用可能通过RAR2深入参与信号的传递。为了研究双酚A与视黄酸受体配体的相关性，进而为开发唇腭裂的预防药物，本研究对95种70%乙醇提取物的加兰烯类化合物进行了研究，寻找一种全反式视黄酸的视黄酸配体来替代。(1)苍术醇为苍术中的视黄醇受体α配体。(2)丁香酚和异丁香酚。

We have elucidated that estradiol, which is estrogen, and bisphenol A (BPA), which is endocrine disrupters, inhibit development of cleft lip and palate in A/J mouse strain, which spontaneously develop cleft lip and palate, and that their inhibitory actions describe an inverted U dose-characteristic curve.1. Correlation between an estrogen receptor and retinoic acid receptor (RAR), which are deeply involved in a process of bone differentiation from mesenchymal stem cells, was studied in order to know mechanism of a BPA action of inhibiting cleft lip and/or palate development.(1) In a study about an effect of BPA on development of RAR using osteoblastic MC3T3-E1 cells, BPA at a concentration of 10-10M and 10-5M had no effect on RAR development.(2) BPA elevated the mRAN level of osteopontin, which is a target gene of RAR, and the action of BPA became the maximum at a concentration of 10-8M shown in an inverted U dose-characteristic curve. The result showed that the action of BPA may possibly be involved deeply in a signal through RAR.2. In order to study correlation between BPA and a RAR ligand, and further, in order to aim at developing a preventive medicine for cleft lip and for palate, 95 kinds of galenicals with 70% ethanol extraction were examined fix finding a RAR ligand to replace an all-trans retinoic acid, which is also a RAR ligand but has a strong action and various side effects.(1) Atractylodinol was identified as a RAR α ligand from Atractylis Rhizoma(2) Eugenol and isoeugenol were isolated and identified from clove.