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

我们发现雌激素雌二醇（estradiol）和内分泌干扰物双酚A （BPA）对自发性唇腭裂小鼠A/J品系的唇腭裂发育具有抑制作用，且其抑制作用呈倒U型剂量特征曲线。本文研究了雌激素受体和视黄酸受体（RAR）之间的相关性，探讨了BPA抑制唇腭裂发育的机制。雌激素受体和视黄酸受体在间充质干细胞向骨分化过程中发挥着重要作用。(1)在一项关于BPA对成骨细胞MC3T3-E1 RAR发育影响的研究中，浓度为10-10M和10-5M的BPA对RAR发育无影响。(2) BPA可提高RAR靶基因骨桥蛋白的mRAN水平，且BPA的作用在浓度为10-8M时达到最大，呈倒U型剂量特征曲线。结果表明，BPA的作用可能深入参与了rar信号的传递。为了研究双酚a与RAR配体的相关性，进一步为了开发唇腭裂的预防药物，我们对95种双酚a进行了70%乙醇提取，找到了一种RAR配体来取代全反式维甲酸，后者也是一种RAR配体，但作用强，副作用多。(1)从白术中鉴定出白术二醇为RAR α配体；(2)从丁香中分离鉴定出丁香酚和异丁香酚。

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.