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

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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.