Human foetal palatal corticoid receptors and teratogens for cleft palate.

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CLEFT secondary palate can be induced experimentally in various mammalian species by the administration of glucocorticoids to pregnant animals1–4. The well known differences in susceptibility to cortisone-induced cleft palate in inbred strains of mice have been explained in terms of genetic differences in foetal facial mesenchymal glucocorticoid receptor levels5,6. The quantity of one protein in particular, with an isoelectric point (pI) of approximately 7.0, seems to be correlated rather closely with the susceptibility of various strains to cortisone-induced cleft palate6. It has also been shown that much of the difference in cleft palate susceptibility between C57BL/10 (B10) and A/J mice can be accounted for by H–2-linked genes7,8, and that there is H–2-linked variation in the level of cortisol-binding proteins obtained from the cytosol fraction of foetal palatal tissue6. As corticoids form a specific cytoplasmic cortisol receptor complex in target tissues which interacts with the genome resulting in activation or depression of transcription9,10, a product of a gene in or near the H–2 locus seems to be the glucocorticoid receptor, the level of which has to be raised for cleft palate to occur. As a first step to determine whether such a mechanism may operate in humans, we have examined whether human palatal mesenchymal cells, obtained in cultures from foetuses shortly after the critical period of secondary palatal closure, contain glucocorticoid receptors. We show here that these cells have specific glucocorticoid receptor proteins with high affinity for dexamethasone and triamcinolone acetonide, and that dexamethasone is displaced from its binding sites only by drugs which produce cleft palate in sensitive mouse strains. Thus, the human foetus contains an active glucocorticoid receptor mechanism immediately after the critical period of palatal organogenesis, which may be involved in palatal clefting.