REVIEW OF THE INTERACTION BETWEEN TCDD AND GLUCOCORTICOIDS IN EMBRYONIC PALATE

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contami nant that produces adverse biological effects including developmental toxicity and teratogenesis. In the mouse embryo, TCDD induces cleft pa late and hydronephrosis. The synthetic glucocorticoid, hydrocortisone (HC), induces cleft palate and a potent, synergistic interaction has b een observed between TCDD and HC in C57BL/6N embryonic mice. The morph ology and etiology of TCDD- and HC-induced clefts are distinctly diffe rent with formation of small palatal shelves following HC exposure and failure of normally-sized shelves to fuse after TCDD treatment. Each exposure also alters expression of several growth factors. When EGF, T GFG alpha, EGF receptor, and the TGF beta's are considered as a combin atorial, interacting set of regulators, TCDD and HC each produce a uni que pattern of increased and/or decreased expression across the set. T he interaction of HC and TCDD results in a cleft palate whose etiology most closely resembles that observed after HC exposure, i.e. small pa latal shelves. HC + TCDD-exposure also produces a pattern of growth fa ctor expression which closely resembles that seen after HC. Both TCDD and HC act through receptor-mediated mechanisms and each compound has its own receptor. The Ah receptor (AhR) binds TCDD and the glucocortic oid receptor (GR) binds HC. On gestation day (GD) 14, in the embryonic palate exposed to TCDD, the AhR was downregulated and the GR expressi on increased. Conversely, following HC exposure, the GR was downregula ted and AhR levels were elevated. HC + TCDD produced increased express ion of both receptors and this pattern would be predicted to produce H C-like clefts as the GR-mediated responses would result in small palat al shelves. The observed cross-regulation of the receptors is believed to be important in the synergistic interaction between TCDD and HC fo r the induction of cleft palate.