INTERACTIVE REGULATION OF AH AND GLUCOCORTICOID RECEPTORS IN THE SYNERGISTIC INDUCTION OF CLEFT-PALATE BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN AND HYDROCORTISONE

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environment al contaminant that produces adverse biological effects including carc inogenesis, reproductive toxicity, immune dysfunction, hyperkeratosis, hepatotoxicity, thymic involution, and teratogenesis. In the mouse em bryo, TCDD induces cleft palate and hydronephrosis. Glucocorticoids ar e endogenous steroid compounds that have an important role in developm ent, but are teratogenic at pharmacological doses. The synthetic gluco corticoid, hydrocortisone (HC), induces cleft palate and a potent, syn ergistic interaction has been observed between TCDD and HC. Both TCDD and HC act through receptor-mediated mechanisms and each compound has its own receptor, the Ah receptor (AhR) and the glucocorticoid recepto r (GR), respectively. The morphology and etiology of TCDD and HC-induc ed clefts are distinctly different, as HC clefting is due to formation of small palatal shelves, while TCDD-treated shelves fail to fuse due to effects on epithelial cell proliferation and differentiation. The present study examines the expression of AhR and GR in the embryonic p alate following exposure to TCDD, HC, and HC + TCDD. C57BL/6N pregnant mice were treated with HC (25 or 100 mg/kg/day GD10-13, sc), TCDD (3 mu g/kg/day GD10-13, or 24 mu g/kg GD10, orally), or HC + TCDD (25 mg/ kg/day sc and 3 mu g/kg/day orally, GD10-13). Craniofacial tissues wer e collected from the embryos on GD14 and examined for AhR and GR expre ssion using in situ hybridization, Northern blots, and immunohistochem istry. We found that in the embryonic palate exposed to TCDD, the AhR was downregulated and the GR expression increased. Conversely, followi ng HC exposure, the GR was downregulated and AhR levels were elevated. HC + TCDD produced increased expression of both receptors. Effects on AhR appeared to be regulated at the transcriptional level, as both pr otein and mRNA were altered in similar directions. The observed cross- regulation of the receptors is believed to be important in the synergi stic interaction between TCDD and HC for the induction of cleft palate . (C) 1994 Academic Press, Inc.