MECHANISMS OF TCDD-INDUCTION OF CLEFT-PALATE - INSIGHTS FROM INVIVO AND INVITRO APPROACHES

TCDD induced cleft palate (CP) in C57BL6N embryos by altering proliferation and differentiation of palatal medial epithelial cells. These effects correlated with altered expression of the growth factors, TGF-alpha, EGF, TGF-beta-1 and TGF-beta-2, and the EGF receptor. Synergistic interactions between TCDD and retinoic acid (RA) or hydrocortisone (HC) resulted in CP induction-at doses too low to induce CP if given alone. Clefts produced by TCDD + RA or TCDD + HC were due to growth inhibition, an outcome differing from that of TCDD alone. TCDD, RA, and HC all had different effects on growth factor expression with the strongest effects on TGF-beta, TGF-alpha, and EGF. In palatal organ culture, concentration-dependent effects on medial epithelial cells occurred in C57BL/6N mouse, F344 rat, and human palates. The responsiveness to TCDD was absent in serum-free cultures, suggesting that an additional factor is required in vitro. The mechanism of TCDD activity appears to involve growth facto expression and may interact with RA and glucocorticoid pathways.