Transforming Growth Factor- 3 Restores Fusion in Palatal Shelves

The pollutant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (“dioxin”), has been implicated in the etiology of a wide variety of human birth defects. In an effort to identify pharmacological blockers of dioxin-induced terata, we performed a histological and microscopic analysis of the developing murine palate that had been exposed to dioxin. In both in vivo and in vitro model systems, we observed that dioxin exposure leads to a reduction in the number of filopodial extensions at the medial epithelial edge of the developing palate. Given that this filopodial aberration is similar to the phenotype observed in Tgf 3 null mice, a mutant known to display a 100% incidence of cleft palate, we examined the interaction between TGF 3 and dioxin in palatal fusion. We found that that the addition of TGF 3 to an in vitro palate culture model prevented the dioxin-induced reduction in filopodial density. Moreover, TGF 3 exposure completely prevented the dioxin-induced block of palatal fusion in this system. Although these data do not point to a direct cellular or molecular mechanism for TGF 3 dioxin antagonism, these results do suggest that TGF 3 or stimulators of this signaling pathway hold potential as antidotes for dioxin-induced terata and that this opposing pharmacology may extend to additional toxicological endpoints.