Transforming growth factor-beta3 restores fusion in palatal shelves exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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 Tgfbeta3 null mice, a mutant known to display a 100% incidence of cleft palate, we examined the interaction between TGFbeta3 and dioxin in palatal fusion. We found that that the addition of TGFbeta3 to an in vitro palate culture model prevented the dioxin-induced reduction in filopodial density. Moreover, TGFbeta3 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 TGFbeta3 dioxin antagonism, these results do suggest that TGFbeta3 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.
Thomae
Tami L
TL
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Stevens
Emily A
EA
Bradfield
Christopher A
CA
D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced* / Q000235:genetics*; D004147:Dioxins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins; D015398:Signal Transduction; D013723:Teratogens; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053782:Transforming Growth Factor beta3
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3