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J. Biol. Chem., Vol. 280, Issue 13, 12742-12746, April 1, 2005

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Transforming Growth Factor-3 Restores Fusion in Palatal Shelves Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin^*

Tami L. Thomae, Emily A. Stevens, and Christopher A. Bradfield

From the McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

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 Tgf3 null mice, a mutant known to display a 100% incidence of cleft palate, we examined the interaction between TGF3 and dioxin in palatal fusion. We found that that the addition of TGF3 to an in vitro palate culture model prevented the dioxin-induced reduction in filopodial density. Moreover, TGF3 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 TGF3 dioxin antagonism, these results do suggest that TGF3 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.

Received for publication, September 20, 2004 , and in revised form, January 21, 2005.

^* This work was supported by the National Institutes of Health Grants R01-ES006883, T32-CA009135, and P30-CA014520. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: McArdle Laboratory for Cancer Research, 1400 University Ave., Madison, WI 53706-1599. Tel.: 608-262-2024; Fax: 608-262-2824; E-mail: Bradfield{at}oncology.wisc.edu.

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