Abstract
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.
Highlights
China and Japan when halogenated dioxins and halogenated dibenzofurans were accidentally introduced into cooking oil [7,8,9], and the exposure of citizens of Seveso, Italy after an explosion at a nearby chlorinated-phenol plant (10 –12)
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
Known Teratology of Dioxins—Halogenated dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, have proven to be powerful tools in understanding environmentally mediated teratogenesis. This power stems from the extensive pharmacological, genetic, and molecular evidence that the teratogenicity of dioxin is mediated through a ligand-activated transcription factor known as the aryl hydrocarbon receptor (AHR) [27,28,29,30,31]
Summary
China and Japan when halogenated dioxins and halogenated dibenzofurans were accidentally introduced into cooking oil [7,8,9], and the exposure of citizens of Seveso, Italy after an explosion at a nearby chlorinated-phenol plant (10 –12). The identification of blockers of dioxin-induced toxicity/teratogenicity could have significant benefit to human and wildlife populations If such antidotes can be developed with a high therapeutic index, they could be used to minimize consequences in situations where dioxin exposure is known and an individual or developing fetus is at high risk. To work toward this goal, we have begun using late stage developmental endpoints and in vitro organ culture models in a search for pharmacological blockers of dioxin teratogenicity. We identified TGF3 as an effective antidote to dioxin-induced cleft palate
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