Journal Article

Dithiocarbamates Induce Craniofacial Abnormalities and Downregulate <i>sox9a</i> during Zebrafish Development

Antonius Leonardus van Boxtel, Bart Pieterse, Peter Cenijn, Jorke Harmen Kamstra, Abraham Brouwer, Wessel van Wieringen, Jacob de Boer and Juliette Legler

in Toxicological Sciences

Volume 117, issue 1, pages 209-217
Published in print September 2010 | ISSN: 1096-6080
Published online June 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq169
Dithiocarbamates Induce Craniofacial Abnormalities and Downregulate sox9a during Zebrafish Development

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Dithiocarbamates (DTCs) have a wide variety of applications in diverse fields ranging from agriculture to medicine. DTCs are teratogenic to vertebrates but the mechanisms by which they exert these effects are poorly understood. Here, we show that low nanomolar exposure to three DTCs, tetraethylthiuram (thiram), tetramethylthiuram (disulfiram), and sodium metam (metam), leads to craniofacial abnormalities in developing zebrafish embryos that are reminiscent of DTC-induced abnormalities found in higher vertebrates. In order to better understand the molecular events underlying DTC teratogenesis, we exposed embryonic zebrafish (PAC2) cells to thiram and disulfiram and measured changes in gene expression with microarrays. We found differential expression of 166 genes that were specific for exposure to DTCs and identified a network of genes related to connective tissue development and function. Additionally, we found eight downregulated genes related to transforming growth factor β-1 (TGF-β1) signaling, including an essential transcription factor for zebrafish craniofacial development, SRY-box–containing gene 9a (sox9a). Finally, we show that sox9a expression is perturbed in the ceratobranchial arches of DTC-exposed zebrafish, suggesting that this is an important event in the development of DTC-induced craniofacial abnormalities. Together, we provide evidence for a novel teratogenic endpoint and a molecular basis for a better understanding of DTC-induced teratogenesis in vertebrates.

Keywords: dithiocarbamate; microarray; sox9a; TGF-β1; zebrafish; craniofacial

Journal Article.  5276 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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