Evaluation of fetal skeletal malformations in deoxynivalenol-treated mice using microarray analysis.
Deoxynivalenol (DON [vomitoxin]), one of trichothecene mycotoxins produced by the fungus Fusarium, is commonly detected in cereal foods across the world. DON induces diverse toxic effects in humans and animals, including emesis and diarrhea, anorexia, and immunotoxicity, and impaired maternal reproduction and fetal development. Recently, the teratogenic potential of DON has been shown and has received much attention. DON can cause various skeletal deformities in fetuses, but the underlying mechanisms have not yet been fully examined. In this study, fetal skeletal malformations in DON-treated maternal mice were thoroughly investigated using microarray assay. The results showed that DON administration caused various skeletal defects in fetuses, including misaligned or fused sternebrae and vertebrae, divided or fused ribs and polydactyly, hemivertebrae, short toes, and tail anomalies. Microarray analysis showed that 282 genes, including 148 downregulated and 134 upregulated genes, were abnormally expressed in fetal vertebral bones after maternal DON exposure. These identified genes can be classified into several categories: skeletal development, carcinogenesis, nervous disorders, sperm development and embryogenesis, and inflammation. Of these, 6 genes, mostly related to bone development, were intentionally selected for further validation using real-time reverse transcription-Polymerase Chain Reaction (RT-PCR). It was confirmed that the mRNA expression of 4 genes, i.e., fibrillin-1, Col9A2, 3-phosphoadenosine 5-phosphosulfate synthase 2, and Pax1, was upregulated significantly by DON administration, whereas that of 2 other genes, Runx2 and parathyroid hormone-like hormone, was downregulated significantly. Taken together, the results of our study suggest that altered expression of these 6 genes plays a critical role in fetal skeletal deformities induced by DON and thus they are worthy of further investigation.