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A MICROARRAY ANALYSIS OF GENE EXPRESSION IN THE EMBRYONIC FORELIMB OF THE C57BL/6J MOUSE REVEALS SIGNIFICANT ALTERATIONS METABOLIC AND DEVELOPMENTAL REGULATION FOLLOWING ETHANOL EXPOSURE.
Citation:
JOHNSON, C., T. B. KNUDSEN, J. E. SCHMID, E. S. HUNTER, AND K. I. SULIK. A MICROARRAY ANALYSIS OF GENE EXPRESSION IN THE EMBRYONIC FORELIMB OF THE C57BL/6J MOUSE REVEALS SIGNIFICANT ALTERATIONS METABOLIC AND DEVELOPMENTAL REGULATION FOLLOWING ETHANOL EXPOSURE. Presented at Teratology Society Meeting, Omaha, NE, June 24 - 29, 2006.
Description:
The observation of transcriptional changes following embryonic ethanol exposure may provide significant insights into the biological response to ethanol exposure. In this study, we used microarray analysis to examine the transcriptional response of the developing limb to a dose of ethanol that we and others have shown to be dysmorphogenic. We considered the transcriptional changes elicited by ethanol at 2, 4, and 6 hours following ethanol exposure, prior to the overt onset of cell death as previously described (Kotch et al., 1992) and confirmed herein. Using Genespring and Ingenuity Pathway Analysis we analyzed gene expression at each time point, and the similarity and differences in gene expression that occurs over time. At different times following exposure to ethanol, the limb bud exhibits transcriptional changes consistent with changes in IGF-1, JAK/Stat, Wnt/ß-catenin, and PPAR signaling. Additionally functional analysis reveals a significant perturbation in cell-cycle control, including those processes of proliferation and cell death. Components of the Parkinson¿s signaling pathway are significantly down-regulated in all treatment groups. A key component of this pathway, PARK7, is an important component of the mitochondrial antioxidant defense. Functional analysis reveals that a number of genes responsible for redox regulation are significantly altered. Fancc, and SOD1, antioxidants, are downregulated, while generators or inducers of reactive oxygen species are upregulated in response to ethanol exposure: EPAS1, PRODH, TNF¿, and p53. We conclude that ethanol exposure results in the discordant regulation of components of the anti- and pro-oxidant system within the developing limb bud, which may contribute to the excessive cell death seen in limbs following ethanol exposure.