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43: The role of cell signaling mechanisms in the downregulation of antioxidant enzymes in the fetal brain in a mouse model of fetal alcohol syndrome

      Objective

      Fetal alcohol syndrome (FAS) is the most common non genetic cause of mental retardation. Prenatal alcohol exposure decreases antioxidant enzymes in the fetal brain in a mouse model of fetal alcohol syndrome. Exposure to alcohol is known to decrease expression of Glycogen Synthase Kinase-3β (GSK-3β) a serine threonine kinase that regulates glycogen synthesis through phosphorylation and inactivation of glycogen synthase. In addition to regulation of glycogen, GSK-3β is positively correlated with expression of nuclear transcription factors, NF-κβ and Nrf2, which are inactive in the cytosol and active within nucleus. Our objective was to evaluate if the effect of prenatal alcohol exposure on fetal brain antioxidants can be explained by an effect on GSK-3β, NF-κβ and Nrf2.

      Study Design

      A well-characterized FAS model was used (Webster, 1980). Timed, pregnant C57BL6/J mice were treated on gestational day 8 (E8) with alcohol (0.03 mL/g) or vehicle. Fetuses were harvested on gestational day 18 (E18), and the brain prepared for protein analysis. Western Blots were performed assessing the protein expression of GSK-3β and cytosolic and nuclear expression of NF-κβ and Nrf2 normalized to Glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Statistical analysis was performed using Student t-test (significance: p<0.05).

      Results

      GSK-3β protein levels were significantly lower (0.73 vs 1.06 ratio protein/GAPDH; p=0.01) and cytosolic Nrf2 protein levels were significantly higher (0.72 vs 0.43 ratio protein/GAPDH; p=0.01) in the brain of pups exposed to alcohol compared with control. There was no significant difference in cytosolic expression of NF-κβ or nuclear expression of NF-κβ and Nrf2 between the two groups.

      Conclusion

      In utero exposure to alcohol reduces GSK-3β and increases cytosolic Nrf2 protein levels in the fetal brain. These findings provide a mechanism for the decrease in antioxidants in the brain of FAS offspring, and a potential target for preventive strategies.