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Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress

¹Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston; ²Department of Medicine, Harvard Medical School, Boston; and ³BioCurrents Research Center, Program in Molecular Physiology, Marine Biological Laboratory, Woods Hole, Massachusetts

Submitted 16 September 2004 ; accepted in final form 25 May 2005

We have shown that neural tube defects (NTD) in a mouse model of diabetic embryopathy are associated with deficient expression of Pax3, a gene required for neural tube closure. Hyperglycemia-induced oxidative stress is responsible. Before organogenesis, the avascular embryo is physiologically hypoxic (2–5% O₂). Here we hypothesized that, because O₂ delivery is limited at this stage of development, excess glucose metabolism could accelerate the rate of O₂ consumption, thereby exacerbating the hypoxic state. Because hypoxia can increase mitochondrial superoxide production, excessive hypoxia may contribute to oxidative stress. To test this, we assayed O₂ flux, an indicator of O₂ availability, in embryos of glucose-injected hyperglycemic or saline-injected mice. O₂ flux was reduced by 30% in embryos of hyperglycemic mice. To test whether hypoxia replicates, and hyperoxia suppresses, the effects of maternal hyperglycemia, pregnant mice were housed in controlled O₂ chambers on embryonic day 7.5. Housing pregnant mice in 12% O₂, or induction of maternal hyperglycemia (>250 mg/dl), decreased Pax3 expression fivefold, and increased NTD eightfold. Conversely, housing pregnant diabetic mice in 30% O₂ significantly suppressed the effect of maternal diabetes to increase NTD. These effects of hypoxia appear to be the result of increased production of mitochondrial superoxide, as indicated by assay of lipid peroxidation, reduced glutathione, and H₂O₂. Further support of this interpretation was the effect of antioxidants, which blocked the effects of maternal hypoxia, as well as hyperglycemia, on Pax3 expression and NTD. These observations suggest that maternal hyperglycemia depletes O₂ in the embryo and that this contributes to oxidative stress and the adverse effects of maternal hyperglycemia on embryo development.

diabetic embryopathy; neural tube; hypoxia; Pax3

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