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

By Rulin Li, Martha Chase, Sung-Kwon Jung, Peter J.S. Smith and Mary R. Loeken

Abstract

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% O(2)). Here we hypothesized that, because O(2) delivery is limited at this stage of development, excess glucose metabolism could accelerate the rate of O(2) 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 O(2) flux, an indicator of O(2) availability, in embryos of glucose-injected hyperglycemic or saline-injected mice. O(2) 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 O(2) chambers on embryonic day 7.5. Housing pregnant mice in 12% O(2), or induction of maternal hyperglycemia (>250 mg/dl), decreased Pax3 expression fivefold, and increased NTD eightfold. Conversely, housing pregnant diabetic mice in 30% O(2) 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 H(2)O(2). 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 O(2) in the embryo and that this contributes to oxidative stress and the adverse effects of maternal hyperglycemia on embryo developmen

Topics: RG
Year: 2005
OAI identifier: oai:eprints.soton.ac.uk:188815
Provided by: e-Prints Soton

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