Antioxidant system and apoptosis in diabetes-induced embryonic malformation.

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We investigated the role of glutathione-dependent antioxidant system and Apoptosis on diabetes-related embryonic malformations. Embryos from streptozotocin-induced diabetic rats on gestational days 11 showed a significantly high frequency of embryonic malformations (neural tube detect 21.5 vs.2.8%, p<0.001) and growth retardation compared with those of normal mothers. The formation of intracellular free oxygen radical species increased in isolated embryonic cells of diabetic rats on days 11. The concentration of intracellular GSH in embryonic tissues of diabetic pregnant rats on day 11 was significantly low compared with those of normal rats. The activity of gamma-glutamylcysteine synthetase (gamma-GCS), the rate limiting GSH synthesizing enzyme, in embryos of diabetic rat was significantly low, associated with reduced expression ofgamma-GCS mRNA.TUNEL-positive apoptotic cells in neuroepithelial cells of closing neural tube in embryo at day 10 were frequently found from normal rats, but few from diabetic rats. Administration of buthionine sulfoxamine (BSO), a specific inhibitor of gamma-GCS, during the period of maximal teratogenic susceptibility (6 to ll day of gestation) to diabetic rats reduced GSH by 46.7% and increased the frequency of neural lesions (62.1 vs. 2l.5%, p<0.0l). Administration of GSH ester to diabetic rats restored GSH concentration in the embryos and reduced the formation of free oxygen radicals leading to normalization of dysmorphogenesis (1.9 vs.21.5%) and improvement in growth retardation : Administration of insulin in another group of pregnant rats during the same period resulted in complete normalization of dysmorphogenesis (4.3 vs.21.5%) and growth retardation. Our results indicate that GSH depletion and impaired responsiveness of GSH-synthesizing enzyme to oxidative stress and decreased concentration of apotosis during neural tube formation are critical in development of embryonic malformations (neural tube defects) in diabetes.