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Decreased cardiac glutathione peroxidase levels and enhanced mandibular apoptosis in malformed embryos of diabetic rats

¹Department of Medical Cell Biology, Uppsala University, SE-75123 Uppsala, Sweden

Objective: To characterize normal and malformed embryos within the same litters from control and diabetic rats for expression of genes related to metabolism of reactive oxygen species (ROS) or glucose, and developmental genes.

Research design and methods: Embryos from non-diabetic and streptozotocin-diabetic rats were collected on gestational day 11 and evaluated for gene expression (PCR) and distribution of activated Caspase-3 and glutathione peroxidase-1 (Gpx-1) by immunohistochemistry.

Results: Maternal diabetes (MD) caused growth retardation and increased malformation rate in the embryos compared to controls (N). We found decreased gene expression of Gpx-1 and increased expression of Vascular endothelial growth factor-A (Vegf-A) in malformed embryos of diabetic rats (MDm), compared with non-malformed littermates (MDn). Alterations of mRNA levels of other genes were similar in MDm and MDn embryos. Thus, expression of Copper Zinc superoxide dismutase (CuZnSOD), Manganese superoxide dismutase (MnSOD), and Sonic hedgehog homolog (Shh) were decreased, and Bone morphogenetic protein-4 (Bmp-4) was increased in the MD embryos compared to N embryos. In MDm embryos, we detected increased activated Caspase-3 immunostaining in the first visceral arch and cardiac area, and decreased Gpx-1 immunostaining in the cardiac tissue, both findings differed from the Caspase/Gpx-1 immunostaining of the MDn and N embryos.

Conclusions: Maternal diabetes causes growth retardation, congenital malformations and decreased general antioxidative gene expression in the embryo. In particular, enhanced apoptosis of the first visceral arch and heart, together with decreased cardiac Gpx-1 levels may compromise the mandible and heart to an increased risk of developing congenital malformation.

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