ToxSci Advance Access originally published online on May 22, 2008
Toxicological Sciences 2008 105(1):166-172; doi:10.1093/toxsci/kfn101
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Maternal Blood Glucose Levels Determine the Severity of Diabetic Embryopathy in Mice with Different Expression of Copper-Zinc Superoxide Dismutase (CuZnSOD)
Department of Medical Cell Biology, Uppsala University, Biomedical Center, SE-751 23 Uppsala, Sweden
1 To whom correspondence should be addressed at Department of Medical Cell Biology, Uppsala University, Biomedical Center, P. O. Box 571, SE-751 23 Uppsala, Sweden. Fax: +46-18-550720. E-mail: Sheller.Zabihi{at}mcb.uu.se.
Received March 25, 2008; accepted May 13, 2008
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Abstract |
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Excess oxygen radical formation is suggested to be involved in the etiology of diabetic embryopathy. We aimed to investigate the effects of altered maternal antioxidative status in conjunction with a varied severity of the maternal diabetic state on embryonic development by using mice with different gene expression of CuZn superoxide dismutase (CuZnSOD). The mice were wild-type (WT), transgenic (TG), or knockout (KO) with regard to CuZnSOD. Alloxan was used to induce diabetes (DWT, DTG, DKO) in female mice before pregnancy and, noninjected mice served as controls (NWT, NTG, NKO). The minimum alloxan dose required to induce diabetes was 80 mg/kg for WT, 100 mg/kg for TG, and 65 mg/kg for KO mice. When KO mice were made diabetic with 80 mg/kg alloxan, they produced no living offspring. The pregnancies were interrupted on gestational day 18, when maternal diabetic state, that is, blood glucose concentration, as well as fetal outcome, genotype and hepatic isoprostane levels were assessed. The mean maternal blood glucose levels were positively associated with the alloxan dose, that is, the DWT and DTG groups had higher blood glucose concentration than the DKO group, and the DWT and DTG fetuses increased their hepatic isoprostane levels, whereas the DKO fetuses did not. However, in all diabetic groups, increased maternal blood glucose concentration was associated with higher resorption and malformation rates as well as lowered fetal and placental weight. Furthermore, diabetes increased the fraction of WT offspring in the TG and KO groups. We conclude that both fetal antioxidative capacity and maternal diabetic state affect the development of the offspring. However, the maternal diabetic state is the major teratogenic factor and overrides the influence of fetal antioxidative capacity.
Key Words: CuZnSOD; transgenic mice; knockout mice; oxidative stress; alloxan; diabetes in pregnancy.