ToxSci Advance Access published online on May 22, 2008
Toxicological Sciences, 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 Uppsala SWEDEN
Parri Wenzel, PhD, Associate Professor, Department of Medical Cell Biology, Uppsala University, Biomedical Center, P.O.Box 571, SE-751 23 Uppsala, Sweden, email Parri.Wentzel{at}mcb.uu.se
Ulf J Eriksson, PhD, Medical Dr, Professor, Department of Medical Cell Biology, Uppsala University, Biomedical Center, P.O.Box 571, SE-751 23 Uppsala, Sweden, email Ulf.Eriksson{at}mcb.uu.se
* Corresponding author: Sheller Zabihi M.Sci. , email: Sheller.Zabihi{at}mcb.uu.seDepartment of Medical Cell Biology, Uppsala University, Biomedical Center, P.O.Box 571, SE-751 23 Uppsala, Sweden Tel: +46-18-4714411. Fax: +46-18-550720
Received March 25, 2008; revision received May 9, 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 knock-out (KO) with regard to CuZnSOD. Alloxan was used to induce diabetes (DWT, DTG, DKO) in female mice before pregnancy and, non-injected 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 i.e. blood glucose concentration, as well as foetal outcome, genotype and hepatic isoprostane levels were assessed. The mean maternal blood glucose levels were positively associated with the alloxan dose, i.e. the DWT and DTG groups had higher blood glucose concentration than the DKO group, and the DWT and DTG foetuses increased their hepatic isoprostane levels, whereas the DKO foetuses did not. However, in all diabetic groups, increased maternal blood glucose concentration was associated with higher resorption and malformation rates as well as lowered foetal and placental weight. Furthermore, diabetes increased the fraction of wildtype offspring in the TG and KO groups. We conclude that both foetal 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 foetal antioxidative capacity.
Key Words: CuZnSOD; transgenic mice; knockout mice; oxidative stress; alloxan; diabetes in pregnancy.