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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)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratologi)
2008 (English)In: Toxicological Sciences, ISSN 1096-6080, Vol. 105, no 1, 166-172 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 105, no 1, 166-172 p.
Keyword [en]
CuZnSOD, transgenic mice, knockout mice, oxidative stress, alloxan, diabetes in pregnancy
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97220DOI: 10.1093/toxsci/kfn101ISI: 000258331600017PubMedID: 18502742OAI: oai:DiVA.org:uu-97220DiVA: diva2:172055
Available from: 2008-05-05 Created: 2008-05-05 Last updated: 2009-10-08Bibliographically approved
In thesis
1. Fetal Outcome in Experimental Diabetic Pregnancy
Open this publication in new window or tab >>Fetal Outcome in Experimental Diabetic Pregnancy
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Women with pregestational diabetes have a 2-5 fold increased risk of giving birth to malformed babies compared with non-diabetic women. Diabetes-induced oxidative stress in maternal and embryonic tissues has been implicated in the teratogenic process. The malformations are likely to be induced before the seventh week of pregnancy, when the yolk sac is partly responsible for the transfer of metabolites to the embryo, and the uterine blood flow to the implantation site determines the net amount of nutrients available to the conceptus. We aimed to evaluate the effect on embryogenesis caused by a diabetes-induced disturbance in yolk sac morphology, uterine blood flow or altered maternal antioxidative status in conjunction with a varied severity of the maternal diabetic state.

We investigated to which extent maternal diabetes with or without folic acid (FA) supplementation affects mRNA levels and protein distribution of ROS scavenging enzymes (SOD, CAT, GPX), vascular endothelial growth factor-A (Vegf-A), folate binding protein-1 (Folbp-1), and apoptosis associated proteins (Bax, Bcl-2, Caspase-3) in the yolk sacs of rat embryos on gestational days 10 and 11. We found that maternal diabetes impairs, and that FA supplementation restores, yolk sac vessel morphology, and that maternal diabetes is associated with increased apoptotic rate in embryos and yolk sacs, as well as impaired SOD gene expression. We assessed uterine blood flow with a laser-Doppler-flow-meter and found increased blood flow to implantation sites of diabetic rats compared with controls. Furthermore, resorbed and malformed offspring showed increased and decreased blood flow to their implantation sites, respectively. In mice with genetically altered CuZnSOD levels, maternal diabetes increased embryonic dysmorphogenesis irrespective of CuZnSOD expression. We thus found the maternal diabetic state to be a major determinant of diabetic embryopathy and that the CuZnSOD status exerts a partial protection for the embryo in diabetic pregnancy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 64 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 352
Cell biology, Rat, Mouse, TG, KO, Diabetes in Pregnancy, Embryo, Folic acid, Superoxide dismutase, Catalase, Glutathione peroxidase, Vascular endothelial growth factor-A, Folate binding protein-1, Bax, Bcl-2, Caspase-3, P53, Pax-3, Blood flow, Cellbiologi
urn:nbn:se:uu:diva-8739 (URN)
Public defence
2008-05-26, C2:301, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2008-05-05 Created: 2008-05-05Bibliographically approved

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