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Combined Supplementation of Folic Acid and Vitamin E Diminishes Diabetes-Induced Embryotoxicity in Rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Teratology)
2006 (English)In: Birth defects research. Clinical and molecular teratology, ISSN 1542-0752, E-ISSN 1542-0760, Vol. 76, no 6, 483-490 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Oxidative stress and enhanced apoptosis may be involved in the induction of embryonic dysmorphogenesis in diabetic pregnancy. Administration of folic acid or vitamin E diminishes embryonic dysmorphogenesis. We aimed to evaluate the effect of combined treatment with folic acid and vitamin E on the disturbed development in embryos of diabetic rats. METHODS: Pregnant nondiabetic and diabetic rats were treated with daily injections of 15 mg/kg folic acid or with 5% vitamin E in the diet. A third group received combined treatment. Day 10 and day 11 embryos were evaluated for development and apoptotic profile. RESULTS: We found increased malformations, resorptions, and profound growth retardation in embryos of diabetic rats compared to control embryos. Vitamin E or folic acid alone, or the 2 compounds combined, normalized embryonic demise. Maternal diabetes caused decreased nuclear factor-kappa B (NF-kappa B) activity and B-cell lymphoma 2 (Bcl-2) protein level, and increased Bcl-2-associated x proteins (Bax) in embryos. Supplementation of vitamin E alone normalized the Bax protein level in a diabetic environment. Administration of folic acid to diabetic rats increased NF-kappa B activity and Bcl-2 protein level. Combined treatment normalized Bcl-2 and Bax protein level in a diabetic environment. CONCLUSIONS: Combined supplementation of folic acid and vitamin E to pregnant diabetic rats diminished diabetes-induced malformations and resorptions, concomitant with normalization of apoptotic protein levels. No treatment completely abolished the embryonic demise; therefore, other mechanisms than oxidative stress and apoptosis are likely to be involved in diabetic embryopathy.

Place, publisher, year, edition, pages
2006. Vol. 76, no 6, 483-490 p.
Keyword [en]
embryopathy, rat, diabetes in pregnancy, folic acid, vitamin E, apoptosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95026DOI: 10.1002/bdra.20278ISI: 000240271300007PubMedID: 16933212OAI: oai:DiVA.org:uu-95026DiVA: diva2:169079
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2011-06-20Bibliographically approved
In thesis
1. Teratogenicity Involved in Experimental Diabetic Pregnancy
Open this publication in new window or tab >>Teratogenicity Involved in Experimental Diabetic Pregnancy
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Maternal diabetes is associated with increased risk of growth disturbances and congenital malformations. The malformations rate in the offspring of diabetic mothers is 2-3 fold higher compared to infants of nondiabetic mothers. In this thesis we have investigated the role of the protein kinase C (PKC) pathway and the apoptotic machinery in embryopathy.

We investigated the involvement of PKC isoforms in the embryopathy of diabetic rat pregnancy. Embryos of diabetic rats showed altered activity and protein distribution of several PKC isoforms compared with embryos of normal rats. Using whole embryo culture we found increased activity of PKC-delta and PKC-zeta after 24h of culture and increased rate of malformations and growth retardation in embryos cultured in high glucose concentration compared to embryos cultured in low glucose concentration. Addition of α-cyano-4-cinnamic acid and N-acetylcysteine to the culture medium normalized malformations and growth retardations whereas specific PKC-inhibitors abolished malformations and partly restored the growth retardations. All treatment normalized glucose-induced increase of PKC activity.

Estimated occurrence of apoptosis in embryos of diabetic rats and in embryonic cells exposed to high glucose concentration showed increased rate of pro-apoptotic markers. The increased apoptosis in the high glucose exposed embryonic cells was normalized by supplementation of N-acetylcysteine or apoptosis inhibitor. Treatment with vitamin E and folic acid to diabetic pregnant rats decreased diabetes-induced malformations and resorptions, concomitant with normalization of apoptotic protein levels.

These results suggest that oxidative stress is augmented in embryos of diabetic rats and that it also plays a role in the activation of PKC and apoptosis. We used antioxidative treatment with beneficial effect although we could not completely abolish the embryonic demise; this may indicate that other mechanisms are involved in diabetic embryopathy. Further studies are needed to develop multi-nutrient dietary supplement to eliminate embryonic abnormalities induced by maternal diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 187
Keyword
Cell biology, Diabetes, Pregnancy, PKC, Apoptosis, Rat, Embryopathy, Vitamin E, Folic acid, CHC, NAC, Cellbiologi
Identifiers
urn:nbn:se:uu:diva-7203 (URN)91-554-6690-7 (ISBN)
Public defence
2006-11-25, B21, Biomedicinskt centrum, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2009-10-14Bibliographically approved

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