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Genetic and environmental influence on diabetic rat embryopathy
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 Cell Biology. (Teratology)
2011 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 300, no 3, E454-E467 p.Article in journal (Refereed) Published
Abstract [en]

We assessed genetic and environmental influence on fetal outcome in diabetic rat pregnancy. Crossing normal (N) and manifestly diabetic (MD) Wistar Furth (W) and Sprague-Dawley (L) females with W or L males yielded 4 different fetal genotypes (WW, LL, WL, LW) in N or MD rat pregnancies for studies. We also evaluated fetal outcome in litters with enhanced or diminished severity of maternal MD state, denoted MD(+)WL and MD(-)LW. The MDWW litters had less malformations and resorptions (0% and 19%) than the MDLL litters (17% and 30%). The MDWL litters (0% and 8%) were less maldeveloped than the MDLW litters (9% and 22%), whereas the MD(+)WL (3% and 23%) and MD(-)LW (1% and 17%) litters showed increased and decreased dysmorphogenesis (compared to MDWL and MDLW litters). The pregnant MDW rats had lower serum levels of glucose, fructosamine and branched chain amino acids than the pregnant MDL rats, whereas the pregnant MD(+)W and MD(-)L rats had levels comparable to those of the MDL and MDW rats, respectively. The 8-iso-PGF2α levels of the malformed MDLW offspring were increased compared to the non-malformed MDLW offspring. Diabetes decreased fetal heart Ret and increased Bmp-4 gene expression in the MDLW offspring, and caused decreased GDNF and Shh expression in the malformed fetal mandible of the MDLW offspring. We conclude that the fetal (epi)genome controls the embryonic dysmorphogenesis in diabetic pregnancy by instigating a threshold level for the teratological insult, and that the maternal genome controls the teratogenic insult by (dys)regulating the maternal metabolism.

Place, publisher, year, edition, pages
2011. Vol. 300, no 3, E454-E467 p.
Keyword [en]
diabetes in pregnancy, congenital abnormalities, teratology, animal experimentation, aldose reductase, glyceraldehyde-3-phosphate dehydrogenase, sonic hedgehog homologue, ret proto-oncogene, glial-derived neurotrophic factor, antioxidative enzymes
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-105013DOI: 10.​1152/​ajpendo.​00543.​2010ISI: 000287796200004PubMedID: 21119026OAI: oai:DiVA.org:uu-105013DiVA: diva2:220345
Available from: 2009-05-31 Created: 2009-05-31 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Genetic predisposition for malformations in diabetic rat pregnancy
Open this publication in new window or tab >>Genetic predisposition for malformations in diabetic rat pregnancy
2008 (English)Licentiate thesis, comprehensive summary (Other academic)
Publisher
10 p.
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-105018 (URN)
Presentation
BMC C2:301, Biomedicinskt Centrum, Uppsala, Uppsala (English)
Opponent
Supervisors
Available from: 2009-07-30 Created: 2009-05-31 Last updated: 2011-11-03Bibliographically approved
2. Teratogenic Predisposition in Diabetic Rat Pregnancy
Open this publication in new window or tab >>Teratogenic Predisposition in Diabetic Rat Pregnancy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pre-gestational diabetes increases the risk of congenital malformation in the offspring and both morbidity and mortality in the diabetic mother and her offspring. During pregnancy, high glucose levels act as a teratogen through several cellular and biochemical pathways and increased production of reactive oxygen species (ROS) has a central role in diabetic embryopathy. The aim of this work was to investigate the importance of genetic predisposition for congenital malformations and to study the genes involved in the teratogenic process of diabetic pregnancy.

The crossbreeding of two rat strains, with both low and high incidence of diabetes-induced malformations, indicated that strain-specific maternal factors, such as disturbed serum levels of amino acids, triglycerides, and β-hydroxybutyrate, were associated with malformation. In addition, disturbed fetal expression of genes involved in ROS defense and development (Shh, Bmp4, Ret and Gdnf) in mandible and heart, and decreased activity of Gapdh and Aldose Reductase were associated with the teratogenic process, and the trans-generational heredity of the mother determined the type of malformations induced by maternal diabetes.

In rat embryos, a diabetic environment in utero changed the expression of genes involved in ROS defense (Nrf2, Gpx1 and Cat), development of mandible and heart (Msx2, Shh, Bmp4, Ret and Gdnf), and neural tube closure and apoptosis (Pax3 and p53). The changes were divergent with tissue-specific alterations of gene expression in developing mandible, heart anlage, and whole embryo.

Disruption of the Receptor for Advanced Glycation End products (RAGE) had a protective effect against diabetic embryopathy in mice, and the blockage of RAGE diminished ROS production in the offspring: this supported oxidative stress being a necessary etiological component in diabetic embryopathy.

Maternal metabolic state and genetic susceptibility influence fetal outcome in experimental diabetic pregnancy. Disturbed protection against oxidative stress and tissue-specific derangements in the expression of developmental genes play pivotal roles in the teratogenic mechanism, and enhanced levels of Advanced Glycation End products (AGE) and RAGE-induced oxidative stress are involved in diabetic dysmorphogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 797
Keyword
diabetes, malformations, teratogenic, advanced glycation end products, AGE, RAGE, oxidative stress, ROS, gene expression
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-178175 (URN)978-91-554-8434-7 (ISBN)
Public defence
2012-09-28, A1:107a, Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-09-07 Created: 2012-07-30 Last updated: 2013-01-22Bibliographically approved

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Ejdesjö, AndreasEriksson, Ulf J.

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