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Alterations in the expression of tissue specific genes of the developing mandible and heart in rat diabetic 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)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background & Aim: Maternal diabetes induces skeletal and cardiac malformations in the offspring, both in human and experimental diabetic pregnancies. A developmental disturbance in neural crest cell (NCC) derived embryonic tissue is a plausible origin for these malformations. Thus, diabetes-exposed and control rat embryos from a locally outbred Sprague-Dawley rat strain were used to investigate tissue-specific alterations in the expression of suggested candidate genes in the developing mandible and heart anlage and in the whole embryo.

Methods: Female non-diabetic (N) and streptozotocin-induced manifestly diabetic (MD) rats were mated with N males. Embryos were collected and morphologically examined on gestational days (GD) 11 and 13. The developing mandible (first pharyngeal arch), heart anlage and the remaining embryonic tissues were prepared and analyzed with quantitative real time PCR.

Results: Maternal diabetes changed the gene expression in the developing mandible where Gpx1 (MD11) and Cat (MD13) decreased. In the heart anlage, diabetes decreased Nrf2 (MD11), whereas, in whole embryo, diabetes increased Nrf2 (MD13). Maternal diabetes changed the gene expression in the developing mandible, Bmp4 (MD13) decreased, and Gdnf (MD11 and MD13) and Ret (MD11 and MD13) increased. In the heart anlage, diabetes decreased Shh (MD11) and Gdnf (MD11 and MD13). In whole embryo, diabetes decreased Shh (MD11) and Gdnf (MD13) and increased Msx2 (MD13) and Ret (MD11 and MD13). Maternal diabetes changed the gene expression in the developing mandible; Pax3 was both increased (MD11) and decreased (MD13). In the heart anlage, diabetes decreased Pax3 (MD13), whereas, in the whole embryo, diabetes increased Pax3 (MD13) and both decreased p53 (MD11) and increased p53 (MD13).

Conclusions: Hyperglycemia in utero causes tissue-specific alterations in embryonic gene expression of several important antioxidative defense and developmental genes. Tissuespecific disturbance of gene expressions suggests a diminished ROS scavenging capacity and a role for altered gene expression of Gdnf, Ret, Bmp4 and Pax3 in the diabetes-induced embryonic dysmorphogenesis.

Keyword [en]
diabetes, malformations, teratogenic, gene expression
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-178168OAI: oai:DiVA.org:uu-178168DiVA: diva2:542210
Available from: 2012-07-30 Created: 2012-07-30 Last updated: 2012-09-17
In thesis
1. 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, Andreas

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