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Teratogenic Predisposition in Diabetic Rat Pregnancy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratology)
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 [en]
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: urn:nbn:se:uu:diva-178175ISBN: 978-91-554-8434-7 (print)OAI: oai:DiVA.org:uu-178175DiVA: diva2:544828
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
List of papers
1. Genetic and environmental influence on diabetic rat embryopathy
Open this publication in new window or tab >>Genetic and environmental influence on diabetic rat embryopathy
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.

Keyword
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:nbn:se:uu:diva-105013 (URN)10.​1152/​ajpendo.​00543.​2010 (DOI)000287796200004 ()21119026 (PubMedID)
Available from: 2009-05-31 Created: 2009-05-31 Last updated: 2017-12-13Bibliographically approved
2. Influence of maternal metabolism and parental genetics on fetal maldevelopment in diabetic rat pregnancy
Open this publication in new window or tab >>Influence of maternal metabolism and parental genetics on fetal maldevelopment in diabetic rat pregnancy
2012 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 302, no 10, E1198-E1209 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to investigate the influence of parental transgenerational genetics and maternal metabolic state on fetal maldevelopment in diabetic rat pregnancy. Rats from an inbred malformation-resistant (W) strain, and an inbred malformation-prone (L) strain, were cross-mated to produce two different F-1 hybrids, WL and LW. Normal (N) and manifestly diabetic (MD) WL and LW females were mated with normal males of the same F1 generation to obtain WLWL and LWLW F-2 hybrids. Maternal diabetes increased malformation and resorption rates in both F-2 generations. MD-WLWL offspring had higher resorption rate but similar malformation rate compared with the MD-LWLW offspring. Malformed MD-WLWL offspring presented with 100% agnathia/micrognathia, whereas malformed MD-LWL offspring had 60% agnathia/micrognathia and 40% cleft lip and palate. The MD-WL dams showed increased beta-hydroxy-butyrate levels and alterations in concentrations of several amino acids (taurine, asparagine, citrulline, cystine, glutamic acid, leucine, tyrosine, and tryptophan) compared with MD-LW dams. Fetal glyceraldehyde-3-phosphate dehydrogenase (Gapdh) activity and gene expression were more altered in MD-WLWL than MD-LWLW. Fetal gene expression of reactive oxygen species (ROS) scavenger enzymes was diminished in MD-WLWL compared with MD-LWLW. Glial cell line-derived neurotrophic factor and Ret proto-oncogene gene expression was decreased in both MD-WLWL and MD-LWLW fetuses, whereas increased bone morphogenetic protein 4 and decreased Sonic hedgehog homolog expression was found only in MD-LWLW fetuses. Despite identical autosomal genotypes, the WL and LW dams gave birth to offspring with markedly different malformation patterns. Together with fetal differences in enzymatic activity and expression of Gapdh, ROS scavengers, and developmental genes, these results may suggest a teratological mechanism in diabetic pregnancy influenced by maternal metabolism and parental strain epigenetics.

Keyword
diabetes, malformations, teratogenic, gene expression
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-176242 (URN)10.1152/ajpendo.00661.2011 (DOI)000304360400005 ()
Available from: 2012-06-19 Created: 2012-06-18 Last updated: 2017-12-07Bibliographically approved
3. Alterations in the expression of tissue specific genes of the developing mandible and heart in rat diabetic embryopathy
Open this publication in new window or tab >>Alterations in the expression of tissue specific genes of the developing mandible and heart in rat diabetic embryopathy
(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
diabetes, malformations, teratogenic, gene expression
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-178168 (URN)
Available from: 2012-07-30 Created: 2012-07-30 Last updated: 2012-09-17
4. Receptor for Advanced Glycation End products (RAGE) knockout reduces fetal dysmorphogenesis in murine diabetic pregnancy
Open this publication in new window or tab >>Receptor for Advanced Glycation End products (RAGE) knockout reduces fetal dysmorphogenesis in murine diabetic pregnancy
Show others...
2016 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 62, 62-70 p.Article in journal (Other academic) Published
Abstract [en]

Background & Aim: The receptor for Advanced Glycation End products (RAGE) is implicated in the pathogenesis of diabetic complications, but its importance for the induction of congenital malformations in diabetic pregnancy is unclear. The aim of the present study was to investigate a possible role of RAGE activation in the induction of diabetic embryopathy.

Methods: Female non-diabetic and diabetic wildtype (WT) C57Bl/6 mice and RAGE knockout C57Bl/6 (RAGE‑/-) mice were mated with males of the same genotype. Diabetes was induced by daily streptozotocin (STZ) injections (50 mg/kg STZ i.p.) on five consecutive days. On gestational day 18, pregnant mice were anesthetized and blood was drawn from the heart to measure maternal metabolic parameters. Fetuses and placentas were excised, weighed, and examined for morphological anomalies, and fetal livers were analyzed for 8‑iso‑PGF levels.

Results: There were no malformations in non-diabetic WT or non-diabetic RAGE‑/- mice. However, resorption rates were higher in non-diabetic WT (10%) than in non-diabetic RAGE‑/- mice (4%). Diabetic WT mice had higher malformation (22%) and resorption (43%) rates than diabetic RAGE‑/- mice (3% malformations and 21% resorptions). Maternal diabetes decreased fetal weight more in WT fetuses (44%) than in RAGE‑/- fetuses (36%). There were no differences in plasma glucose levels between the diabetic WT and RAGE‑/- mice, but plasma levels of triglycerides and cholesterol were lower in diabetic WT mice than in diabetic RAGE-/- mice. Diabetes increased maternal plasma levels of methylglyoxal in WT and RAGE‑/- mice, and increased fetal hepatic levels of 8-iso-PGF in WT fetuses, but not in RAGE‑/- fetuses.

Discussion: Knockout of RAGE diminished the rates of fetal malformations and resorptions, despite similar levels of hyperglycemia in pregnant diabetic mice. An anti-teratogenic effect was present in RAGE‑/- mice despite having a more severe diabetic state than diabetic WT mice. As 8-iso-PGF, a marker of oxidative stress, only increased in diabetic WT offspring, this suggested a pivotal role of RAGE activation and oxidative stress in the pathogenesis of diabetic embryopathy.

Keyword
Diabetes; AGE; RAGE; Oxidative stress; Diabetic embryopathy; Neural tube defects; Experimental teratology
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-178170 (URN)10.1016/j.reprotox.2016.04.015 (DOI)000378367700008 ()27109771 (PubMedID)
Funder
Swedish Diabetes AssociationNovo NordiskSwedish Research Council, 54X-21117German Research Foundation (DFG), SFB1118
Available from: 2012-07-30 Created: 2012-07-30 Last updated: 2017-12-07Bibliographically approved

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Citation style
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