title: Effect of Hyperglycemia on Gene Expression during Early Organogenesis in Mice.
abstract: BACKGROUND
  Cardiovascular and neural malformations are common sequels of diabetic pregnancies, but the underlying molecular mechanisms remain unknown. We hypothesized that maternal hyperglycemia would affect the embryos most shortly after the glucose-sensitive time window at embryonic day (ED) 7.5 in mice.
  
  
  METHODS
  Mice were made diabetic with streptozotocin, treated with slow-release insulin implants and mated. Pregnancy aggravated hyperglycemia. Gene expression profiles were determined in ED8.5 and ED9.5 embryos from diabetic and control mice using Serial Analysis of Gene Expression and deep sequencing.
  
  
  RESULTS
  Maternal hyperglycemia induced differential regulation of 1,024 and 2,148 unique functional genes on ED8.5 and ED9.5, respectively, mostly in downward direction. Pathway analysis showed that ED8.5 embryos suffered mainly from impaired cell proliferation, and ED9.5 embryos from impaired cytoskeletal remodeling and oxidative phosphorylation (all P ≤ E-5). A query of the Mouse Genome Database showed that 20-25% of the differentially expressed genes were caused by cardiovascular and/or neural malformations, if deficient. Despite high glucose levels in embryos with maternal hyperglycemia and a ~150-fold higher rate of ATP production from glycolysis than from oxidative phosphorylation on ED9.5, ATP production from both glycolysis and oxidative phosphorylation was reduced to ~70% of controls, implying a shortage of energy production in hyperglycemic embryos.
  
  
  CONCLUSIONS
  Maternal hyperglycemia suppressed cell proliferation during gastrulation and cytoskeletal remodeling during early organogenesis. 20-25% of the genes that were differentially regulated by hyperglycemia were associated with relevant congenital malformations. Unexpectedly, maternal hyperglycemia also endangered the energy supply of the embryo by suppressing its glycolytic capacity.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Theodorus B M
authors.initials: TB
authors.lastname: Hakvoort
authors.affiliation: Bioinformatics Laboratory, Department of Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: A Marcel
authors.initials: AM
authors.lastname: Willemsen
authors.affiliation: Bioinformatics Laboratory, Department of Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.affiliation: Department of Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Milka
authors.initials: M
authors.lastname: Sokolovic
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bradley
authors.affiliation: Department of Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Vincent C J
authors.initials: VC
authors.lastname: de Boer
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Bioinformatics Laboratory, Department of Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Biosystems Data Analysis Group, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Antoine H C
authors.initials: AH
authors.lastname: van Kampen
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D063990:Gene Ontology; D006019:Glycolysis / Q000235:genetics; D006330:Heart Defects, Congenital / Q000209:etiology / Q000235:genetics*; D006943:Hyperglycemia / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D051379:Mice; D058977:Molecular Sequence Annotation; D005810:Multigene Family; D009421:Nervous System Malformations / Q000209:etiology / Q000235:genetics*; D010085:Oxidative Phosphorylation; D011247:Pregnancy; D013311:Streptozocin
chemical_list: D013311:Streptozocin; D000255:Adenosine Triphosphate