Effect of hyperglycemia on gene expression during early organogenesis. Mus musculus

Background: Cardiovascular and neural-tube malformations are common sequels of diabetic pregnancies, but the underlying molecular mechanisms remain unknown. We hypothesized that maternal hyperglycemia in mice would affect the embryos most shortly after the glucose-sensitive time window at embryonic day (ED) 7.5. 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 involved 1024 and 2148 regulated unique genes with a known function 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 ~54% of the differentially expressed genes were responsible for cardiovascular and/or neural-tube malformations, if deficient. At ED9.5, ATP production from glycolysis was ~150-fold that from oxidative phosphorylation and both oxidative phosphorylation and glycolysis in cells from embryos with maternal hyperglycemia had decreased to ~70% of controls. Conclusion: Maternal hyperglycemia suppressed cell proliferation during gastrulation and cytoskeletal remodeling during early organogenesis. More than half 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.