Diabetic hyperglycemia causes developmental delay and death in early-somite mouse embryos.. Mus musculus

Background: Maternal hyperglycemia is a major cause of congenital malformations in offspring. The prevalence of maternal diabetes is increasing annually. The reason responsible for those complications in offspring induced by maternal hyperglycemia is still unknown.Methods: We investigated effects of maternal diabetes on mouse embryos during somitogenesis. Mice were made diabetic with 5 daily injections of 60 mg/mL streptozotocin (blood glucose ~26 mol/L), treated with controlled-release insulin implants, and mated. Blood glucose concentrations increased again to plateau after embryonic day (ED) 8.5. Embryos were studied on ED7.5-11.5.Results: Maternal hyperglycemia induced severe growth retardation (~1 day) in ~50% of the embryos on ED8.5, death in most of these embryos on ED9.5, and the termination of pregnancy on ED10.5 in litters with >20% dead embryos, so that developmental delays and a reduction in litter size were no longer observed on ED10.5. Male and female embryos were equally sensitive to hyperglycemia-induced developmental delay and premature death. High-throughput mRNA sequencing and pathway analysis of the differentially expressed genes showed that the retarded diabetic embryos failed to mount the adaptive suppression of gene expression that characterized the non-retarded diabetic embryos.Conclusions: This failure to shut down many pathways that are strongly down-regulated in non-retarded diabetic embryos may well be responsible for the observed failure to grow and, subsequently, to survive in half of the hyperglycemic perigastrulation embryos. Consequently, malformations develop in the subset of embryos that survive the early and generalized adverse effect of hyperglycemia during and immediately after gastrulation. When extrapolated to the human situation, embryonic death would occur in the third week of gestation and may not be noted, except possibly for a perceived difficulty to become pregnant.