Abstract
Maternal diabetes causes congenital malformations and delays embryonic growth in the offspring. We investigated effects of maternal diabetes on mouse embryos during gastrulation and early organogenesis (ED7.5–11.5). Female mice were made diabetic with streptozotocin, treated with controlled-release insulin implants, and mated. Maternal blood glucose concentrations increased up to embryonic day (ED) 8.5. Maternal hyperglycemia induced severe growth retardation (approx.1 day) in 53% 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. Due to this selection, developmental delays and reduction in litter size were no longer observed thereafter in diabetic pregnancies. Male and female embryos were equally sensitive. High-throughput mRNA sequencing and pathway analysis of differentially expressed genes showed that retarded embryos failed to mount the adaptive suppression of gene expression that characterized non-retarded embryos (cell proliferation, cytoskeletal remodeling, oxidative phosphorylation). We conclude that failure of perigastrulation embryos of diabetic mothers to grow and survive is associated with their failure to shut down pathways that are strongly down-regulated in otherwise similar non-retarded embryos. Embryos that survive the early and generalized adverse effect of maternal diabetes, therefore, appear the subset in which malformations become manifest.
Highlights
The incidence of diabetes is increasing annually world-wide[1], including that in pregnant young adults[2]
A major difference between our and earlier reported findings is that many ED8.5 and ED9.5 mouse embryos of diabetic mothers (“experimental” embryos) were developmentally retarded, whereas growth retardation and developmental delay were explicitly reported as not being observed in ED10.5 litters of diabetic dams[23,25]
We investigated the developmental progress of embryos from diabetic mothers between ED7.5 and ED11.5 to determine if the manifestation of diabetic embryopathy at and after ED10.5 was preceded by a more general adverse effect on embryonic development
Summary
The incidence of diabetes is increasing annually world-wide[1], including that in pregnant young adults[2]. Neural-tube defects range from a wavy neural tube via spina bifida at various locations to exencephaly and craniorhachischisis[12], while cardiovascular malformations typically display defects of the outflow tract, atrial septum and atrioventricular valves, and extensive apoptosis[9,13]. The frequency of these malformations in several mouse strains is 10–15% of live ED10.5–13.5 embryos[7,9,13,14]. That maternal hyperglycemia affected the expression of genes involved in apoptosis, proliferation, migration and differentiation during organogenesis in the offspring[9,12,22,23,24]. Pathway analysis after high-throughput mRNA sequencing of one-day retarded experimental embryos revealed that these embryos typically failed to mount the adaptive and generally suppressive response in gene expression that characterized the ED8.5 and ED9.5 experimental embryos that were not retarded
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