ABSTRACT
Diabetes in the mother during pregnancy is a risk factor for birth defects and perinatal complications and can affect long-term health of the offspring through developmental programming of susceptibility to metabolic disease. We previously showed that Streptozotocin-induced maternal diabetes in mice is associated with altered cell differentiation and with smaller size of the placenta. Placental size and fetal size were affected by maternal diet in this model, and maternal diet also modulated the risk for neural tube defects. In the present study, we sought to determine the extent to which these effects might be mediated through altered expression of nutrient transporters, specifically glucose and fatty acid transporters in the placenta. Our results demonstrate that expression of several transporters is modulated by both maternal diet and maternal diabetes. Diet was revealed as the more prominent determinant of nutrient transporter expression levels, even in pregnancies with uncontrolled diabetes, consistent with the role of diet in placental and fetal growth. Notably, the largest changes in nutrient transporter expression levels were detected around midgestation time points when the placenta is being formed. These findings place the critical time period for susceptibility to diet exposures earlier than previously appreciated, implying that mechanisms underlying developmental programming can act on placenta formation.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diet, High-Fat/adverse effects , Membrane Transport Proteins/metabolism , Nutrients/metabolism , Placenta/pathology , Pregnancy in Diabetics/metabolism , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/pathology , Fatty Acids/metabolism , Female , Fetal Development , Glucose/metabolism , Humans , Mice , Pregnancy , Pregnancy in Diabetics/etiology , Pregnancy in Diabetics/pathology , Streptozocin/toxicityABSTRACT
Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development, and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that identifies impaired migration of nascent mesodermal cells in the primitive streak as the morphogenetic basis underlying the pathogenesis of neural tube defects. We conclude that perturbed gastrulation not only explains the neurulation defects, but also provides a unifying etiology for the broad spectrum of congenital malformations in diabetic pregnancies.
Subject(s)
Diabetes, Gestational/genetics , Nerve Tissue Proteins/genetics , Neural Plate/metabolism , Neural Tube Defects/genetics , Animals , Diabetes, Gestational/metabolism , Diabetes, Gestational/pathology , Disease Models, Animal , Embryo, Mammalian , Female , Gastrulation/genetics , Gene Expression Profiling , Gene Expression Regulation, Developmental , High-Throughput Nucleotide Sequencing , Humans , Laser Capture Microdissection , Mice , Mice, Inbred NOD , Nerve Tissue Proteins/metabolism , Neural Plate/embryology , Neural Plate/pathology , Neural Tube Defects/embryology , Neural Tube Defects/metabolism , Neural Tube Defects/pathology , PregnancyABSTRACT
Gastrulation is the process in which the three germ layers are formed that contribute to the formation of all major tissues in the developing embryo. We here review mouse genetic models in which defective gastrulation leads to mesoderm insufficiencies in the embryo. Depending on severity of the abnormalities, the outcomes range from incompatible with embryonic survival to structural birth defects, such as heart defects, spina bifida, or caudal dysgenesis. The combined evidence from the mutant models supports the notion that these congenital anomalies can originate from perturbations of mesoderm specification, epithelial-mesenchymal transition, and mesodermal cell migration. Knowledge about the molecular pathways involved may help to improve strategies for the prevention of major structural birth defects.
