Hyperglycemia induces embryopathy, even in the absence of systemic maternal diabetes: An in vivo test of the fuel mediated teratogenesis hypothesis

Baack, Michelle; Wang, Chunlin; Hu, Shanming; Segar, Jeffrey L.; Norris, Andrew W.

doi:10.1016/j.reprotox.2014.03.013

Cited by 32 publications

(27 citation statements)

References 49 publications

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“…Diabetes exposes the embryo to many maternally-derived insults, including hyperglycemia, altered lipid levels, and inflammation. The effect of hyperglycemia alone was recently demonstrated to cause a spectrum of defects in rat embryos in vivo, consistent with diabetic emrbyopathy in humans (Baack et al, 2014). The mechanism of this fuel-mediated teratogenesis may be disruption of glycolysis, an extremely important source of ATP during gastrulation and early organogenesis (Hunter and Sadler, 1989).…”

Section: Diabetesmentioning

confidence: 77%

Prenatal exposure to environmental factors and congenital limb defects

Alexander

Clark

Tuan

2016

Birth Defects Research Pt C

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Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact. This is limited by the insufficiencies of currently available models. Specifically, in vivo approaches using guideline animal models have inherently deficient predictive power due to genomic and anatomic differences that complicate mechanistic comparisons. On the other hand, in vitro two-dimensional (2D) cell cultures, while accessible for cellular and molecular experimentation, do not reflect the three-dimensional (3D) morphogenetic events in vivo nor systemic influences. More robust and accessible models based on human cells that accurately replicate specific processes of embryonic limb development are needed to enhance limb teratogenesis prediction and to permit mechanistic analysis of the adverse outcome pathways. Recent advances in elucidating mechanisms of normal development will aid in the development of process-specific 3D cell cultures within specialized bioreactors to support multicellular microtissues or organoid constructs that will lead to increased understanding of cell functions, cell-to-cell signaling, pathway networks, and mechanisms of toxicity. The promise is prompting researchers to look to such 3D microphysiological systems to help sort out complex and often subtle interactions relevant to developmental malformations that would not be evident by standard 2D cell culture testing. Birth Defects Research (Part C) 108:243-273, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Diabetesmentioning

confidence: 77%

Prenatal exposure to environmental factors and congenital limb defects

Alexander

Clark

Tuan

2016

Birth Defects Research Pt C

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“…Second, it is well recognized that maternal hyperglycemia, particularly early in the pregnancy (during organogenesis), is associated with structural birth defects including cardiac anomalies (3,6), which would impact cardiac function in newborn offspring. Gestational diabetes, which typically develops later in pregnancy, is less likely associated with structural heart defects (11).…”

Section: Study Limitationsmentioning

confidence: 99%

Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction

Mdaki

Larsen

Wachal

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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161

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Offspring of diabetic pregnancies are at risk of cardiovascular disease at birth and throughout life, purportedly through fuel-mediated influences on the developing heart. Preventative measures focus on glycemic control, but the contribution of additional offenders, including lipids, is not understood. Cellular bioenergetics can be influenced by both diabetes and hyperlipidemia and play a pivotal role in the pathophysiology of adult cardiovascular disease. This study investigated whether a maternal high-fat diet, independently or additively with diabetes, could impair fuel metabolism, mitochondrial function, and cardiac physiology in the developing offspring's heart. Sprague-Dawley rats fed a control or high-fat diet were administered placebo or streptozotocin to induce diabetes during pregnancy and then delivered offspring from four groups: control, diabetes exposed, diet exposed, and combination exposed. Cardiac function, cellular bioenergetics (mitochondrial stress test, glycolytic stress test, and palmitate oxidation assay), lipid peroxidation, mitochondrial histology, and copy number were determined. Diabetes-exposed offspring had impaired glycolytic and respiratory capacity and a reduced proton leak. High-fat diet-exposed offspring had increased mitochondrial copy number, increased lipid peroxidation, and evidence of mitochondrial dysfunction. Combination-exposed pups were most severely affected and demonstrated cardiac lipid droplet accumulation and diastolic/systolic cardiac dysfunction that mimics that of adult diabetic cardiomyopathy. This study is the first to demonstrate that a maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancies through metabolic stress and serves as a critical step in understanding the role of cellular bioenergetics in developmentally programmed cardiac disease.

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“…To better understand the interaction between glucose and the fetal myocardium, our laboratory has utilized a recently established rat model [ 16 , 17 ] that delivers localized hyperglycemia to selected fetus in nondiabetic dams. Using this model of maternal diabetes, we examined the effects of hyperglycemia on the fetal myocardium during late gestation.…”

Section: Introductionmentioning

confidence: 99%

Maternal Hyperglycemia Directly and Rapidly Induces Cardiac Septal Overgrowth in Fetal Rats

Gordon

Reinking

et al. 2015

Journal of Diabetes Research

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Cardiac septal overgrowth complicates 10–40% of births from diabetic mothers, but perplexingly hyperglycemia markers during pregnancy are not reliably predictive. We thus tested whether fetal exposure to hyperglycemia is sufficient to induce fetal cardiac septal overgrowth even in the absence of systemic maternal diabetes. To isolate the effects of hyperglycemia, we infused glucose into the blood supply of the left but not right uterine horn in nondiabetic pregnant rats starting on gestational day 19. After 24 h infusion, right-sided fetuses and dams remained euglycemic while left-sided fetuses were moderately hyperglycemic. Echocardiograms in utero demonstrated a thickened cardiac septum among left-sided (glucose-exposed, 0.592 ± 0.016 mm) compared to right-sided (control, 0.482 ± 0.016 mm) fetuses. Myocardial proliferation was increased 1.5 ± 0.2-fold among left-sided compared to right-sided fetuses. Transcriptional markers of glucose-derived anabolism were not different between sides. However, left-sided fetuses exhibited higher serum insulin and greater JNK phosphorylation compared to controls. These results show that hyperglycemic exposure is sufficient to rapidly induce septal overgrowth even in the absence of the myriad other factors of maternal diabetes. This suggests that even transient spikes in glucose may incite cardiac overgrowth, perhaps explaining the poor clinical correlation of septal hypertrophy with chronic hyperglycemia.

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Hyperglycemia induces embryopathy, even in the absence of systemic maternal diabetes: An in vivo test of the fuel mediated teratogenesis hypothesis

Cited by 32 publications

References 49 publications

Prenatal exposure to environmental factors and congenital limb defects

Prenatal exposure to environmental factors and congenital limb defects

Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction

Maternal Hyperglycemia Directly and Rapidly Induces Cardiac Septal Overgrowth in Fetal Rats

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