Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

Chang, Tara I.; Horal, Melissa; Jain, Sushil K.; Wang, F.; Patel, Rakesh P.; Loeken, Mary R.

doi:10.1007/s00125-003-1063-2

Cited by 144 publications

(188 citation statements)

References 64 publications

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“…Antimycin A is a mitochondrial complex III inhibitor that stimulates superoxide production [40,41] and mimics the effects of maternal diabetes on Pax3 expression and NTD [39,47]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Non-diabetic Glut2 +/− male and female mice were mated and hyperglycaemia or oxidative stress was induced on day 7.5 as described previously [34,39]. Briefly, transient hyperglycaemia was induced by injecting 2 ml of 12.5% glucose-PBS solution subcutaneously approximately every 1-2 h between 09.00 and 17.00 h. Blood glucose concentrations were checked hourly, and animals were re-injected as needed to maintain the blood glucose concentration ≥300 mg/dl (16.65 mmol/l).…”

Section: Methodsmentioning

confidence: 99%

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Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Thorens

Loeken

2007

Diabetologia

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Aims/hypothesis Excess glucose transport to embryos during diabetic pregnancy causes congenital malformations. The early postimplantation embryo expresses the gene encoding the high-K m GLUT2 (also known as SLC2A2) glucose transporter. The hypothesis tested here is that high-K m glucose transport by GLUT2 causes malformations resulting from maternal hyperglycaemia during diabetic pregnancy. Materials and methods Glut2 mRNA was assayed by RT-PCR. The K m of embryo glucose transport was determined by measuring 0.5-20 mmol/l 2-deoxy[ 3 H]glucose transport. To test whether the GLUT2 transporter is required for neural tube defects resulting from maternal hyperglycaemia, Glut2 +/− mice were crossed and transient hyperglycaemia was induced by glucose injection on day 7.5 of pregnancy. Embryos were recovered on day 10.5, and the incidence of neural tube defects in wild-type, Glut2 +/− and Glut2 −/− embryos was scored. Results Early postimplantation embryos expressed Glut2, and expression was unaffected by maternal diabetes. Moreover, glucose transport by these embryos showed Michaelis-Menten kinetics of 16.19 mmol/l, consistent with transport mediated by GLUT2. In pregnancies made hyperglycaemic on day 7.5, neural tube defects were significantly increased in wild-type embryos, but Glut2 +/− embryos were partially protected from neural tube defects, and Glut2 −/− embryos were completely protected from these defects. The frequency of occurrence of wild-type, Glut2 +/− and Glut2 −/− embryos suggests that the presence of Glut2 alleles confers a survival advantage in embryos before day 10.5. Conclusions/interpretations High-K m glucose transport by the GLUT2 glucose transporter during organogenesis is responsible for the embryopathic effects of maternal diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Thorens

Loeken

2007

Diabetologia

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“…The congenital malformations associated with diabetic pregnancy affect many major organs, including the central nervous, cardiovascular, gastrointestinal, urogenital and musculoskeletal systems [5,6]. The pathogenesis of congenital anomalies is complex and still poorly understood, although it has been suggested that excessive reactive oxygen species (ROS) associated with hyperglycaemia are responsible for the increased risk of malformation [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

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Aims/hypothesis Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetesinduced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocininduced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos −/− ). Results ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetesrelated congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos −/− mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

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“…For example, the oxidative stress caused by hyperglycemia has been shown to disrupt the expression of genes such as Pax3 that is involved in neural tube formation which explains in part that hyperglycemia-induced oxidative stress alters gene expression leading to NTD [32] . Hyperglycemia-induced birth defects are attributed to the excessive production of reactive oxygen species (ROS) which has been shown to cause oxidative stress and subsequently increase the risk for fetal malformations [33,34] . Administration of antioxidants such as vitamin E and overexpression of ROS scavenging enzymes such as superoxide dismutase have been shown to prevent or reduce the risk for diabetic malformations in several animal studies although the exact mechanism is unknown [35][36][37][38][39][40] .…”

Section: Characterisation Of Metabolic Pathways In Ntdsmentioning

confidence: 99%

Frontiers in research on maternal diabetes-induced neural tube defects: Past, present and future

Sudhaharan

Bay²,

Tay³

et al. 2012

WJD

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Diabetes mellitus rightly regarded as a silent-epidemic is continually on the rise and estimated to have a global prevalence of 6.4 % as of 2010. Diabetes during pregnancy is a well known risk factor for congenital anomalies in various organ systems that contribute to neonatal mortality, including cardiovascular, gastrointestinal, genitourinary and neurological systems, among which the neural tube defects are frequently reported. Over the last two to three decades, several groups around the world have focussed on identifying the molecular cues and cellular changes resulting in altered gene expression and the morphological defects and in diabetic pregnancy. In recent years, the focus has gradually shifted to looking at pre-programmed changes and activation of epigenetic mechanisms that cause altered gene expression. While several theories such as oxidative stress, hypoxia, and apoptosis triggered due to hyperglycemic conditions have been proposed and proven for being the cause for these defects, the exact mechanism or the link between how high glucose can alter gene expression/transcriptome and activate epigenetic mechanisms is largely unknown. Although preconceptual control of diabetes, (i.e., managing glucose levels during pregnancy), and in utero therapies has been proposed as an effective solution for managing diabetes during pregnancy, the impact that a fluctuating glycemic index can have on foetal development has not been evaluated in detail. A tight glycemic control started before pregnancy has shown to reduce the incidence of congenital abnormalities in diabetic mothers. On the other hand, a tight glycemic control after organogenesis and embryogenesis have begun may prove insufficient to prevent or reverse the onset of congenital defects. The importance of determining the extent to which glycemic levels in diabetic mothers should be regulated is critical as foetal hypoglycemia has also been shown to be teratogenic. Finally, the major question remaining is if this whole issue is negligible and not worthy of investigation as the efficient management of diabetes during pregnancy is well in place in many countries.

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Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

Cited by 144 publications

References 64 publications

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Frontiers in research on maternal diabetes-induced neural tube defects: Past, present and future

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