Vitamin E Decreases the Occurrence of Malformations in the Offspring of Diabetic Rats

Simán, C Martin; Eriksson, UJ

doi:10.2337/diab.46.6.1054

Cited by 128 publications

(35 citation statements)

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“…Consequently, supplementation of anti-oxidants is able to lower the incidence of defects in diabetic pregnancies [Reece and Wu, 1997; Siman and Eriksson, 1997; Wiznitzer et al, 1999a; Cederberg et al, 2001; Sugimura et al, 2009]. It has been suggested that in this context, folic acid also acts as an anti-oxidant, as it is able to reduce neural tube defect rates in pregnancies affected by hyperglycemia [Gareskog et al, 2006; Oyama et al, 2009].…”

Section: Maternal Diabetes and Neural Tube Defects In Animal Modelsmentioning

confidence: 99%

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Kappen¹

2013

American J of Med Genetics Pt C

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Head morphogenesis is a complex process that is controlled by multiple signaling centers. The most common defects of cranial development are craniofacial defects, such as cleft lip and cleft palate, and neural tube defects, such as anencephaly and encephalocoele in humans. More than 400 genes that contribute to proper neural tube closure have been identified in experimental animals, but only very few causative gene mutations have been identified in humans, supporting the notion that environmental influences are critical. The intrauterine environment is influenced by maternal nutrition, and hence, maternal diet can modulate the risk for cranial and neural tube defects. This article reviews recent progress toward a better understanding of nutrients during pregnancy, with particular focus on mouse models for defective neural tube closure. At least four major patterns of nutrient responses are apparent, suggesting that multiple pathways are involved in the response, and likely in the underlying pathogenesis of the defects. Folic acid has been the most widely studied nutrient, and the diverse responses of the mouse models to folic acid supplementation indicate that folic acid is not universally beneficial, but that the effect is dependent on genetic configuration. If this is the case for other nutrients as well, efforts to prevent neural tube defects with nutritional supplementation may need to become more specifically targeted than previously appreciated. Mouse models are indispensable for a better understanding of nutrient–gene interactions in normal pregnancies, as well as in those affected by metabolic diseases, such as diabetes and obesity.

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Section: Maternal Diabetes and Neural Tube Defects In Animal Modelsmentioning

confidence: 99%

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Kappen¹

2013

American J of Med Genetics Pt C

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“…There is ample experimental support that oxidative stress contributes to malformations in animal models exposed to a high glucose milieu [37, 51–55]. In addition to increased superoxide production from increased oxidative metabolism, the pathways responsible for oxidative stress are complex; they include decreased expression of γ -glutamyl-cysteine synthetase, which would decrease production of the antioxidant, reduced glutathione (GSH) [123, 124], and increased activity of the hexosamine flux pathway and diacylglycerol/protein kinase C signaling [40, 125].…”

Section: Mechanisms By Which Maternal Diabetes Disrupts Pax3 Gene Expmentioning

confidence: 99%

“…In general, these models result in malformation of craniofacial structures and the neural tubes and growth retardation. There are several biochemical disturbances that have been proposed to play a role in the defective development, such as increased protein kinase C activity [38–40], decreased arachidonic acid uptake [41, 42], defective prostaglandin synthesis [43, 44], PPAR signaling [45–48], random DNA mutations [49, 50], and oxidative stress [37, 51–55]. However, none of these studies revealed how these biochemical disturbances could disturb morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

Diabetes and apoptosis: neural crest cells and neural tube

2009

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Birth defects resulting from diabetic pregnancy are associated with apoptosis of a critical mass of progenitor cells early during the formation of the affected organ(s). Insufficient expression of genes that regulate viability of the progenitor cells is responsible for the apoptosis. In particular, maternal diabetes inhibits expression of a gene, Pax3, that encodes a transcription factor which is expressed in neural crest and neuroepithelial cells. As a result of insufficient Pax3, cardiac neural crest and neuroepithelial cells undergo apoptosis by a process dependent on the p53 tumor suppressor protein. This, then provides a cellular explanation for the cardiac outflow tract and neural tube and defects induced by diabetic pregnancy.

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“…That homozygous mutant Pax3 mouse embryos develop NTD and COTD with 100% penetrance (13,14) supports the notion that inhibition of Pax3 below a critical threshold is sufficient to cause NTD or COTD in embryos of diabetic mothers. Several studies have indicated that oxidative stress produced in the embryo in response to increased glucose metabolism is responsible for diabetic pregnancy–induced malformations (15–20). We have shown that oxidative stress inhibits expression of Pax3 (21,22).…”

Section: Introductionmentioning

confidence: 99%

Increased DNA Methyltransferase 3b (Dnmt3b)-Mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy

Wei

Loeken

2014

Diabetes

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Previous studies have shown that diabetic embryopathy results from impaired expression of genes that are required for formation of embryonic structures. We have focused on Pax3, a gene that is expressed in embryonic neuroepithelium and is required for neural tube closure. Pax3 expression is inhibited in embryos of diabetic mice due to hyperglycemia-induced oxidative stress. DNA methylation silences developmentally expressed genes before differentiation. We hypothesized that hypomethylation of Pax3 upon neuroepithelial differentiation may be inhibited by hyperglycemia-induced oxidative stress. We tested this using embryos of pregnant hyperglycemic mice and mouse embryonic stem cells (ESC). Methylation of a Pax3 CpG island decreased upon neurulation of embryos and formation of neuronal precursors from ESC. In ESC, this was inhibited by oxidative stress. Use of short hairpin RNA in ESC demonstrated that DNA methyltransferase 3b (Dnmt3b) was responsible for methylation and silencing of Pax3 before differentiation and by oxidative stress. Although expression of Dnmt3b was not affected by oxidative stress, DNA methyltransferase activity was increased. These results indicate that hyperglycemia-induced oxidative stress stimulates Dnmt3b activity, thereby inhibiting chromatin modifications necessary for induction of Pax3 expression during neurulation and thus providing a molecular mechanism for defects caused by Pax3 insufficiency in diabetic pregnancy.

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Vitamin E Decreases the Occurrence of Malformations in the Offspring of Diabetic Rats

Cited by 128 publications

References 0 publications

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Diabetes and apoptosis: neural crest cells and neural tube

Increased DNA Methyltransferase 3b (Dnmt3b)-Mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy

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