Dietary vitamin E prophylaxis and diabetic embryopathy: Morphologic and biochemical analysis

Sivan, Eyal; Reece, E. Albert; Wu, Ying; Homko, Carol J.; Polansky, Marcia; Borenstein, Michael

doi:10.1016/s0002-9378(96)80001-9

Cited by 122 publications

(99 citation statements)

References 19 publications

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“…For example, excess oxygen radical activity has been reported to be associated with disturbed embryogenesis in diabetic pregnancy (13). Other studies have also shown a reduction in the severity of these diseases with administration of vitamin E during early pregnancy (14,15). These findings, together with the present results, suggest that embryogenesis, especially the formation of the placental labyrinthine trophoblasts, is more susceptible to oxidative stress.…”

Section: Discussionsupporting

confidence: 85%

α-Tocopherol Transfer Protein Is Important for the Normal Development of Placental Labyrinthine Trophoblasts in Mice

Jishage¹,

Arita²,

Igarashi³

et al. 2001

Journal of Biological Chemistry

169

139

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␣-Tocopherol transfer protein (␣-TTP), a cytosolic protein that specifically binds ␣-tocopherol, is known as a product of the causative gene in patients with ataxia that is associated with vitamin E deficiency. Targeted disruption of the ␣-TTP gene revealed that ␣-tocopherol concentration in the circulation was regulated by ␣-TTP expression levels. Male ␣-TTP ؊/؊ mice were fertile; however, placentas of pregnant ␣-TTP ؊/؊ females were severely impaired with marked reduction of labyrinthine trophoblasts, and the embryos died at mid-gestation even when fertilized eggs of ␣-TTP ؉/؉ mice were transferred into ␣-TTP ؊/؊ recipients. The use of excess ␣-tocopherol or a synthetic antioxidant (BO-653) dietary supplement by ␣-TTP ؊/؊ females prevented placental failure and allowed full-term pregnancies. In ␣-TTP ؉/؉ animals, ␣-TTP gene expression was observed in the uterus, and its level transiently increased after implantation (4.5 days postcoitum). Our results suggest that oxidative stress in the labyrinth region of the placenta is protected by vitamin E during development and that in addition to the hepatic ␣-TTP, which governs plasma ␣-tocopherol level, the uterine ␣-TTP may also play an important role in supplying this vitamin.Vitamin E (␣-tocopherol) is the most potent lipid-soluble antioxidant in biological membranes, where it contributes to membrane stability. Patients with ataxia and isolated vitamin E deficiency (AVED) 1 have low or undetectable serum vitamin E concentrations and exhibit neurological dysfunction and muscular weakness. It is now established that ␣-tocopherol transfer protein (␣-TTP), a cytosolic liver protein known to specifically bind to ␣-tocopherol (1), is defective in AVED patients (2), indicating that ␣-TTP is a major determinant of plasma ␣-tocopherol level. Although ␣-tocopherol was initially identified as an anti-sterility factor to prevent abortion (3), the mechanism of action and the molecules responsible for its antisterility effect remain unknown. One of the reasons for this is that vitamin E is difficult to deplete from tissues and requires elaborate manipulations to cause deficiency symptoms to occur in experimental animals. In this study, we established a mouse model lacking ␣-TTP by targeted mutagenesis. This animal model for human AVED patients is suitable for examination of the complex pathophysiology of diseases associated with vitamin E deficiency and/or caused by oxidative stress. Here we examined the role of ␣-TTP in pregnancy and embryogenesis using our new animal model. MATERIALS AND METHODSGeneration of ␣-TTP Knockout Mice-An ␣-TTP targeting vector was constructed from an 8.8-kb ␣-TTP genome fragment encompassing exon 1. We inserted a fragment of PGK-neo cassette into the SmaI-SmaI site positioned 5Ј and 3Ј to exon 1 and flanked a 1.8-kb fragment of HSV-tk gene downstream of exon 2. AB2.2-Prime ES cells (Lexicon Genetics) or A3-1 ES (4) cells were transfected by electroporation with a linearized targeting vector. G418/gancyclovir-resistant clones were screened by PCR, and...

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Section: Discussionsupporting

confidence: 85%

α-Tocopherol Transfer Protein Is Important for the Normal Development of Placental Labyrinthine Trophoblasts in Mice

Jishage¹,

Arita²,

Igarashi³

et al. 2001

Journal of Biological Chemistry

169

139

View full text Add to dashboard Cite

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“…Numerous studies have shown that antioxidants can prevent the developmental defects caused by maternal diabetes in experimental animals [14,18,19,20,21,22,23]. Interestingly, vitamin E was first identified as an essential nutrient for prenatal (but not postnatal) life [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…mutase, can prevent structural defects caused by high glucose in rodent embryos [13,14,17,18,19,20,21,22,23], this indicates that hyperglycaemia-induced oxidative stress plays a causal role in diabetes-induced congenital defects.…”

mentioning

confidence: 96%

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

et al. 2003

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Aims/hypothesis. Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. Methods. Maternal diabetes-induced oxidative stress was blocked with α-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Results. Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and α-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by α-tocopherol and GSHethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. Conclusion/interpretation. Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress. [Diabetologia (2003) 46:538-545]

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“…Preventive strategies have been examined in laboratory animals based on knowledge of these pathways, in attempts to reduce diabetic embryopathy associated with high glucose levels. For example, birth defect incidence has been reduced in diabetic mice by dietary supplementation with myoinositol (Baker et al, 1990), arachidonic acid (Goldman et al, 1985;Pinter et al, 1986), lipoic acid (Wiznitzer et al, 1999), or antioxidants including vitamin E (Sivan et al, 1996) and vitamin C (Siman and Eriksson, 1997). Torchinsky et al (1997) stimulated uterine immune cells in pregnant mice in an attempt to reduce fetal resorptions associated with diabetes, and made the unexpected observation of significantly reduced malformed fetuses.…”

Section: Maxillary Lengthmentioning

confidence: 99%

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

Hrubec

Prater

Toops

et al. 2005

Birth Defects Research Pt B

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BACKGROUND: Maternal diabetes can induce a number of developmental abnormalities in laboratory animals and humans, including facial deformities and defects in neural tube closure. The incidence of birth defects in newborns of diabetic women is approximately 3–5 times higher than among non‐diabetics. In mice, non‐specific activation of the maternal immune system can reduce fetal abnormalities caused by diverse etiologies, including diabetes induced neural tube defects. This study was conducted to determine whether non‐specific maternal immune stimulation could reduce diabetes‐induced craniofacial defects as well. METHODS: Maternal immune function was stimulated before streptozocin (STZ) treatment by maternal footpad injection with Freund's complete adjuvant (FCA), maternal intraperitoneal (i.p.) injection with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), or maternal i.p. injection with interferon‐γ (IFNγ). Streptozocin (200 mg/kg i.p.) was used to induce hyperglycemia (26–35 mmol blood glucose) in female ICR mice before breeding. Fetuses from 12–18 litters per treatment group, were collected at Day 17 of gestation. RESULTS: Craniofacial defects were observed in fetuses from all hyperglycemic groups. The incidence of defects was significantly decreased in fetuses from dams immune stimulated with IFNγ or GM‐CSF. The most common defects were reduced maxillary and mandibular lengths. Both were prevented by maternal stimulation with GM‐CSF. CONCLUSION: Maternal immune stimulation reduced the incidence of diabetic craniofacial embryopathy. The mechanisms for these protective effects are unknown but may involve maternal or fetal production of cytokines or growth factors that protect the fetus from the dysregulatory effects of hyperglycemia. Birth Defects Res Part B 2006. © 2005 Wiley‐Liss, Inc.

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Dietary vitamin E prophylaxis and diabetic embryopathy: Morphologic and biochemical analysis

Cited by 122 publications

References 19 publications

α-Tocopherol Transfer Protein Is Important for the Normal Development of Placental Labyrinthine Trophoblasts in Mice

α-Tocopherol Transfer Protein Is Important for the Normal Development of Placental Labyrinthine Trophoblasts in Mice

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

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

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