Significance of Glutathione Depletion and Oxidative Stress in Early Embryogenesis in Glucose-Induced Rat Embryo Culture

Trocino, R. A.; Akazawa, Shoichi; Ishibashi, Miwa; Matsumoto, Kazunari; Matsuo, Hiroshi; Yamamoto, H.; Goto, Shinji; Urata, Yoshishige; Kondo, Takahito; Nagataki, Shigenobu

doi:10.2337/diab.44.8.992

Cited by 106 publications

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“…It has been suggested that embryonic dysmorphogenesis in a diabetic or hyperglycaemic environment might be induced by the generation of ROS [9] and that ROS-scavenging enzymes can protect diabetic embryos from glucoseinduced malformations [10]. Trocino et al showed that anomalies induced in rat embryos grown under hyperglycaemic conditions are associated with glutathione (GSH) depletion and that GSH esters can attenuate hyperglycaemia-induced abnormalities [11]. The teratogenic effect of diabetic serum was prevented by superoxide dismutase (SOD) and N-acetylcysteine in rat whole embryo culture [12].…”

Section: Introductionmentioning

confidence: 99%

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

et al. 2010

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Aims/hypothesis Experimental studies have suggested that apoptosis is involved in diabetic embryopathy through oxidative stress. However, the precise mechanism of diabetic embryopathy is not yet clear. Thioredoxin (TRX) is a small, ubiquitous, multifunctional protein, which has recently been shown to protect cells from oxidative stress and apoptosis. Using transgenic mice that overproduce human TRX-1 (TRX-Tg mice), we examined whether oxidative stress is involved in fetal dysmorphogenesis in diabetic pregnancies. Methods Non-diabetic and streptozotocin-induced diabetic (DM) female mice were mated with male TRX-Tg mice. Pregnant mice were killed either at day 10 or day 17 of gestation, and viable fetuses and their placentas were recovered, weighed and assessed for gross and histological morphology, biochemical markers and gene expression. Results In both wild-type (WT) and transgenic (Tg) groups, fetal and placental weights in the diabetic group were significantly decreased compared with the non-diabetic group. The incidence of malformation was higher in the diabetic group, and was significantly decreased in the TRXTg group (DM-WT vs DM-Tg; 28.6% vs 10.4%). Oxidative stress markers such as thiobarbituric acid reactive substances and 8-hydroxy-2′-deoxyguanosine were increased in DM-WT group fetuses but were decreased in fetuses from the DM-Tg group. Furthermore, immunohistochemically assayed apoptosis and cleaved caspase-3 production in embryonic neuroepithelial cells was significantly increased in the DM-WT group, and was significantly decreased in the DM-Tg group. Conclusions/interpretation These results indicate that oxidative stress is involved in diabetic embryopathy, and that the antioxidative protein TRX at least partially prevents diabetic embryopathy via suppression of apoptosis.

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Section: Introductionmentioning

confidence: 99%

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

et al. 2010

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“…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.…”

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confidence: 95%

“…Since excess glucose increases ROS in embryos [13,14,15], and oxidants can regulate cellular signalling pathways, including those that control transcriptional responses [30,31], excess oxidants could interfere with signals that induce the expression of Pax-3. Here we tested this hypothesis by alleviating oxidative stress with antioxidant administration, and by inducing oxidative stress with an electron transport complex III inhibitor.…”

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confidence: 99%

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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“…This may illustrate a difference in acute and chronic effects on the embryonic tissue exerted by a diabetic environment, but could also indicate that the major effect of the diabetic milieu is a decrease in antioxidant capacity rather than an outright increase in oxygen radical production. This notion is strengthened by the clear antiteratogenic effect of supplementing either NAC (present study) or GSH ester [41] to high-glucose cultured embryos. In addition, it has been shown that culture of rat embryos in high glucose concentration decreases cellular glutathione levels and decreases the activity of the rate-limiting GSH-synthesising enzyme, g -glutamylcysteine synthetase [41].…”

Section: Discussionmentioning

confidence: 73%

“…This notion is strengthened by the clear antiteratogenic effect of supplementing either NAC (present study) or GSH ester [41] to high-glucose cultured embryos. In addition, it has been shown that culture of rat embryos in high glucose concentration decreases cellular glutathione levels and decreases the activity of the rate-limiting GSH-synthesising enzyme, g -glutamylcysteine synthetase [41].…”

Section: Discussionmentioning

confidence: 73%

Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture

1997

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Diabetic embryopathy and growth retardation are approximately 2-3 times more common in infants of diabetic women than in offspring of non-diabetic pregnancy [1]. The mechanisms causing these developmental disturbances are unknown [2,3]. Experimental studies in vivo and in vitro have suggested that glucose and b -hydroxybutyrate cause growth retardation and malformations in rodent embryos [4][5][6]. In an earlier study we showed that serum from insulin-treated diabetic rats is teratogenic despite normalisation of glucose and b -hydroxybutyrate concentrations [7], in line with similar results by Buchanan et al. [8]. These studies support the notion of a multifactorial aetiology of embryonic dysmorphogenesis in diabetic pregnancy [9,10].In the present work we have extended these studies by assessing the components in excess of high glucose and high ketone bodies that may exert significant teratogenic activity in vitro. This was done by culturing day 9 rat embryos for 48 h in serum from normal rats and rats made diabetic either with 50 mg/kg streptozotocin (STZ) or with 75 mg/kg STZ (denoted 50 MD and 75 MD). The glucose concentration of the culture media was set at 30 mmol/l, Diabetologia (1997) 40: 7-14 Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture Summary Congenital malformations are more common in offspring of diabetic mothers than offspring of non-diabetic mothers. The precise cell biological mechanism leading to the increased incidence of congenital malformations in diabetic pregnancy is not known. In previous studies increased glucose and b -hydroxybutyrate concentrations were found to cause embryonic dysmorphogenesis. We have previously shown that rat embryos, cultured in serum from insulin-treated diabetic rats, develop malformations, despite normalisation of glucose and b -hydroxybutyrate concentration, thereby suggesting a multifactorial teratological nature of the diabetic environment. In the present study, therefore, we aimed to characterise the teratogenic activity of various components of diabetic serum and in addition to study the possible antiteratogenic effects of supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. We found that diabetic serum has a teratogenic effect on embryo development, a capacity residing in the alteration of several serum components in addition to glucose. Improving the embryonic capability to scavenge oxygen radicals, either by increasing superoxide dismutase activity or by supplying a ratelimiting precursor (N-acetylcysteine) for the enhanced synthesis of reduced glutathione, blocks the embryonic dysmorphogenesis. [Diabetologia (1997) 40: 7-14] Keywords Diabetic pregnancy, embryo development, congenital malformation, glucose, b -hydroxybutyrate, branched chain amino acids, embryo culture, superoxide dismutase, N-acetylcysteine.Received: 16 July 1996 and in revised form: 30 September 1996Corresponding author: P. Wentzel, Department of Medical Cell ...

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Significance of Glutathione Depletion and Oxidative Stress in Early Embryogenesis in Glucose-Induced Rat Embryo Culture

Cited by 106 publications

References 0 publications

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

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

Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture

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