Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos

Hagay, Zion; Weiss, Yael; Zusman, Igor; Peled-Kamar, Mira; Reece, E. Albert; Eriksson, Ulf J.; Groner, Yoram

doi:10.1016/0002-9378(95)91323-8

Cited by 147 publications

(114 citation statements)

References 20 publications

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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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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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“…Additionally, this model system mimics the morphological and biochemical vascular defects in the embryo and yolk sac observed in vivo (New et al, 1976;Mills et al, 1979;Sadler and Warner, 1984). Though the underlying mechanisms are unknown, the yolk sac has been suggested as a target of the hyperglycemic insult via excess production of reactive oxygen species (ROS), and a link between yolk sac injury and multi-system embryopathy has been proposed (Eriksson and Borg, 1991;Eriksson and Borg, 1993;Hagay et al, 1995;Hunter and Sadler, 1992;Pinter et al, 1986;Reece et al, 1989;Reece et al, 1994;Wentzel and Eriksson, 1998;Zusman et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

et al. 2004

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Nitric oxide (NO) has been demonstrated to mediate events during ovulation,pregnancy, blastocyst invasion and preimplantation embryogenesis. However,less is known about the role of NO during postimplantation development. Therefore, in this study, we explored the effects of NO during vascular development of the murine yolk sac, which begins shortly after implantation. Establishment of the vitelline circulation is crucial for normal embryonic growth and development. Moreover, functional inactivation of the endodermal layer of the yolk sac by environmental insults or genetic manipulations during this period leads to embryonic defects/lethality, as this structure is vital for transport, metabolism and induction of vascular development. In this study, we describe the temporally/spatially regulated distribution of nitric oxide synthase (NOS) isoforms during the three stages of yolk sac vascular development (blood island formation, primary capillary plexus formation and vessel maturation/remodeling) and found NOS expression patterns were diametrically opposed. To pharmacologically manipulate vascular development,an established in vitro system of whole murine embryo culture was employed. During blood island formation, the endoderm produced NO and inhibition of NO(L-NMMA) at this stage resulted in developmental arrest at the primary plexus stage and vasculopathy. Furthermore, administration of a NO donor did not cause abnormal vascular development; however, exogenous NO correlated with increased eNOS and decreased iNOS protein levels. Additionally, a known environmental insult (high glucose) that produces reactive oxygen species(ROS) and induces vasculopathy also altered eNOS/iNOS distribution and induced NO production during yolk sac vascular development. However, administration of a NO donor rescued the high glucose induced vasculopathy, restored the eNOS/iNOS distribution and decreased ROS production. These data suggest that NO acts as an endoderm-derived factor that modulates normal yolk sac vascular development, and decreased NO bioavailability and NO-mediated sequela may underlie high glucose induced vasculopathy.

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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: 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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Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos

Cited by 147 publications

References 20 publications

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

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

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

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

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