Immunostimulation increases the resistance of mouse embryos to the teratogenic effect of diabetes mellitus

Torchinsky, Arkady; Toder, V.; Savion, Shoshana; Shepshelovich, Jeanne; Orenstein, Hasida; Fein, Amos

doi:10.1007/s001250050727

Cited by 36 publications

(34 citation statements)

References 26 publications

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“…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. These authors later reported beneficial effects of maternal immune stimulation on uterine cytokines tumor necrosis factor-alpha (TNFa; Fein et al, 2001) and transforming growth factor-beta (TGFb; Fein et al, 2002) that show distorted expression in diabetic animals.…”

Section: Maxillary Lengthmentioning

confidence: 99%

“…Maternal immune stimulation reduced or blocked digit and limb defects (Prater et al, 2004), tail malformations, cleft palate (Sharova et al, 2002), and neural tube defects (Torchinsky et al, 1997;Punareewattana et al, 2003;Punareewattana and Holladay, 2004). Diverse means of maternal immune stimulation have proved effective in reducing defects including intraperitoneal (i.p.)…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Maxillary Lengthmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Blastocysts incubated in media preconditioned with uterine explants from diabetic rats developed less well than those incubated in control media [4]. Finally various studies [5,6,7] showed that the pregnancy rate of chemically induced diabetic mice is lower than in their non-diabetic counterparts. This decrease in pregnancy rate was accompanied by increased expression of TNF-α in uterine cells from the beginning of implantation onwards [8].…”

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confidence: 99%

TNF-? acts to prevent occurrence of malformed fetuses in diabetic mice

et al. 2004

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Aims/hypothesis. Activation of apoptosis in embryos is thought to be a key event in the pathogenesis of diabetes-induced embryopathies such as early embryonic death and inborn structural anomalies. TNF-α can activate apoptotic and anti-apoptotic signalling cascades, indicating its ability to contribute to and counteract diabetes-induced maldevelopment. To investigate how TNF-α regulates the response of embryos to diabetesinduced embryopathic stress, we used streptozotocininduced diabetic TNF-α knockout mice. Materials. To evaluate the reproductive performance, mated diabetic female mice were examined on days 4 and 8 of pregnancy for the presence of blastocysts or embryos in uterine horns. To evaluate the teratogenic effect, the female mice were killed on day 18 of pregnancy and fetuses were examined for gross external anomalies. In addition, apoptotic nuclei were localised by the TUNEL assay and DNA-binding activity of the transcription factor NF-κB was evaluated by electrophoretic mobility shift assay in 10-and 11-day-old embryos respectively. Results. Severely diabetic TNF-α +/+ female mice had a much greater decrease in pregnancy rate but a lower incidence of malformed fetuses in litters than severely diabetic TNF-α −/− female mice. Also, the intensity of excessive apoptosis was higher, but the amount of active NF-κB complexes was lower in malformed TNF-α −/− embryos than in TNF-α +/+ embryos. Conclusions/interpretation. TNF-α contributes to death of peri-implantation embryos and possibly protects postimplantation embryos exposed to diabetes-induced teratogenic stimuli via activation of NF-κB-mediated anti-apoptotic signalling. It seems that TNF-α prevents the birth of malformed offspring in severely diabetic mice. [Diabetologia (2004) 47:132-139] Keywords Diabetes · teratogenic effect · inborn structural anomalies · apoptosis · TNF-α · NF-κB verse effects on early embryos. Thus the amount of TNF-α released into the culture supernatant by uterine explants dissected from diabetic rats at the time of implantation was four times higher than in uterine explants dissected from non-diabetic rats [3]. Blastocysts incubated in media preconditioned with uterine explants from diabetic rats developed less well than those incubated in control media [4]. Finally various studies [5,6,7] showed that the pregnancy rate of chemically induced diabetic mice is lower than in their non-diabetic counterparts. This decrease in pregnancy rate was accompanied by increased expression of TNF-α in uterine cells from the beginning of implantation onwards [8].Other data suggest that TNF-α could be involved in the formation of teratogen-induced structural anomaTumour necrosis factor-α, a multifunctional cytokine, is expressed by uterine, placental and embryonic cells practically at all stages of development [1,2]. In the last decade convincing evidence has been collected that TNF-α plays a role in mediating diabetes-induced ad-

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“…Sharova et al (2002) showed that interferon-gamma and Freund's complete adjuvant reduced severity of the urethane -induced cleft palate in mice . Torkinsky et al (1997) reported that immune stimulation in diabetic mice, which show a high spontaneous rate of cleft palate, decreased in malformed fetuses, significantly (Torkinsky et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Prophylactic Effects of Melatonin on Sodium Valproate-Induced Neural Tube Defects and Skeletal Malformations in Rat Embryos

Rahgazar¹,

Ranjbar²,

Varzi³

et al. 2011

American Journal of Applied Sciences

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Problem statement: Some reports showed the teratogenic effects of sodium valproate can be prevented by application of antioxidant drugs and stimulation of the maternal immune system. Therefore, in this study, the prophylactic effect of melatonin on teratogenic effects of sodium valproate was compared. Approach: This study was performed on 31 pregnant rats that were divided into five groups. Control group received normal saline and test groups received sodium valproate (300 mg kg ), intraperitonealy at 8-9th days of gestation, respectively. Fetuses were collected at 20th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Results: Cleft palate, spina bifida and exencephaly incidence were 17.70, 20 and 20% in fetuses of rats that received only sodium valproate. Cleft palate, spina bifida and exencephaly incidence were 4.16, 8.33 and 8.33% range in group which received sodium valproate plus melatonin (5 mg kg −1 ), respectively. However, Cleft palate, spina bifida and excencaphaly incidence were 4/76, 0 and 0% in group which received sodium valproate plus melatonin (10 mg kg −1 ), respectively. The mean of weight and length of animals' fetuses that received melatonin were significantly greater than those received only sodium valproate. Conclusion: It is concluded that melatonin with dose of 10 mg kg −1 had significantly more prophylactic effect than melatonin with dose of 5 mg kg −1 on incidence of sodium valproate-induced skeletal malformations.

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Immunostimulation increases the resistance of mouse embryos to the teratogenic effect of diabetes mellitus

Cited by 36 publications

References 26 publications

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

TNF-? acts to prevent occurrence of malformed fetuses in diabetic mice

Prophylactic Effects of Melatonin on Sodium Valproate-Induced Neural Tube Defects and Skeletal Malformations in Rat Embryos

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