The Role of Pro‐ and Anti‐apoptotic Molecular Interactions in Embryonic Maldevelopment

Toder, V.; Carp, Howard; Fein, Amos; Torchinsky, Arkady

doi:10.1034/j.1600-0897.2002.01130.x

Cited by 33 publications

(27 citation statements)

References 99 publications

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“…A malformation might be induced when apoptosis is increased or occurred at an inappropriate spatiotemporal manner [102]. A malformation might be induced when apoptosis is increased or occurred at an inappropriate spatiotemporal manner [102].…”

Section: Maternal Diabetes-induced Pro-inflam-matory Mediators Duringmentioning

confidence: 99%

Diabetic Pregnancies: The Challenge of Developing in a Pro-Inflammatory Environment

Jawerbaum

González²

2006

CMC

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The maternal diabetic environment alters the embryo and the feto-placental development. The results of these alterations are: increased embryo resorption and malformation rates, placental dysfunction, fetal alterations that lead to increased neonatal morbidity and mortality rates, and also diseases that will be evident later in the adult life of the newborn. The etiology of these many maternal diabetes-induced complications are not yet understood in full. In this review the role of maternal diabetes as an inductor of a pro-inflammatory environment that impairs embryo and placental development is discussed. An overproduction of pro-inflammatory agents is found in the uterus during implantation and the developing embryo and placenta from experimental models of diabetes, as well as in placenta from diabetic women. In these tissues there are increases in reactive oxygen species, pro-inflammatory cytokines and prostaglandins, nitric oxide and peroxynitrites. These pro-inflammatory agents lead to the intrauterine activation of matrix metalloproteinases, proteases involved in remodeling the extracellular matrix during implantation and feto-placental development. Many of these pro-inflammatory agents have overlapping mechanisms of action and cross regulatory pathways that propagate the inflammatory processes. Antioxidants, PPARgamma activators, and NF-kappaB inhibitors are able to reduce the concentrations of these agents in intrauterine gestational tissues. This article reviews the current understanding of maternal diabetes-induced changes in pro-inflammatory and anti-inflammatory pathways that affect the embryo and placental development in maternal diabetes, and stresses the need of a strict maternal control of the pathology to prevent deleterious consequences in the offspring.

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Section: Maternal Diabetes-induced Pro-inflam-matory Mediators Duringmentioning

confidence: 99%

Diabetic Pregnancies: The Challenge of Developing in a Pro-Inflammatory Environment

Jawerbaum

González²

2006

CMC

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“…Also, the expression of TNF-α protein was higher in embryos cultured in a media with teratogenic concentrations of glucose [10]. Teratogens usually initiate maldevelopment by activating the apoptosis program in target embryonic structures [11]. It is conceivable that TNF-α, with its potential to activate apoptotic signalling cascades [12], acts as a mediator of stimuli inducing embryonic maldevelopment.…”

Section: Electrophoretic Mobility Shift Assay (Emsa)mentioning

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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“…12 Other factors that have been found to alter levels of apoptosis are maternal diabetes and exposure to potent anticancer drugs and antibiotics. 23 The mechanism by which environmental factors and mutations in the CASP10 gene may be involved in the development of ITEV warrants further investigation. The finding of a deletion in the chromosomal region of 2q31-33 associated with TEV, taken together with our findings of positive linkage and association with ITEV and microsatellite markers in this region and an allele in the CASP10 gene on 2q33, strongly implicates this region in the pathogenesis of ITEV.…”

Section: Discussionmentioning

confidence: 99%

“…Embryos exposed to chemical teratogens may display increased activation of the caspases 8 and 3, as it has been proposed that caspases are the first molecules targeted by toxins in the developing fetus. 23 Mutations in CASP10 may make individuals more susceptible to clubfoot through the actions of toxins such as smoking. Smoking has been associated with ITEV, with an estimated relative risk of 1.5 for the lightest smokers to 3.9 for the heaviest smokers.…”

Section: Discussionmentioning

confidence: 99%

Variation in CASP10 Gene Is Associated With Idiopathic Talipes Equinovarus

Heck¹,

Bray²,

Scott³

et al. 2005

Journal of Pediatric Orthopaedics

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Idiopathic talipes equinovarus (ITEV), more commonly known as clubfoot, is a developmental deformity characterized by rigid ankle equinus, hindfoot varus, and forefoot adduction. This common birth defect is treatable, but the etiology of ITEV is largely unknown. Recently, a deletion in the chromosomal region 2q31-33 was found to be associated with clubfoot. Microsatellite markers spanning the region were genotyped in 57 multiplex ITEV families and 83 simplex trios. Family-based analysis revealed that two microsatellite markers, GATA149B10 and D2S1371, were associated with ITEV in the simplex trios. The 6cM region between the two markers contained the candidate genes CASP8, CASP10, and CFLAR. These genes encode proteins that are regulators of apoptosis, which is important during growth and development. Genotyping of SNPs throughout the genes in this sample of ITEV families has revealed positive linkage with association to the major allele of a variant in CASP10 in simplex ITEV white and Hispanic trios. This study is the first to find evidence for a candidate gene for ITEV and provides a scientific foundation to further explore the contributions of other apoptotic genes in the etiology of clubfoot.

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The Role of Pro‐ and Anti‐apoptotic Molecular Interactions in Embryonic Maldevelopment

Cited by 33 publications

References 99 publications

Diabetic Pregnancies: The Challenge of Developing in a Pro-Inflammatory Environment

Diabetic Pregnancies: The Challenge of Developing in a Pro-Inflammatory Environment

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

Variation in CASP10 Gene Is Associated With Idiopathic Talipes Equinovarus

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