TNF‐α Protects Embryos Exposed to Developmental Toxicants

Torchinsky, Arkady; Shepshelovich, Jeanne; Orenstein, Hasida; Zaslavsky, Zeev; Savion, Shoshana; Carp, Howard; Fein, Amos; Toder, V.

doi:10.1034/j.1600-0897.2003.01174.x

Cited by 64 publications

(54 citation statements)

References 38 publications

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“…As mentioned earlier, NF-kB is transcriptionally active in the organogenesis stage embryos and previous studies (Torchinsky et al 2002(Torchinsky et al , 2003(Torchinsky et al , 2006 suggest that the suppression of NF-kB DNA-binding activity may be a pathogenetic event for CP teratogenesis. The transcription factor has a potential of both activating cell proliferation and suppressing apoptosis.…”

Section: Discussionmentioning

confidence: 93%

“…There is also considerable evidence demonstrating NF-kB as an inducer of cell proliferation in cells exposed to toxic stimuli (Chen et al 2001, Shishodia & Aggarwal 2004. The involvement of NF-kB in regulating the teratogenic response has been suggested by the results of studies with such teratogens as CP (Torchinsky et al 2002(Torchinsky et al , 2003(Torchinsky et al , 2006, alcohol (Acquaah-Mensah et al 2002), thalidomide (Hansen et al 2002), diabetes (Torchinsky et al 2004), and phenytoin (an anticonvulsant drug; Kennedy et al 2004). Finally, considerable evidence has been presently collected suggesting the existence of the mechanisms by which NF-kB and p53 are able to regulate each other's activity (Webster & Perkins 1999, Ryan et al 2000, Pommier et al 2004.…”

Section: Introductionmentioning

confidence: 99%

“…Cell proliferation was evaluated as described elsewhere (Torchinsky et al 2003). Briefly, pregnant mice were injected intraperitoneally with 5 0 -bromo-2 0 -deoxyuridine (BrdU; Sigma) in a dose of 200 mg/kg in 0.5 ml PBS/20 g body weight at 0700 h on day 13 of pregnancy.…”

Section: Cell Proliferationmentioning

confidence: 99%

“…Tissue sections (7 mm) were prepared and the localization of apoptotic cells in the tested organs was visualized by TUNEL as described elsewhere (Torchinsky et al 2003). Briefly, after deparafinization, nuclei were labeled with biotinylated dUTP (Promega) using the TdTenzyme (Promega).…”

Section: Apoptosismentioning

confidence: 99%

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p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

Pekar¹,

Molotski²,

Savion³

et al. 2007

Reproduction

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The tumor suppressor protein p53 regulates the sensitivity of embryos to such human teratogens as ionizing radiation, diabetes, and cytostatics. Yet, the molecular mechanisms whereby it fulfills this function remain undefined. We used p53 heterozygous (p53 C/K ) female mice mated with p53 C/K males and then exposed to cyclophosphamide (CP) to test whether caspases 3, 8, and 9 and the transcription factor nuclear factor (NF)-kB may serve as p53 targets. Mice were exposed to CP on day 12 of pregnancy and killed on days 15 and 18 of pregnancy to evaluate CP-induced teratogenic effect. The brain and limbs of embryos harvested 24 h after CP treatment were used to evaluate NF-kB (p65) DNA-binding activity by an ELISA-based method, the activity of the caspases by appropriate colorimetric kits, apoptosis, and cell proliferation by TUNEL, and 5 0 -bromo-2 0 -deoxyuridine incorporation respectively. We observed that the activation of caspases 3, 8, and 9 and the suppression of NF-kB DNA binding following CP-induced teratogenic insult took place only in teratologically sensitive organs of p53 C/C but not p53 K/K embryos. CP-induced apoptosis and suppression of cell proliferation were also more intensive in the former, and they exhibited a higher incidence of structural anomalies, such as open eyes, digit, limb, and tail anomalies. The analysis of the correlations between the p53 embryonic genotype, the activity of the tested molecules, and the CP-induced dysmorphic events at the cellular and organ level suggests caspases 3, 8, and 9 and NF-kB as components of p53-targeting mechanisms in embryos exposed to the teratogen.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Cell Proliferationmentioning

confidence: 99%

Section: Apoptosismentioning

confidence: 99%

See 2 more Smart Citations

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

Pekar¹,

Molotski²,

Savion³

et al. 2007

Reproduction

Self Cite

View full text Add to dashboard Cite

show abstract

“…42 It has been proposed that TNF␣ is essential in preventing the birth of offspring with structural anomalies 43 and protects embryos who are exposed to developmental toxins. 44 Therefore, the rise in TNF␣ and other cytokines could be secondary to the insult caused by the pre- mature entry of oxygenated maternal blood in the developing placenta in TM. If the offspring is otherwise normal, elevated TNF␣ levels, in fact, might have a protective effect to dampen the harm that is caused by oxidative stress, thus allowing the TM to proceed to a normal outcome.…”

Section: Commentmentioning

confidence: 99%

Pro- and antiinflammatory cytokines in threatened miscarriages

Calleja‐Agius

Muttukrishna

Pizzey

et al. 2011

American Journal of Obstetrics and Gynecology

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OBJECTIVE:The purpose of this study was to evaluate circulating and intracellular levels of Th1 and Th2 cytokines in women with threatened miscarriage (TM) and subsequent outcome.STUDY DESIGN: Plasma levels of tumor necrosis factor (TNF)-receptors 1 and 2, TNF␣, interferon gamma (IFN␥), and interleukins (IL) -6 and -10 were measured by flow cytometric bead assays in 80 women with TM: 53 women with normal outcome and 27 women who miscarried. Fluorescent antibody labeling was also performed on whole blood in a subgroup of 27 women of TM: 16 women with normal outcome and 11 women who miscarried. RESULTS:Monocyte expression of TNF␣ and circulating levels of TNF␣, IFN␥, IL-10, IL-6, and TNF-R1 were significantly lower, whereas circulating levels of TNF␣/IL-10, IFN␥/IL-10, and TNF␣/IL-6 ratios were significantly higher, in women with TM who subsequently miscarried, compared with the women with normal outcome.CONCLUSION: An increased Th1 type of immune response, which was similar to that observed in preterm delivery, was found in TM cases that were complicated by a subsequent miscarriage.

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Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell–cell interactions, inflammatory response, and blood pressure regulation

Carmichael

Shaw

Iovannisci³

et al. 2006

American J of Med Genetics Pt A

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This study explored risks of limb deficiency anomalies associated with 29 single nucleotide polymorphisms (SNPs) of genes involved in homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. The authors genotyped 96 cases and 437 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Increased risk of limb anomaly was observed for three SNPs: heterozygosity for F5 Arg506Gln, with an odds ratio (OR) of 2.5 (95% confidence interval (CI), 1.0, 6.5); heterozygosity for TNF (-376)G > A, OR 2.1 (0.7, 6.2); and homozygosity for NPPA 2238T > C, OR 4.0 (1.1, 15.4). We hypothesized that effects of variant genotypes in the presence of maternal smoking, and/or in the absence of supplement intake, may exceed effects of any of these factors alone. In particular, findings for polymorphisms in SERPINE1, ITGA2, SELE, TNF, LTA, NPPA, GNB3, and ADRB2 supported the hypotheses, both for smoking and for supplement intake. These results suggest involvement of genetic variation of biologically relevant candidate genes, and gene-environment interaction, for some limb anomalies whose pathogenesis may be related to altered vascular tone or integrity.

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TNF‐α Protects Embryos Exposed to Developmental Toxicants

Abstract: This work demonstrates for the first time that TNF-alpha may act as a protector of embryos exposed to teratogenic stress. One possible mechanism may be restoration of NF-kappaB activity in embryonic cells surviving the teratogenic insult.

Cited by 64 publications

References 38 publications

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

Pro- and antiinflammatory cytokines in threatened miscarriages

Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell–cell interactions, inflammatory response, and blood pressure regulation

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