Apoptosis, Expression of PAX3 and P53, and Caspase Signal in Fetuses with Neural Tube Defects

Wang, Linlin; Lin, Shanshan; Yi, Dengxia; Huang, Yun; Wang, Caiyun; Jin, Lei; Liu, Jufen; Zhang, Yali

doi:10.1002/bdr2.1094

Cited by 31 publications

(26 citation statements)

References 27 publications

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“…Interestingly, our previous studies found higher levels of oxidative damage markers in the serum of pregnant women who delivered NTD-affected foetuses than women who delivered healthy newborns [28] . Furthermore, we observed more apoptotic cells in neural tissues of NTD cases than normal foetuses [25] . It is well documented that PAHs could induce oxidative stress and human observational studies suggest an association between PAH exposure and oxidative damage with increased risks of NTDs.…”

Section: Introductionmentioning

confidence: 63%

“…Apoptosis occurs at various developmental stages as a homeostatic mechanism to maintain cell populations in tissues [24] . During the formation of the neural tube, apoptosis appears to be dispensable; however excessive apoptosis could potentially result in NTDs by causing insufficient cells to be present in the fusing neural folds or by disrupting the physical continuity of the dorsal midline [1] , [25] . Excess apoptosis is observed in the neuroepithelium of rodent embryos exposed to high levels of glucose in maternal serum, and deletion of pro-apoptosis kinase genes reduces the incidence of NTDs in these embryos [26] , [27] .…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress and Apoptosis in Benzo[a]pyrene-Induced Neural Tube Defects

Lin

Ren

Wang

et al. 2018

Free Radical Biology and Medicine

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Neural tube defects (NTDs) are among the most common and severe congenital malformations and result from incomplete closure of the neural tube during early development. Maternal exposure to polycyclic aromatic hydrocarbons (PAHs) has been suggested to be a risk factor for NTDs and previous studies imply that the mechanism underlying the association between PAH exposure and NTDs may involve oxidative stress and apoptosis. The objectives of this study were to investigate whether there is a direct effect of maternal benzo[α] pyrene (BaP) exposure on the closure of the neural tube in mice, and to examine the underlying mechanisms by combining animal experiments and human subject studies. We found that intraperitoneal injection of BaP from embryonic day 7 at a dose of 250 mg kg-1 induced NTDs (13.3% frequency) in ICR mice. BaP exposure significantly increased expression of genes associated with oxidative stress, Cyp1a1, Sod1 and Sod2, while repressing Gpx1. Elevated apoptosis and higher protein expression of cleaved caspase-3 in the neuroepithelium of treated embryos were observed. Pre-treatment with vitamin E, added to food, significantly protected against BaP-induced NTDs (1.4% frequency) (P < 0.05). Vitamin E also partly normalized oxidative stress related gene expression and excess apoptosis in BaP-treated embryos. Examination of human neural tissues revealed that increased levels of protein carbonyl and apoptosis were related with maternal exposure to PAHs and the risk of NTDs. Collectively, these results suggest that BaP exposure could induce NTDs and that this may involve increased oxidative stress and apoptosis, while vitamin E may have a protective effect.

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Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Oxidative Stress and Apoptosis in Benzo[a]pyrene-Induced Neural Tube Defects

Lin

Ren

Wang

et al. 2018

Free Radical Biology and Medicine

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“…In human NTDs cases, more apoptotic cells were observed in the central nervous tissue [71]. Higher levels of p53 were observed in anencephaly cases [71]. Cleaved caspase 3 levels were elevated in encephalocele cases and cleaved caspase 8 levels were higher in spina bifida cases relative to controls [71].…”

Section: Discussionmentioning

confidence: 95%

“…On the other hand, excessive apoptosis in the lumbar sacral neuroepithelium has been observed with retinoic acid-induced spina bifida [70]. In human NTDs cases, more apoptotic cells were observed in the central nervous tissue [71]. Higher levels of p53 were observed in anencephaly cases [71].…”

Section: Discussionmentioning

confidence: 99%

Association between rare variants in specific functional pathways and human neural tube defects multiple subphenotypes

et al. 2020

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Background: Neural tube defects (NTDs) are failure of neural tube closure, which includes multiple central nervous system phenotypes. More than 300 mouse mutant strains exhibits NTDs phenotypes and give us some clues to establish association between biological functions and subphenotypes. However, the knowledge about association in human remains still very poor. Methods: High throughput targeted genome DNA sequencing were performed on 280 neural tube closure-related genes in 355 NTDs cases and 225 ethnicity matched controls, Results: We explored that potential damaging rare variants in genes functioning in chromatin modification, apoptosis, retinoid metabolism and lipid metabolism are associated with human NTDs. Importantly, our data indicate that except for planar cell polarity pathway, craniorachischisis is also genetically related with chromatin modification and retinoid metabolism. Furthermore, single phenotype in cranial or spinal regions displays significant association with specific biological function, such as anencephaly is associated with potentially damaging rare variants in genes functioning in chromatin modification, encephalocele is associated with apoptosis, retinoid metabolism and one carbon metabolism, spina bifida aperta and spina bifida cystica are associated with apoptosis; lumbar sacral spina bifida aperta and spina bifida occulta are associated with lipid metabolism. By contrast, complex phenotypes in both cranial and spinal regions display association with various biological functions given the different phenotypes. Conclusions: Our study links genetic variant to subphenotypes of human NTDs and provides a preliminary but direct clue to investigate pathogenic mechanism for human NTDs.

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“…The subjects were recruited from five rural counties of Shanxi Province (Xiyang, Shouyang, Taigu, Pingding, and Zezhou) in northern China from 2011 to 2014 (Wang et al 2017). The NTD cases were fetuses terminated following the prenatal diagnosis of an NTD.…”

Section: Study Populationmentioning

confidence: 99%

Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects

et al. 2020

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Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in the development of NTDs. Torrent™ Personal Genome Machine™ (PGM) sequencing was designed for selected PCP genes in paired DNA samples extracted from the tissues of lesion sites and umbilical cord from 48 cases. Sanger sequencing was used to validate the detected mutations. The source and distribution of the validated mutations in tissues from different germ layers were investigated. Subcellular location, western blotting, and luciferase assays were performed to better understand the effects of the mutations on protein localization, protein level, and pathway signaling. ix somatic mutations were identified and validated, which showed diverse distributions in different tissues. Three somatic mutations were novel/rare: CELSR1 p.Gln2125His, FZD6 p.Gln88Glu, and VANGL1 p.Arg374His. FZD6 p.Gln88Glu caused mislocalization of its protein from the cytoplasm to the nucleus, and disrupted the colocalization of CELSR1 and FZD6. This mutation affected non-canonical WNT signaling in luciferase assays. VANGL1 p.Arg374His impaired the co-localization of CELSR1 and VANGL1, increased the protein levels of VANGL1, and influenced cell migration. In all, 7/48 (14.5%) of the studied NTD cases contained somatic PCP mutations. Somatic mutations in PCP genes (e.g., FZD6 and VANGL1) are associated with human NTDs, and they may occur in different stages and regions during embryonic development, resulting in a varied distribution in fetal tissues/organs.

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Apoptosis, Expression of PAX3 and P53, and Caspase Signal in Fetuses with Neural Tube Defects

Abstract: These findings provide some evidence that excessive apoptosis in fetal central nervous tissues may be associated with the development of human NTDs. Birth Defects Research 109:1596-1604, 2017. © 2017 Wiley Periodicals, Inc.

Cited by 31 publications

References 27 publications

Oxidative Stress and Apoptosis in Benzo[a]pyrene-Induced Neural Tube Defects

Oxidative Stress and Apoptosis in Benzo[a]pyrene-Induced Neural Tube Defects

Association between rare variants in specific functional pathways and human neural tube defects multiple subphenotypes

Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects

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