Occurrence Of Neural Tube Defects Research Articles

MTHFR C677T and MTR A2756G Gene Polymorphism in Neural Tube Defect Patients and Its Association with Red Blood Cell Folate Level in Eastern Indian Population.

Single-nucleotide polymorphism (SNP) is a single-nucleotide change in a deoxyribose nucleic acid (DNA) sequence that occurs in >1% of population. Methylene tetra hydro folate reductase (MTHFR) C677T (rs1801133) and methionine synthase enzyme (MTR) A2756G (rs1805087) are two such SNPs occurring in coding sequence of the respective genes, which are frequently seen with neural tube defects (NTDs). MTHFR and MTR genes are involved in folate metabolism. The folate level in the course of pregnancy is treated as vital in the etiopathogenesis of NTDs. This study aims to explore the association of SNPs of both genes and red blood cell (RBC) folate levels in the predisposition to NTDs. The purpose of this investigation was to determine the relationship of NTDs with polymorphisms in MTHFR and MTR genotype and to estimate and compare the RBC folate levels in NTD patients and controls. A total of 397 individuals were enrolled (163 patients and 234 controls) for this observational study. Genotyping to find out MTHFR C677T and MTR A2756G was performed by polymerase chain reaction-restriction fragment length polymorphism technique from DNA extracted from the subject's blood. RBC folate level was estimated by chemiluminescence immunoassay method with the same blood sample. The total RBC folate levels were significantly less among cases compared to controls (P = 0.020). A significant difference for RBC folate was observed between case and control groups of various genotypes of MTHFR C677T, except heterozygote CT (P = 0.459). Among MTR A2756G, genotypes with only homozygous AA have significant difference (P = 0.003) for RBC folate levels. Among different types of NTDs, there were no significant differences for RBC folate levels. Among MTHFR C677T, T allele possessed 1.9 times risk compared to C allele for the occurrence of NTDs. In MTR A2756G polymorphism, the odds of developing NTDs were 1.6 times in heterozygous AG compared to homozygous AA. Similarly, the risk for NTDs was three times higher in subjects with both heterozygous AG and CT genotypes compared to wild-type homozygous AA and CC genotypes. The total RBC folate levels were significantly less among cases compared to controls, and the genotypes had no such effect in decrease in RBC folate levels. The presence of mutant allele in homozygous or heterozygous condition for both SNPs had increased risk associated with NTDs.

Maternal Obesity and the Risk of Selected Foetal Abnormalities (Neural Tube Defects and Orofacial Clefts) In Malaysia: A Retrospective Observational Study

Objective: To evaluate the association between maternal obesity and the risk of selected foetal abnormalities (neural tube defects and orofacial clefts) in Malaysia. Materials and Methods: We conducted a single-centre retrospective observational study on all women who delivered at Hospital Sultanah Aminah Johor Bahru, Malaysia from 1st January 2017 to 31st December 2018. The presence of neural tube defects (NTD) and orofacial clefts (OC) were identified from medical records, including all live births, stillbirths and terminations of pregnancy. All deliveries during the study period were reviewed to collect data on maternal weight, height and demographics. We performed multiple logistic regression to estimate factors contributing to selected anomalies. Results: A total of 28,228 pregnancies were included. There were 57 NTD-affected pregnancies and 34 OCaffected pregnancies identified during the two-year study period. There was no statistically significant association found between maternal obesity and the occurrence of NTDs or OCs. Pre-gestational diabetes had a significant association with NTD-affected pregnancies (aOR 3.454, 95% CI [1.017, 11.725], p=0.091). The highest incidence rate of NTDs was among Malaysian Indians (2.540 per 1,000 deliveries). Malaysian Chinese and Malaysians of other ethnicities were found to have a significantly higher risk of having OC-affected pregnancies with aOR of 2.371 (95% CI [1.035-5.428], p=0.024) and 4.910 (95% CI [1.454-16.579], p=0.024) respectively. Conclusion: Our study showed no significant association between maternal obesity and selected foetal abnormalities (NTD and OC), and that pre-gestational diabetes is a significant risk factor for NTD in Malaysia.

Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT)

Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA. This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia. For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests. Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P=0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P=0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P=0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ. High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism.

Genetic Polymorphisms in DNA Repair Gene APE1/Ref-1 and the Risk of Neural Tube Defects in a High-Risk Area of China.

Apurinic/apyrimidinic endonuclease 1/redox-factor 1 (APE1/Ref-1) gene encodes a multifunctional protein involved in the DNA base excision repair (BER) pathway, which initiates repair of apurinic/apyrimidinic (AP) sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone. APE1/Ref-1 polymorphisms are related to the occurrence of neural tube defects (NTDs), but the association between APE1/Ref-1 polymorphisms and NTDs is not reported in Chinese Han population. The aim of the present study was to evaluate the association of APE1/Ref-1 polymorphism and the risk of NTD occurrence for Han population in a high-risk area of China. APE1/Ref-1 genotypes were determined by iPLEX Gold SNP genotyping. AP sites and folate level of brain tissues were measured. The results showed that three polymorphisms (rs3136817, rs77794916, and rs1760944) of APE1/Ref-1 were statistically associated with NTD subtypes. Allele C of rs3136817, allele T of rs77794916, and allele G of rs1760944 were associated with an increased risk for encephalocele (OR = 2.52, 95% CI [1.25-5.07], P < 0.01; OR = 1.80, 95% CI [1.04-3.12], P = 0.04; and OR = 1.96, 95% CI [1.12-3.45], P = 0.02), compared with those harboring the alleles T, C, and T, respectively. The folate level in NTDs was lower than that in controls. DNA AP sites in the encephalocele were significantly higher than the control (P < 0.01). The three polymorphisms of APE1/Ref-1 were significantly related to NTD occurrence, which indicated that APE1/Ref-1 might be a potential genetic risk factor for encephalocele in a high-risk area of NTDs in China.

Organoids as a new model system to study neural tube defects.

The neural tube is the first critically important structure that develops in the embryo. It serves as the primordium of the central nervous system; therefore, the proper formation of the neural tube is essential to the developing organism. Neural tube defects (NTDs) are severe congenital defects caused by failed neural tube closure during early embryogenesis. The pathogenesis of NTDs is complicated and still not fully understood even after decades of research. While it is an ethically impossible proposition to investigate the in vivo formation process of the neural tube in human embryos, a newly developed technology involving the creation of neural tube organoids serves as an excellent model system with which to study human neural tube formation and the occurrence of NTDs. Herein we reviewed the recent literature on the process of neural tube formation, the progress of NTDs investigations, and particularly the exciting potential to use neural tube organoids to model the cellular and molecular mechanisms underlying the etiology of NTDs.

Prenatal exposure to barium and the occurrence of neural tube defects in offspring

Neural tube defects (NTDs) have a complex etiology. Few studies have assessed alkaline earth metals exposures and occurrence of NTDs. We examined the association between prenatal exposure to magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba) and risk for NTDs in a case-control study, and assessed the teratogenic effects of Ba on mice. Placentas were collected from 408 women with NTD-affected pregnancies and 593 women who delivered healthy infants, and concentrations of these metals were determined as prenatal exposure markers. The single effect of individual exposure and joint effect of coexposure to these metals were evaluated with logistic regression and Bayesian kernel machine regression (BKMR), respectively. Barium chloride (BaCl2) was intragastrically administered to pregnant ICR mice and fetal mice were examined for NTDs. Median concentrations of Mg and Ba were higher in NTD cases than in controls (Pall < 0.001). In logistic regression, higher levels of Ba were associated with 1.6-fold increased risk for NTDs (95% confidence interval: 1.06–2.43). In BKMR, the joint effect of the four-metal mixture on NTD risk increased steadily with the levels of the mixture. A change in Ba concentration from the 25th to 75th percentile displayed a risk effect when the other three metals were fixed at the 25th, 50th or 75th percentile, while such a change in Ca concentration showed a protective effect when the other metals were held at the 25th or 50th percentile. No interactions among metals were found. In the mouse experiment, dams treated with 200 mg/kg BaCl2 showed 16.8% of NTDs in fetal mice, compared to 2.6% in the untreated control group (P < 0.01). Taken together, higher mixture levels of the four alkaline earth metals were associated with increased risk for NTDs, with Ba being the major contributor for the joint effect. Intragastric administration of Ba can induce NTDs in mice.

Prenatal Ultrasonographic and Magnetic Resonance Imaging Diagnosis of Occipital Meningio-Encephalocele- An Interesting Case Report

Meningo encephalocele is a congenital anomaly and is a neural tube defect with occipital meningo encephalocele being the most common and is a result of a failure of the surface ectoderm to separate from the neuroectoderm. This condition can be identified in 1st trimester in 80% of cases and almost all by 2nd trimester. A 20-year-old third gravida was referred for antenatal Ultrasonography at five months of amenorrhoea to rule out fetal anomalies. On targeted imaging, for fetal anomalies, a defect was seen in occipital bone with herniation of posterior fossa contents with overlying meningeal covering. No other fetal anomalies were noted. A diagnosis of isolated occipital meningoencephalocele was made with additional fetal MRI correlation. The mother underwent termination of her pregnancy by Department of Obstetrics and Gynecology because of the grim fetal prognosis. The mother was advised to plan the subsequent pregnancies and was advised pre-conceptional folic acid supplementation. We present a case of isolated occipital meningoencephalocele- a rare congenital anomaly which was diagnosed prenatally in our hospital. This case provides an opportunity for identifying such neurological defects early and prompt termination of pregnancy to prevent comorbidity to mother. This study also helps to establish occipital meninigioencephalocele as an isolated clinicoradiological diagnosis and to distinguish it from syndrome associated occipital meninigioencephalocele or those associated with other neural tube defects like Chiari III malformations. It also allows us to stress once again the role of periconceptional folic acid in preventing the occurrence of neural tube defects.

Neural Tube Defects and Associated Anomalies before and after Folic Acid Fortification

To examine the prevalence and types of neural tube defects and the types of anomalies co-occurring with neural tube defects in 6years before fortification of cereal grain flour with folic acid (1992-1998) and 20years after fortification (1999-2018) in South Carolina, a state with a historically high prevalence of these birth defects. The prevalence of neural tube defects was determined by active and passive surveillance methods in South Carolina since 1992. The types of neural tube defects and co-occurring malformations were determined by prenatal ultrasound and post-delivery examination. In the 6 prefortification years, 363 neural tube defects were identified among 279 163 live births and fetal deaths (1/769), 305 (84%) of which were isolated defects of the calvaria or spine. In the 20 fortification years, there were significant reductions in the prevalence and percentage of isolated defects: 938 neural tube defects were identified among 1 165 134 live births and fetal deaths (1/1242), 696 (74.2%) of which were isolated. The current prevalence of neural tube defects in South Carolina (0.56/1000 live births and fetal deaths) is comparable with that nationwide. The continued occurrence of neural tube defects, the majority of which are isolated, after folic acid fortification of cereal grain flours suggests that additional prevention measures are necessary to reduce further the prevalence of these serious defects of the brain and spine.

Altered Glutaminase 1 Activity During Neurulation and Its Potential Implications in Neural Tube Defects.

The neurulation process is regulated by a large amount of genetic and environmental factors that determine the establishment, folding, and fusion of the neural plate to form the neural tube, which develops into the main structure of the central nervous system. A recently described factor involved in this process is glutamate. Through NMDA ionotropic receptor, glutamate modifies intracellular Ca2+ dynamics allowing the oriented cell migration and proliferation, essentials processes in neurulation. Glutamate synthesis depends on the mitochondrial enzyme known as glutaminase 1 (GLS1) that is widely expressed in brain and kidney. The participation of GLS 1 in prenatal neurogenic processes and in the adult brain has been experimentally established, however, its participation in early stages of embryonic development has not been described. The present investigation describes for the first time the presence and functionality of GLS1 in Xenopus laevis embryos during neurulation. Although protein expression levels remains constant, the catalytic activity of GLS1 increases significantly (~66%) between early (stage 12) and middle to late (stages 14–19) neurulation process. Additionally, the use of 6-diazo-5-oxo-L-norleucine (L-DON, competitive inhibitor of glutamine-depend enzymes), reduced significantly the GLS1 specific activity during neurulation (~36%) and induce the occurrence of neural tube defects involving its possible participation in the neural tube closure in Xenopus laevis embryos.

The effect of folic acid deficiency on Mest/Peg1 in neural tube defects

Objective Neural tube defects (NTDs) are one of the most common and serious birth defects in human beings caused by genetic and environmental factors. Folate insufficiency is involved in the occurrence of NTDs and folic acid supplementation can prevent NTDs occurrence, however, the underlying mechanism remains poorly understood. Methods We established cell and animal models of folic acid deficiency to detect the methylation modification and expression levels of genes by MassARRAY and real-time PCR, respectively. Results and conclusion: In the present study, we found firstly that in human folic acid-insufficient NTDs, the methylation level of imprinted gene Mest/Peg1 was decreased. By using a folic acid-deficient cell model, we demonstrated that Mest/Peg1 methylation was descended. Meanwhile, the mRNA level of Mest/Peg1 was up-regulated via hypomethylation modification under low folic acid conditions. Consistent with the results in cell models, Mest/Peg1 expression was elevated through hypomethylation regulation in folate-deficient animal models. Furthermore, the up-regulation of Mest/Peg1 inhibited the expression of Lrp6 gene, a crucial component of Wnt pathway. Similar results with Lrp6 down-regulation of fetal brain were verified in animal models under folic acid-deficient condition. Taken together, our findings indicated folic acid increased the expression of Mest/Peg1 via hypomethylation modification, and then inhibited Lrp6 expression, which may ultimately impact on the development of nervous system through the inactivation of Wnt pathway.

Effects of Quetiapine on Neural Tube Development in the Early Stage of Chicken Embryos.

To investigate the effects of quetiapine exposure on neural tube development in early stage chicken embryos. Eighty-four fertilised specific pathogen-free chicken eggs were divided into four equal groups (groups 1?4). Three experimental groups (groups 2, 3 and 4) and a single control group (group 1) were used. Each egg in group 2 (n=21) was injected with 20 ?L of saline after 30 hours of incubation. Eggs in groups 3 and 4 were injected with 0.02 ml of a solution containing 400 and 800 ?g of quetiapine dose, respectively. Incubation was continued until the end of 72 hours. All embryos were then removed from the eggs and histopathologically examined. Normal development and the closed neural tubes were shown in 18, 16, 13 and 9 embryos in groups 1 2, 3 and 9, respectively, of the 84 embryos incubated. Open neural tubes were found in one, three and five embryos in groups 2, 3 and 5, respectively. Also, developmental anomalies were found in three, four, five and seven embryos in groups 1, 2, 3 and 4, respectively. Moreover, no significant relationship between NTD and quetiapine exposure had been found. Quetiapine has no significant effect on the occurrence of neural tube defects in the chicken embryo model.

Amniotic fluid levels of selected trace elements and heavy metals in pregnancies complicated with neural tube defects.

The aims of this study were to determine the levels of trace elements and heavy metals, namely aluminum (Al), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), molybdenum (Mo), cadmium (Cd), tin (Sn), antimony (Sb), mercury (Hg), and lead (Pb), in the amniotic fluid of pregnant women, and to investigate their relationship with neural tube defects (NTDs). The study included 36 pregnant women whose fetuses were complicated with NTDs (study group) and 39 pregnant women with unaffected healthy fetuses (control group), who were matched for body mass index and gestational weeks. The amniotic fluid levels of trace elements and heavy metals were measured using inductively coupled plasma-mass spectrometry and compared between the two groups. Significantly lower mean levels of Zn and Mo and significantly higher levels of Al, Sn, Sb, and Hg in the study group than in the healthy control group were observed, which implied that these elements are possibly correlated with risk factors for the occurrence of NTDs. In contrast, there were no significant differences in the levels of Cr, Mn, Co, Ni, Cu, As, Cd, and Pb between the groups (P ≥ .05).

Effect of periconceptional folic acid supplementation on the risk of neural tube defects associated with a previous spontaneous abortion or maternal first-trimester fever.

Does maternal periconceptional no folic acid supplementation have an increased risk of neural tube defects (NTDs) associated with previous spontaneous abortion or first-trimester fever? Maternal periconceptional no folic acid supplementation can increase the risk of NTDs associated with previous spontaneous abortion or first-trimester fever, independent of known confounding factors. Maternal periconceptional folic acid deficiency can increase the risk of NTDs. However, whether an interaction between periconceptional no folic acid supplementation and history of spontaneous abortion or first-trimester fever may have an increased risk of NTDs remains unknown. A population-based case-control study was performed including 104 nuclear families with offspring with NTDs and 100 control families with normal offspring between 1993 and 2002. We investigated the potential interaction between periconceptional no folic acid use and a maternal history of spontaneous abortion or first-trimester fever in the risk for NTDs. Information on exposure factors was obtained at the onset of pregnancy, and pregnancy outcomes were collected during the first week after delivery or at the time of termination of the pregnancy. A multivariate logistic regression analysis was performed. The interaction between periconceptional no folic acid use and a maternal history of spontaneous abortion markedly increased the risk of NTDs (adjusted odds ratio (aOR) 18.68, 95% CI, 4.43-78.76) after adjusting for potential confounding factors. The interaction coefficient was found to be 2.08, higher than 1, indicating that there is a significant interaction between two factors. Mothers who did not take periconceptional folic acid and had first-trimester fever had an increased risk of NTDs (aOR 21.81, 95% CI, 8.81-80.73). However, the interaction coefficient was found to be 0.62, less than 1, indicating that there is no significant interaction between two factors. A potential limitation was that the interval between the previous spontaneous abortion and the beginning of the subsequent pregnancy could not be estimated accurately, but was at least 1year or more. We emphasize that a previous spontaneous abortion may represent a first occurrence of NTDs rather than be the cause of NTDs. Our findings indicate that mothers with a history of spontaneous abortion are ideal candidates for periconceptional folic acid supplementation. This work was supported by National Natural Science Foundation of China (41871360) and Danone Nutrition Center for Dietary Nutrition Research and Education Foundation (DIC2015-05). There are no competing interests to declare.

Abnormal Amino Acid Profiles of Blood and Cerebrospinal Fluid from Cystathionine β-Synthase-Deficient Mice, an Animal Model of Homocystinuria.

Mental retardation is the most common feature among inborn errors of amino acid metabolism. Patients with homocystinuria/homocysteinemia caused by cystathionine β-synthase (CBS) deficiency suffer from thromboembolism and mental retardation from early ages; therefore, detection by newborn screening is performed. Furthermore, elevated levels of serum homocysteine during pregnancy are associated with the occurrence of neural tube defects (NTDs) in newborns. However, the causes of such central nervous system (CNS) defects are unknown. We found previously impaired learning abilities in Cbs-deficient (Cbs-/-) mice (but not NTD births). Here, we investigated the amino acid profiles of serum and cerebrospinal fluid (CSF) from Cbs-/- mice. Mice deficient in cystathionine γ-lyase (Cth), a downstream enzyme of CBS in transsulfuration, as well as wild-type mice, were analyzed as controls. Cbs-/- and Cth-/- mice were smaller than wild-type mice, and CSF yields in Cbs-/- mice were lower than the others. CSF amino acid levels were generally lower than those in serum, and compared with the dramatic amino acid level alterations in Cbs-/- mouse serum, alterations in CSF were less apparent. However, marked upregulation (versus wild-type) of aspartic acid/asparagine (Asp/Asn), glutamine (Gln), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), methionine (Met), total homocysteine, and citrulline, and downregulation of lysine (Lys) were found in Cbs-/- mouse CSF. Because similar regulation of total homocysteine/citrulline/Lys was observed in the CSF of Cth-/- mice, which are free of CNS dysfunction, the reduced CSF volumes and the level changes of other amino acids could be relevant to Cbs-/--specific CNS defects.

The Japanese Teratology Society declares "Folic Acid Awareness Day" and "Neural Tube Defect Prevention Month".

The Japanese Teratology Society (JTS) is sending an important message to Japanese people through the declaration of Folic Acid Awareness Day and Neural Tube Defect Prevention Month. The purpose of this statement is to prevent the occurrence of Neural Tube Defects (NTDs) as much as possible through folic acid supplementation1 prior to and during conception. Briefly, NTDs, such as myelomeningocele and anencephaly, are congenital anomalies involving defects in the brain and/or spinal cord that develop around gestation week 6 (4 weeks after fertilization). A randomized controlled trial from United Kingdom in 19912 and a cohort study from China in 19993 demonstrated that NTDs are partially folic acid-preventable and that periconceptional folic acid supplementation could decrease the occurrence or recurrence by 40% to 70%. In 2000, the Ministry of Health and Welfare of Japan recommended that women planning a pregnancy should take folic acid 0.4 mg daily, from 4 weeks prior to conception to 12 weeks of gestation.4 Risk factors of NTDs among Japanese women comprise of not taking folic acid supplements, presence of myelomeningocele in patients within third-degree relatives, use of anti-epileptic drugs without folic acid, and low birth weight in the newborn.5 In 2017, JTS stressed on importance of taking folic acid 0.4 mg daily for those who plan to conceive, in order to reduce the risk of NTDs in the developing fetus.6 During the past quarter of century, the prevalence of myelomeningocele has not declined, while that of anencephaly has significantly decreased because the majority of pregnancies involving such fetal defects were terminated. The low awareness rates of the role that folic acid plays in the pregnancy7 and the low rates of folic acid supplementation prior to getting pregnant8 account for the overall trend for a lack of NTD decline in Japan. Hence, the present communication is urgent and important for not only the Japanese people but also people living in countries without folic acid fortification. We have decided that 3 April will be considered Folic Acid Awareness Day, as the pronunciation of “folic acid” in Japanese (You Sann) is similar to that of “3 April” (Yonn Sann). Further, the whole month of April will be remembered as the Neural Tube Defect Prevention Month. It is hoped that through the commemoration of this day and month every year with the character representing folic acid (Figure 1), Japanese people will recognize the importance and necessity of taking folic acid supplementation prior to and during pregnancy.9 We urge those of other academic societies who read or hear of this notice to voice solidarity with our endeavor and co-operate with us by spreading information and educating people regarding the great benefits of folic acid.

Progress in biomechanical mechanism of neurulation

Neurulation is a critical step in the early embryonic development of chordate and its failure causes the occurrence of neural tube defect (NTD). This is a type of serious birth defects of the nervous system, including anencephaly, spina bifida, meningeal or encephalocele and myelomeningocele.The average incidence of NTD is 1 per 1000 pregnancies worldwide.Its pathogenesis is not yet clear.Currently, research on neural tube defect has always been elucidated from the perspective of nutrition such as folic acid, or from a molecular potion related to neural tube closure.These efforts have been successful in identifying numerous cell biological processes essential to neurulation and genes associated with neural tube defect.However, as an event of tissue morphogenesis, neurulation is the result of a series of events involving the signaling pathway, cytoskeletal components, cellular, and tissue-level mechanical interactions.Only when the various aspects of neurulation are determined can it be better understood.Developmental biologists have been discussing biomechanical mechanisms that drive neurulation for many years, but there is still a lack of a unified understanding of them.The biomechanical mechanisms involved in neurulation are reviewed. Key words: Neurulation; Biomechanical mechanism; Neural tube defect

P53 Mutant p53N236S Induces Neural Tube Defects in Female Embryos.

The p53 is one of the most important tumor suppressors through surveillance of DNA damages and abnormal proliferation signals, and activation the cell cycle arrest and apoptosis in response to stress. However, the mutation of p53 is known to be oncogenic by both loss of function in inhibiting cell cycle progress and gain of function in promoting abnormal proliferation. In the present study, we have established a knock in mouse model containing an Asn-to-Ser substitution at p53 amino acid 236 by homologous recombination (p53N236S). Other than tumorigenesis phenotype, we found that p53S/Smice displayed female-specific phenotype of open neural tube in brain (exencephaly) and spinal cord (spina bifida). The occurrence rate for embryonic exencephaly is 68.5% in female p53S/S mice, which is much more than that of in p53-/- mice (37.1%) in the same genetic background. Further study found that p53N236S mutation increased neuronal proliferation and decreased neuronal differentiation and apoptosis. To rescue the phenotype, we inhibited cell proliferation by crossing Wrn-/-mice with p53S/S mice. The occurrence of NTDs in p53S/S Wrn-/-mice was 35.2%, thus suggesting that the inhibition of cell proliferation through a Wrn defect partially rescued the exencephaly phenotype in p53S/S mice. We also report that p53S decreased expression of UTX at mRNA and protein level via increasing Xist transcript, result in high female-specific H3K27me3 expression and repressed Mash1 transcription, which facilitating abnormal proliferation, differentiation, and apoptosis, result in the mis-regulation of neurodevelopment and neural tube defects (NTDs).

Inhibition of NRF2 signaling and increased reactive oxygen species during embryogenesis in a rat model of retinoic acid-induced neural tube defects

Exposure to retinoic acid (RA) during pregnancy increases the risk of serious neural tube defects (NTDs) in the developing fetus. The precise molecular mechanism for this process is unclear; however, RA is associated with oxidative stress mediated by reactive oxygen species. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of oxidative stress that directs the expression of antioxidant genes and detoxifying proteins to maintain redox homeostasis. We established a rat model of NTDs in which pregnant dams were administered all-trans (at)RA on gestational day 10, and oxidative stress levels and the spatiotemporal expression of NRF2 and its downstream targets were examined in the resulting embryos and in maternal blood. In the NTD group, total antioxidative capacity decreased and 8-hydroxy-2′-deoxyguanosine increased in maternal serum and fetal spinal cord tissues. Plasma GSH content, the GSH/GSSG ratio, and glutathione peroxidase activity in fetal spinal cords were lower in the NTD group relative to controls. We detected NRF2 protein reduction and concomitant upregulation of Kelch-like ECH-associated protein 1 (KEAP1) - a cytoplasmic inhibitor of NRF2 - in the NTD group. The mRNA and protein levels of downstream targets of NRF2 were downregulated in the spinal cords of NTD embryos. These data demonstrate substantial oxidative stress and NRF2 signaling pathway disruption in a model of NTDs induced by atRA. The inhibitory effects of atRA on NRF2 signaling may lower cellular defenses against RA-induced oxidative stress and could play important roles in NTD occurrence during embryonic development.

Maternal risk factors associated with neural tube defects in Tigray regional state of Ethiopia

IntroductionUnlike developing countries, including Ethiopia the identification of the risk factors in decreasing the burden of neural tube defects (NTDs) is well established in the developed world. Hence, we sought to determine the factors associated with NTDs in Tigray – Ethiopia. MethodsWe undergo a case-control analysis where all NTDs cases were compared to a group of controls derived randomly from the same hospitals where cases were recruited from. The NTDs survey tool which contains a standard questionnaire was prepared. Parental socio-demographic and clinical information such, maternal age, obstetric history, illnesses, drug intake, radiation, occupation, education, history of congenital anomalies, residence, exposure to pollutants such as smoking, chemicals, paternal history, and folic acid utilization was collected and analyzed using SPSS version 20. ResultThis study has shown the maternal age, and residency, birth order 3 and 4, unplanned pregnancy, history of breastfeeding above 2 years, history of stillbirths, history of male gender predominance were found to have a strong association with an occurrence of NTDs (p = 0.0001). Though the binary logistic regression analysis showed no significant association in some of the risk factors such as maternal health and drug history, the frequency analysis showed they may have an impact on the incidence of NTDs. ConclusionThis study has shown the majority of the maternal risk factors and other lifestyle patterns had a significant impact on the occurrence of NTDs. Therefore, efficient monitoring of NTDs in Ethiopia is vital, so our study could be groundwork information in Ethiopia for future programs.

Preconception folic acid supplementation use and the occurrence of neural tube defects in Japan: A nationwide birth cohort study of the Japan Environment and Children's Study.

We evaluated the relationship between preconception folic acid supplementation and the occurrence of neural tube defects (NTDs) in offspring, using data from the Japan Environment and Children's Study (a nationwide prospective birth cohort study) database. Of 92 269 participants with single pregnancies, 74 cases (offspring or fetuses) had NTDs, including 32 cases of spina bifida, 24 cases of anencephaly, and 19 cases of encephalocele. A total of 7634 participants (8.27%) used preconception folic acid supplementation, and of these, 621 (0.67%) also took in dietary folic acid at ≥480 μg/day. Multivariate logistic regression analyses demonstrated no association between preconception folic acid supplementation and NTDs in offspring or fetuses (odds ratio [OR] 0.622; 95% confidence interval [CI]: 0.226-1.713). Moreover, the participants who combined preconception folic acid supplement use with dietary folic acid intake ≥480 μg/day demonstrated no incidence of NTDs in offspring or fetuses. Our analysis is limited by the absence of the data on the daily amount of supplementary folic acid intake, requiring careful attention to the interpretation. Additional surveys are required in Japan to resolve those limitations for further comprehensive assessment.