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Nutrients Mar 2024Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis.... (Review)
Review
Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.
Topics: Animals; Mice; Humans; Dietary Supplements; Folic Acid; Neural Tube Defects; Family; Drug-Related Side Effects and Adverse Reactions
PubMed: 38474883
DOI: 10.3390/nu16050755 -
Journal of Medicine and Life 2021Spina bifida is a disorder characterized by failure of the neural tube to form during embryological development. The early signs in the head and spine may be detected on...
Spina bifida is a disorder characterized by failure of the neural tube to form during embryological development. The early signs in the head and spine may be detected on ultrasound from 11 weeks of gestation. Diabetes is a well-known teratogen factor that increases the chances of birth defects, such as neural tube defects. We report a 12 weeks case of spina bifida in type 1 diabetes.
Topics: Diabetes Mellitus; Female; Humans; Neural Tube Defects; Pregnancy; Spinal Dysraphism; Ultrasonography
PubMed: 35126760
DOI: 10.25122/jml-2021-0249 -
Developmental Dynamics : An Official... Aug 2020A common theme in organogenesis is how the final structure of organs emerge from epithelial tube structures, with the formation of the neural tube being one of the best... (Review)
Review
A common theme in organogenesis is how the final structure of organs emerge from epithelial tube structures, with the formation of the neural tube being one of the best examples. Two types of cell movements co-occur during neural tube closure involving the migration of cells toward the midline of the embryo (mediolateral intercalation or convergent extension) as well as the deep movement of cells from inside the embryo to the outside of the lateral side of the neural plate (radial intercalation). Failure of either type of cell movement will prevent neural tube closure, which can produce a range of neural tube defects (NTDs), a common congenital disease in humans. Numerous studies have identified signaling pathways that regulate mediolateral intercalation during neural tube closure. Less understood are the pathways that govern radial intercalation. Using the Xenopus laevis system, our group reported the identification of transient receptor potential (TRP) channels, TRPM6 and TRPM7, and the Mg ion they conduct, as novel and key factors regulating both mediolateral and radial intercalation during neural tube closure. Here we broadly discuss tubulogenesis and cell intercalation from the perspective of neural tube closure and the respective roles of TRPM7 and TRPM6 in this critical embryonic process.
Topics: 3T3 Cells; Animals; Cell Movement; Embryonic Development; Gene Expression Regulation, Developmental; Humans; Ions; Magnesium; Mice; Neural Plate; Neural Tube; Neural Tube Defects; Neurulation; Protein Domains; Protein Serine-Threonine Kinases; Signal Transduction; TRPM Cation Channels; Xenopus Proteins; Xenopus laevis; Zebrafish
PubMed: 32315468
DOI: 10.1002/dvdy.182 -
American Journal of Public Health Mar 2021
Topics: Anencephaly; Dietary Supplements; Female; Folic Acid; Folic Acid Deficiency; Food, Fortified; Humans; Maternal Nutritional Physiological Phenomena; Neural Tube Defects; Pregnancy; Pregnancy Outcome; Recommended Dietary Allowances
PubMed: 33566656
DOI: 10.2105/AJPH.2020.306067 -
Cells Jun 2023Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural...
Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds of genetic mouse models of neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette cortical organoid (SOSR-COs) system, we have developed a high-throughput image analysis pipeline for evaluating the SOSR-CO structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. GSK3β and HDAC inhibitors caused similar lumen expansion; however, RNA sequencing suggests VPA does not inhibit GSK3β at these concentrations. The knockout of , a well-known NTD-related gene, also caused expansion of the lumen, as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction, suggesting that impingement of this process is a shared mechanism for VPA treatment and -KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.
Topics: Pregnancy; Female; Humans; Mice; Animals; Valproic Acid; Anencephaly; Glycogen Synthase Kinase 3 beta; Mice, Knockout; Neural Tube Defects; Spinal Dysraphism; Brain; Microfilament Proteins
PubMed: 37443734
DOI: 10.3390/cells12131697 -
American Journal of Public Health May 2018
Topics: Europe; Folic Acid; Food, Fortified; Humans; Neural Tube Defects; Prevalence; Spinal Dysraphism
PubMed: 29617604
DOI: 10.2105/AJPH.2018.304389 -
Human Molecular Genetics Nov 2020Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although...
Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8-/- mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To date, no publication has reported any association between FKBP8 and human NTDs. Using Sanger sequencing on genomic DNA samples from 472 SB and 565 control samples, we identified five rare (MAF ≤ 0.001) deleterious variants in SB patients, while no rare deleterious variant was identified in the controls (P = 0.0191). p.Glu140* affected FKBP8 localization to the mitochondria and created a truncated form of the FKBP8 protein, thus impairing its interaction with BCL2 and ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. p.Lys315Asn further increased the cellular apoptosis. RNA sequencing on anterior and posterior tissues isolated from Fkbp8-/- and wildtype mice at E9.5 and E10.5 showed that Fkbp8-/- embryos have an abnormal expression profile within tissues harvested at posterior sites, thus leading to a posterior NTD. Moreover, we found that Fkbp8 knockout mouse embryos have abnormal expression of Wnt3a and Nkx2.9 during the early stage of neural tube development, perhaps also contributing to caudal specific NTDs. These findings provide evidence that functional variants of FKBP8 are risk factors for SB, which may involve a novel mechanism by which Fkbp8 mutations specifically cause SB in mice.
Topics: Animals; Apoptosis; Female; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Infant, Newborn; Male; Mice; Mice, Knockout; Nervous System Malformations; Neural Tube Defects; Risk Factors; Spinal Dysraphism; Tacrolimus Binding Proteins; Transcription Factors; Wnt3A Protein
PubMed: 32969478
DOI: 10.1093/hmg/ddaa211 -
The Pan African Medical Journal 2022
Topics: Female; Humans; Neural Tube Defects; Pregnancy; Prenatal Diagnosis; Spinal Dysraphism; Ultrasonography, Prenatal
PubMed: 36160275
DOI: 10.11604/pamj.2022.42.146.35644 -
American Journal of Obstetrics and... May 2015Maternal diabetes-induced birth defects occur in 6-10% of babies born to mothers with pregestational diabetes, representing a significant maternal-fetal health problem.... (Review)
Review
Maternal diabetes-induced birth defects occur in 6-10% of babies born to mothers with pregestational diabetes, representing a significant maternal-fetal health problem. Currently, these congenital malformations represent a significant maternal-fetal medicine issue, but are likely to create an even greater public health threat as 3 million women of reproductive age (19-44 years) have diabetes in the United States alone, and this number is expected to double by 2030. Neural tube defects (NTDs) and congenital heart defects are the most common types of birth defects associated with maternal diabetes. Animal studies have revealed that embryos under hyperglycemic conditions exhibit high levels of oxidative stress resulting from enhanced production of reactive oxygen species and impaired antioxidant capability. Oxidative stress activates a set of proapoptotic kinase signaling intermediates leading to abnormal cell death in the embryonic neural tube, which causes NTD formation. Work in animal models also has revealed that maternal diabetes triggers a series of signaling intermediates: protein kinase C (PKC) isoforms, PKCα, βII and δ; apoptosis signal-regulating kinase 1; c-Jun-N-terminal kinase (JNK)1/2; caspase; and apoptosis. Specifically, maternal diabetes in rodent models activates the proapoptotic unfolded protein response and endoplasmic reticulum (ER) stress. A reciprocal causation between JNK1/2 activation and ER stress exists in diabetic embryopathy. Molecular studies further demonstrate that deletion of the genes for Prkc, Ask1, Jnk1, or Jnk2 abolishes maternal diabetes-induced neural progenitor apoptosis and ameliorates NTD formation. Similar preventive effects are also observed when apoptosis signal-regulating kinase 1, JNK1/2, or ER stress is inhibited. Cell membrane stabilizers and antioxidant supplements are also effective in prevention of diabetes-induced birth defects. Mechanistic studies have revealed important insights into our understanding the cause of diabetic embryopathy and have provided a basis for future interventions against birth defects or other pregnancy complications associated with maternal diabetes. The knowledge of a molecular pathway map identified in animal studies has created unique opportunities to identify molecular targets for therapeutic intervention.
Topics: Apoptosis; Endoplasmic Reticulum Stress; Female; Heart Defects, Congenital; Humans; Hyperglycemia; Neural Tube Defects; Oxidative Stress; Pregnancy; Pregnancy in Diabetics; Protein Kinases; Signal Transduction
PubMed: 25434839
DOI: 10.1016/j.ajog.2014.11.036 -
BMJ Open Nov 2023This study aims to estimate the prevalence of neural tube defects (NTDs) and to identify potential risk factors in the Ethiopian context. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study aims to estimate the prevalence of neural tube defects (NTDs) and to identify potential risk factors in the Ethiopian context.
STUDY DESIGN
Systematic review and meta-analysis.
STUDY PARTICIPANTS
A total of 611 064 participants were included in the review obtained from 42 studies.
METHODS
PubMed (Medline), Embase and Cochrane Library databases in combination with other potential sources of literature were systematically searched, whereby studies conducted between January 2010 and December 2022 were targeted in the review process. All observational studies were included and heterogeneity between studies was verified using Cochrane Q test statistics and I test statistics. Small study effects were checked using Egger's statistical test at a 5% significance level.
RESULT
The pooled prevalence of all NTDs per 10 000 births in Ethiopia was 71.48 (95% CI 57.80 to 86.58). The between-study heterogeneity was high (I= 97.49%, p<0.0001). Birth prevalence of spina bifida (33.99 per 10 000) was higher than anencephaly (23.70 per 10 000), and encephalocele (4.22 per 10 000). Unbooked antenatal care (AOR 2.26, 95% CI (1.30 to 3.94)), preconception intake of folic acid (AOR 0.41, 95% CI (0.26 to 0.66)), having chronic medical illness (AOR 2.06, 95% CI (1.42 to 2.99)), drinking alcohol (AOR 2.70, 95% CI (1.89 to 3.85)), smoking cigarette (AOR 2.49, 95% CI (1.51 to 4.11)), chewing khat (AOR 3.30, 95% CI (1.88 to 5.80)), exposure to pesticides (AOR 3.87, 95% CI (2.63 to 5.71)), maternal age ≥35 (AOR 1.90, 95% CI (1.13 to 3.25)), maternal low educational status (AOR 1.60, 95% CI (1.13 to 2.24)), residing in urban areas (AOR 0.75, 95% CI (0.58 to 0.97))and family history of NTDs (AOR 2.51, 95% CI (1.36 to 4.62)) were associated with NTD cases.
CONCLUSION
The prevalence of NTDs in Ethiopia is seven times as high as in other Western countries where prevention measures are put in place. Heredity, maternal and environmental factors are associated with a high prevalence of NTDs. Mandatory fortification of staple food with folic acid should be taken as a priority intervention to curb the burden of NTDs. To smoothen and overlook the pace of implementation of mass fortification, screening, and monitoring surveillance systems should be in place along with awareness-raising measures.
PROSPERO REGISTRATION NUMBER
CRD42023413490.
Topics: Female; Pregnancy; Humans; Prevalence; Ethiopia; Neural Tube Defects; Folic Acid; Risk Factors; Food, Fortified
PubMed: 37940152
DOI: 10.1136/bmjopen-2023-077685