Folate-resistant Neural Tube Defects Research Articles

Arsenic disturbs neural tube closure involving AMPK/PKB-mTORC1-mediated autophagy in mice

Arsenic exposure is a significant risk factor for folate-resistant neural tube defects (NTDs), but the potential mechanism is unclear. In this study, a mouse model of arsenic-induced NTDs was established to investigate how arsenic affects early neurogenesis leading to malformations. The results showed that in utero exposure to arsenic caused a decline in the normal embryos, an elevated embryo resorption, and a higher incidence of malformed embryos. Cranial and spinal deformities were the main malformation phenotypes observed. Meanwhile, arsenic-induced NTDs were accompanied by an oxidant/antioxidant imbalance manifested by elevated levels of reactive oxygen species (ROS) and decreased antioxidant activities. In addition, changes in the expression of autophagy-related genes and proteins (ULK1, Atg5, LC3B, p62) as well as an increase in autophagosomes were observed in arsenic-induced aberrant brain vesicles. Also, the components of the upstream pathway regulating autophagy (AMPK, PKB, mTOR, Raptor) were altered accordingly after arsenic exposure. Collectively, our findings propose a mechanism for arsenic-induced NTDs involving AMPK/PKB-mTORC1-mediated autophagy. Blocking autophagic cell death due to excessive autophagy provides a novel strategy for the prevention of folate-resistant NTDs, especially for arsenic-exposed populations.

Metabotype analysis of Mthfd1l-null mouse embryos using desorption electrospray ionization mass spectrometry imaging.

Mammalian folate-dependent one-carbon (1C) metabolism provides the building blocks essential during development via amino acid interconversion, methyl-donor production, regeneration of redox factors, and de novo purine and thymidylate synthesis. Folate supplementation prevents many neural tube defects (NTDs) that occur during the embryonic process of neurulation. The mechanism by which folate functions during neurulation is not well understood, and not all NTDs are preventable by folate supplementation. Mthfd1l is a mitochondrial 1C metabolism enzyme that produces formate, a 1C donor that fuels biosynthesis and the methyl cycle in the cytoplasm. Homozygous deletion of the Mthfd1l gene in mice (Mthfd1lz/z) causes embryonic lethality, developmental delay, and folate-resistant NTDs. These mice also have defects in cranial mesenchyme formation. In this work, mass spectrometry imaging was used to obtain ion maps of the cranial mesenchyme that identified the spatial distribution and relative abundance of metabolites in wild-type and Mthfd1lz/z embryos. The relative abundances of purine and thymidylate derivatives, as well as amino acids, were diminished in the cranial mesenchyme of Mthfd1lz/z embryos. Loss of Mthfd1l activity in this region also led to abnormal levels of methionine and dysregulated energy metabolism. These alterations in metabolism suggest possible approaches to preventing NTDs in humans.

Systematic analysis of the biological roles and pharmacological properties of D-chiro-inositol

D-chiroinositol (DCI) is one of the 9 inositol isomers that forms inositol phosphoglycans, which are mediators of the action of insulin. The metabolism of DCI and myo-inositol (MI) is impaired against the background of insulin resistance, including the patients with polycystic ovary syndrome (PCOS).
 Aim. Highlight the most characteristic pharmacological properties of DCI.
 Materials and methods. Systematic computer analysis of 45 600 publications on the biological roles of inositol by methods of the topological theory of pattern recognition and systems biology analysis of human proteome.
 Results. A complex of interactions between metabolic disorders of DCI, PCOS, ovulation disorders, obesity associated with numerous hormonal disorders is described. Supplements with DCI and MI increase the sensitivity of cells to insulin and normalize the metabolism of androgens. An important difference between DCI and MI is the presence of DCI in the composition of inositol phosphoglycans that mediate the action of insulin on cells, as well as its participation in the realization of the therapeutic effects of metformin. The use of the MI+DCI combination allows achieving positive dynamics in reducing excess body weight, normalizing blood lipids, glucose and insulin levels, restoring the ovulatory menstrual cycle, improving oocyte quality, and helps prevent gestational diabetes in pregnant women and macrosomia of the fetus. DCI is more effective than MI in reducing the risk of folate-resistant neural tube defects.
 Conclusion. The therapeutic potential of DCI in combination with MI for treating PCOS and hyperandrogenism is evident. Depending on the therapeutic expediency, various ratios of MI:DCI can be used for the treatment of PCOS and disorders of carbohydrate and lipid metabolism.A

Lifestyle, metabolite, and genetic determinants of formate concentrations in a cross-sectional study in young, healthy adults

Formate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants. This study aimed to define formate concentrations and their determinants in a healthy young population. Serum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors. Serum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12. Formate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.

Myoinositol: The Bridge (PONTI) to Reach a Healthy Pregnancy.

The use of folic acid in the periconceptional period can prevent about 70% of neural tube defects (NTDs). In the remaining cases, no medical prevention is available, and those conditions should be defined as folate-resistant NTDs. Rodent models suggest that some folate-resistant NTDs can be prevented by inositol (myoinositol and chiroinositol) supplementation prior to pregnancy. Should folic acid be combined with myoinositol periconceptional supplementation to reduce the overall risk of NTDs even in humans? Hereafter, we discuss the results from the PONTI study that strongly support both the effectiveness and safety of myoinositol periconceptional supplementation in preventing human NTDs. We further report on the largest case series of pregnancies treated with myoinositol and folic acid. At our institution, a sequential study during 12 years involved mothers at risk of fetal NTDs, and 29 babies from 27 pregnancies were born after periconceptional combined myoinositol and folic acid supplementation. No case of NTDs was observed, despite the high recurrence risk in the mothers. Taken together, those data suggest that periconceptional folic acid plus myoinositol can reduce both the occurrence and recurrence risks of NTDs in a greater number of cases than folic acid alone.

The Neural Tube Defect: Issues of Prenatal Diagnosis, Genetic Counselling, Prevention and Management

Neural tube defects (NTDs) are among the most common major congenital abnormalities with a prevalence rate of approximately 1 per 1000 births, although it varies significantly according to geographical location. NTDs represent the first congenital malformations shown to be preventable through simple public health measures. Ensuring adequate periconceptional folic acid intake prevents both occurrence and recurrence of a significant proportion of NTDs, but distinguishing folate resistant NTDs is not yet possible. Despite improvements in the prenatal screening, diagnosis and management of NTDs, antenatal prediction and prevention of neurological disabilities after birth remains difficult, with over one-third of long-term survivors continuing to require daily care. Ultrasound examination has virtually replaced amniotic fluid AFP and cholinesterase measurement for the diagnosis of NTDs. Emphasis now should be on primary prevention, early detection and prevention of long-term morbidity. Effective prenatal diagnosis and proper genetic counselling provides parents with a variety of options that may be appropriate for their individual situation.

Inositol prevents folate-resistant neural tube defects in the mouse.

Clinical trials demonstrate that up to 70% of neural tube defects (NTDs) can be prevented by folic acid supplementation in early pregnancy, whereas the remaining NTDs are resistant to folate. Here, we show that a second vitamin, myo-inositol, is capable of significantly reducing the incidence of spinal NTDs in curly tail mice, a genetic model of folate-resistant NTDs. Inositol increases flux through the inositol/lipid cycle, stimulating protein kinase C activity and upregulating expression of retinoic acid receptor beta, specifically in the caudal portion of the embryonic hindgut. This reduces the delay in closure of the posterior neuropore, the embryonic defect that is known to lead directly to spina bifida in curly tail embryos. Our findings reveal a molecular pathway of NTD prevention and suggest the possible efficacy of combined treatment with folate and inositol in overcoming the majority of human NTDs.