vitamin-b-12 and Cleft-Palate

Animal models have shown evidence of the role of maternal methyl donor status and its metabolism (one-carbon metabolism) in normal embryonic maxillofacial development. Nevertheless, studies in humans have shown conflicting results for the association of maternal methylation status biomarkers in the aetiology of the main craniofacial birth defects: non-syndromic orofacial clefts (NSOFCs). The aim of this study was to perform a meta-analysis assessing the relationship between maternal levels of methylation status biomarkers (plasma and erythrocyte folates and plasma vitamin B12 and homocysteine) and the risk of NSOFCs. A literature search of the conventional and grey medical-scientific databases identified 12 studies considering these variables. Based on standardized differences between means among cases and controls (Cohen's d test), evidence was found of an association only with high plasma homocysteine (d=0.37; P=0.026) when single effects were pooled. In addition to its usefulness as a marker of poor methyl-donor intake and/or metabolism, homocysteine appears to have a teratogenic effect. Although the results are based on a relatively small number of reports and/or studies of small sample sizes showing between-study heterogeneity, these problems were resolved by including an additional analysis. Therefore these findings constitute a real contribution towards explaining the complex aetiology of orofacial clefts.

Topics: Biomarkers; Cleft Lip; Cleft Palate; Female; Folic Acid; Homocysteine; Humans; Methylation; Pregnancy; Vitamin B 12

The aims of this study were to assess the association between polymorphisms within genes involved in vitamin B12 transport and nonsyndromic cleft lip with or without cleft palate (NSCL/P) and global DNA methylation in Chile. From 247 cases and 453 controls, we obtained variant genotypes for CBLIF, CUBN, AMN, ABCC1, CD320, and TCN2 from a single nucleotide polymorphisms array. Global DNA methylation in 95 controls was obtained through LINE-1 methylation. After multiple comparison corrections, only rs780807 in CUBN remains associated with NSCL/P at dominant model (OR 0.564, p-value = 0.0006, q-value = 0.0450). Carriers of protective allele showed lower levels of DNA methylation than non-carriers (p = 0.0259). Further studies are necessary in order to explain relations with the phenotype and DNA methylation due to the absence of functional evidence for rs780807 in CUBN.

Topics: Case-Control Studies; Chile; Cleft Lip; Cleft Palate; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide; Vitamin B 12

The causal role of maternal nutrition in orofacial clefts is uncertain. We tested hypotheses that low maternal vitamin B. Case-mothers of CL±P children (n = 47) and control-mothers of unaffected children (n = 50) were recruited an average of 1.4 years after birth of the index child and plasma vitamin B. Odds ratios (ORs) contrasting biomarker levels showed associations between case-mothers and low versus high plasma vitamin B. Mothers of CL±P children in southern India were 6.5 times more likely to have poor vitamin B

Topics: Case-Control Studies; Child; Cleft Lip; Cleft Palate; Female; Folic Acid; Humans; India; Risk Factors; Vitamin B 12; Vitamins

The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dexamethasone (DEX). We examined the morphological and histological features of the palatal shelf and expression levels of key signaling molecules (transforming growth factor-β3 (TGF-β3) and TGF-β type I receptor (activin receptor-like kinase 5, ALK5)) during palatogenesis among a control group (Group A), TCDD+DEX exposed group (Group B), and TCDD+DEX+vitamin B12 exposed group (Group C). While we failed to find that vitamin B12 decreased the incidence of cleft palate induced by TCDD+DEX treatment, the expression levels of key signaling molecules (TGF-β3 and ALK5) during palatogenesis were significantly modulated. In TCDD+DEX exposed and TCDD+DEX+vitamin B12 exposed groups, palatal shelves could not contact in the midline due to their small sizes. Our results suggest that vitamin B12 may inhibit the expression of some cleft palate inducers such as TGF-β3 and ALK5 in DEX+TCDD exposed mice, which may be beneficial against palatogenesis to some degree, even though we were unable to observe a protective role of vitamin B12 in morphological and histological alterations of palatal shelves induced by DEX and TCDD.

Topics: Animals; Cleft Palate; Dexamethasone; Drug Interactions; Female; Histocytochemistry; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Palate; Polychlorinated Dibenzodioxins; Pregnancy; Protein Serine-Threonine Kinases; Random Allocation; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA; Specific Pathogen-Free Organisms; Transforming Growth Factor beta; Vitamin B 12

Riboflavin is a cofactor for the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme involved in the homocysteine pathway. The aim of this study was to investigate the effects of maternal riboflavin intake and two MTHFR polymorphisms (677C>T; Ala222Val and 1298A>C; Glu429Ala substitutions) on the biomarkers of the homocysteine pathway, and investigate the risk of having offspring with an orofacial cleft (OFC).. In a case-control study design, dietary riboflavin intake and the MTHFR 677C>T and 1298A>C polymorphisms were evaluated in 123 OFC and 108 control mothers by using food frequency questionnaires and blood samples. Homocysteine (tHcy), folate and vitamin B12 concentrations in blood were analyzed in 70 cases and 68 controls. Linear and logistic regression analyses were applied.. At 14 months postpartum riboflavin intake and MTHFR 677C>T and 1298A>C genotypes were not significantly different between cases and controls. The 677TT genotype showed lower folate concentrations compared to C-allele carriers with a mean difference of 2.8 nmol/l in serum and 174 nmol/l in red blood cell (both P's=0.01). Every mg per day increase of dietary riboflavin intake was positively associated with increase in vitamin B12 concentration by 52.1% (P<0.01). This effect was most pronounced in MTHFR 677TT homozygotes (205.1%, P=0.03). The riboflavin-adjusted MTHFR 677TT and 1298CC genotypes showed a trend toward an increasing risk for OFC, adjusted odds ratio 1.7 (confidence interval (95% CI), 0.7-4.5) and 1.6 (95% CI, 0.7-4.2), respectively.. Maternal riboflavin intake is significantly associated with biomarkers of the homocysteine pathway, with the strongest effects in MTHFR 677TT homozygotes. The maternal risk of having OFC offspring, however, is not associated with dietary riboflavin intake.

Topics: Biomarkers; Case-Control Studies; Cleft Lip; Cleft Palate; Female; Folic Acid; Genetic Predisposition to Disease; Genotype; Homocysteine; Humans; Linear Models; Logistic Models; Methylenetetrahydrofolate Reductase (NADPH2); Nutrigenomics; Odds Ratio; Polymorphism, Genetic; Riboflavin; Risk Factors; Surveys and Questionnaires; Vitamin B 12

B vitamins rescue cleft palate induced by glucocorticoids in rodents; however, the mechanism of this effect remains largely unknown. The objective of our study was to assess the effect of dexamethasone and Vitamin B12 on cell proliferation and apoptosis during palatogenesis. In our study, mesenchymal cell proliferation in mouse embryonic palates decreased when the subjects were administered dexamethasone at embryo day 13.5 (E 13.5). However, mesenchymal cell proliferation was increased after dexamethasone exposure at E 14.0 and E 14.5 in comparison with the control group. After Vitamin B12 treatment, proliferation of mesenchymal cells was restored. No apoptosis was detected until bilaterial palatal shelves adhered and formed a medial epithelium seam in the control group and Vitamin B12-treated group. However, the apoptotic cells were detected under the medial edge epithelium before the palate contacted after dexamethasone treatment. The results suggested that Vitamin B12 restored proliferation, which had been reduced by dexamethasone via a delayed cellular cycle and apoptosis. This study implies that Vitamin B12 may be used to prevent or alleviate cleft palate induced by dexamethasone during embryonic palatogenesis.

Topics: Animals; Apoptosis; Cell Proliferation; Cleft Palate; Dexamethasone; Disease Models, Animal; Glucocorticoids; Mice; Mice, Inbred C57BL; Palate; Vitamin B 12; Vitamins

Metabonomic analysis has been increasingly used to monitor metabolic abnormalities in cells and their micro-environment in order to detect the biomarkers recently. This study evaluated the feasibility of applying 1H-nuclear magnetic resonance (1H-NMR) based metabonomic method to detect the differences of the early development of cleft palate in the plasma from control group and experimental group.. Pregnant mice (inbred C57BL/6J strain) with vitamin B12 injected only were assigned as the control group, pregnant mice with excessive Dex, injected after vitamin B12 as the experimental group, each group includes 12 mice. And the effect of B12 to rate of cleft palate was observed. The technology of nuclear magnetic resonance (NMR) was used to detect the endogenous small molecule metabolites. Finally, changes of metabolites ingredients were ascertained by using the method of principal component analysis (PCA).. There was significant difference in PCA scores plot between the two groups according to whether cleft palate occurred.. The 1H-NMR based metabonomic approach might be used as a feasible and efficient method for a deep exploration of the pathogenesis of cleft lip and palate and an early exploration of the mechanism of vitamin B12.

Topics: Animals; Cleft Lip; Cleft Palate; Dexamethasone; Female; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Metabolomics; Mice; Mice, Inbred C57BL; Pregnancy; Principal Component Analysis; Vitamin B 12

The Fgf10 signaling pathway plays an important role in early stages of mouse embryonic palatal development, which is associated with cell proliferation and differentiation. The objective of this study was to assess whether dexamethasone and vitamin B(12) affected the Fgf10 signal pathway of mouse embryonic palate.. Immunohistochemical studies were performed for expression of Fgf10, Fgfr2b, and sonic hedgehog and for cell proliferation and apoptosis of mouse embryonic palate.. The expression of Fgf10, Fgfr2b, and sonic hedgehog was changed in mouse embryonic palate after dexamethasone and vitamin B(12) treatment, resulting in reduced and restored proliferation of mesenchymal cells.. Dexamethasone and vitamin B(12) affected the Fgf10 signaling pathway and cell proliferation of mouse embryonic palate. Cell apoptosis was not altered after dexamethasone and vitamin B(12) exposure.

Topics: Animals; Apoptosis; Cell Proliferation; Cleft Palate; Dexamethasone; Disease Models, Animal; Embryonic Development; Female; Fibroblast Growth Factor 10; Gene Expression Regulation, Developmental; Glucocorticoids; Male; Mice; Mice, Inbred C57BL; Palate; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Vitamin B 12

Excessive dexamethasone (Dex) administrated into pregnant mice during critical periods of palatal development can produce a high incidence of cleft palate. Its mechanisms remain unknown. Vitamin B12 has been shown to antagonize the teratogenic effects of Dex, which, however, remains controversial. In this study, we investigated the effects of Dex and vitamin B12 on murine embryonic palatal shelf fusion using organ culture of murine embryonic shelves. The explanted palatal shelves on embryonic day 14 (E14) were cultured for 24, 48, 72 or 96 h in different concentrations of Dex and/or vitamin B12. The palatal shelves were examined histologically for the morphological alterations on the medial edge epithelium (MEE) and fusion rates among different groups. It was found that the palatal shelves were not fused at 72 h or less of culture in Dex group, while they were completely fused in the control and vitamin B12-treated groups at 72 and 96 h, respectively. The MEE still existed and proliferated. In Dex+vitamin B12 group the palatal shelves were fused at each time point in a similar rate to controls. These results may suggest that Dex causes teratogenesis of murine embryonic palatal shelves and vitamin B12 prevents the teratogenic effect of Dex on palatogenesis on murine embryos in vitro.

Topics: Animals; Cell Proliferation; Cleft Palate; Dexamethasone; Epithelial Cells; Female; Glucocorticoids; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Organ Culture Techniques; Teratogens; Time Factors; Vitamin B 12

Periconceptional folic acid supplementation is suggested to prevent orofacial clefts (OFCs). Other B vitamins however may be beneficial as well.. To investigate the maternal periconceptional dietary intake of thiamine, riboflavin, niacin, pyridoxine and cobalamin in association with the occurrence of OFC.. Two hundred and six mothers of a child with nonsyndromic OFC and 203 control mothers filled out a general questionnaire and a food frequency questionnaire around 14 months postpartum as a proxy for periconceptional intake. After exclusion of known pregnant and lactating mothers, those who reported to have altered their diet compared to the periconceptional period, and mothers with incidental folic acid supplement use periconceptionally, data of 182 OFC mothers and 173 controls were analysed. After logarithmic transformation, geometric means (P5-P95) were calculated and compared between the groups. After subsequent adjustment for energy, quintiles of dietary B vitamin intake were created.. The periconceptional intake of thiamine, niacin and pyridoxine was significantly lower in mothers of an OFC child. A trend towards risk reduction for OFC with increasing dietary intake was demonstrated for thiamine (p = 0.04) and pyridoxine (p = 0.03). Risk reductions were only demonstrated in women using folic acid supplements periconceptionally. Supplement users tended to consume a diet richer in B vitamins.. Periconceptional intake of thiamine, niacin and pyridoxine seems to contribute to the prevention of OFC.

Topics: Adult; Case-Control Studies; Cleft Lip; Cleft Palate; Diet; Energy Intake; Female; Folic Acid; Humans; Infant, Newborn; Niacin; Preconception Care; Pregnancy; Prenatal Care; Pyridoxine; Riboflavin; Risk Reduction Behavior; Surveys and Questionnaires; Thiamine; Vitamin B 12; Vitamin B Complex

This study was undertaken to investigate the involvement of maternal and infant B vitamins and homocysteine as risk factors for orofacial clefting.. Venous blood samples were taken from 96 infants with nonsyndromic orofacial clefts and 88 infants without a congenital malformation and from their mothers at approximately 14 months after the index pregnancy. Red blood cell and serum folate, serum vitamin B(12), whole blood vitamin B(6) as pyridoxal-5'-phosphate (PLP), and plasma homocysteine concentrations were measured.. A vitamin B(12) concentration of 185 pmol/L or less and a PLP concentration of 44 nmol/L or less in mothers increased the risk of having a child with an orofacial cleft (odds ratio [OR]=3.1; 95% CI: 1.3-7.4, OR=2.9; 95% CI: 1.2-7.1, respectively). Infants with orofacial clefts had a 15% lower serum folate concentration compared with controls (P=.06).. A low vitamin B(12) and PLP concentration in mothers increased the risk of orofacial clefts in the offspring. A possible role of the infant's folate status is suggested.

Topics: Cleft Lip; Cleft Palate; Female; Folic Acid; Homocysteine; Humans; Infant; Mothers; Pyridoxal Phosphate; Risk Factors; Vitamin B 12; Vitamin B 6

To investigate the molecular mechanism of congenital cleft palate induced by Dexamethasone (DEX) and the counteractive effect of Vitamin B12.. The RT-PCR was used to detect the independent and joint effects of DEX and Vitamin B12 on the gene expressions of A/J embryonic mouse palatal cells.. DEX stimulated the gene expressions of EGF and TGFbeta1, while the expression of TGFalpha left unchanged in the palatal cells. Vitamin B12 had no direct effects on the gene expressions of EGF, TGFalpha, and TGFbeta1; however, it counteracted the effects of DEX on the palate cells.. DEX induces cleft palate through increasing some gene expressions of growth factors, which can be inhibited by Vitamin B12.

Topics: Animals; Cells, Cultured; Cleft Palate; Dexamethasone; Embryo, Mammalian; Epidermal Growth Factor; Mice; Palate; Transforming Growth Factor alpha; Transforming Growth Factor beta; Vitamin B 12

Maternal folic acid supplementation has been suggested to play a role in the prevention of nonsyndromic orofacial clefts, i.e., cleft lip +/- cleft palate. Using a case-control design, we investigated vitamin-dependent homocysteine metabolism in 35 mothers with nonsyndromic orofacial cleft offspring and 56 control mothers with nonmalformed offspring. A standardized oral methionine loading test was performed, in which fasting and afterload plasma total homocysteine, serum and red-cell folate, serum vitamin B12, and whole-blood vitamin B6 levels were determined. We found that both fasting (P < 0.01) as well as afterload (P < 0.05) homocysteine concentrations were significantly higher in cases compared to controls. Hyperhomocysteinemia, defined by a fasting and/or afterload homocysteine concentration above the 97.5th percentile, was present in 15.6% of the cases and in 3.6% of controls (odds ratio, 5.3 (1.1-24.2)). The median concentrations of serum (P < 0. 01) and red-cell (P < 0.05) folate were significantly higher, and vitamin B6 concentrations appeared to be significantly lower (P < 0. 05), in cases compared with controls. No significant difference was observed between groups for vitamin B12. These preliminary data offer evidence that maternal hyperhomocysteinemia may be a risk factor for having nonsyndromic orofacial cleft offspring.

Topics: Adult; Case-Control Studies; Child, Preschool; Cleft Lip; Cleft Palate; Erythrocytes; Fasting; Female; Folic Acid; Homocysteine; Humans; Infant; Maternal-Fetal Exchange; Methionine; Pregnancy; Pyridoxine; Risk Factors; Vitamin B 12

Topics: Animals; Cleft Lip; Cleft Palate; Mice; Mice, Inbred Strains; Vitamin B 12

Ddy mice which were treated with 0.32 mg of dexamethasone were used. Vitamin B12 was injected subcutaneously into the animals from the 10th day to the 13th day with a dosage of 0.1r, 1r, or 10r. The rate of incidence of cleft palate was decreased to 77.0% in the 0.1r group, 58.1% in the 1r group and 67.9% in the 10r group as compared to the control value of 88.5%.

Topics: Animals; Cleft Palate; Dexamethasone; Female; Mice; Mice, Inbred Strains; Teratogens; Time Factors; Vitamin B 12

Topics: Ascorbic Acid; Calcium; Cleft Lip; Cleft Palate; Female; Folic Acid; Humans; Infant, Newborn; Maternal-Fetal Exchange; Niacinamide; Pregnancy; Pregnancy Trimester, First; Pyridoxine; Riboflavin; Thiamine; Vitamin B 12; Vitamins