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Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

ABSTRACT: DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5-formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs.

SUBMITTER: Wang X

PROVIDER: S-EPMC4379001 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

Wang Xiuwei X Guan Zhen Z Chen Yan Y Dong Yanting Y Niu Yuhu Y Wang Jianhua J Zhang Ting T Niu Bo B

PloS one 20150330 3

DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ioniza ...[more]

PMID: 25822193

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Project description:BackgroundEpidemiological studies have found that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with increased risk for neural tube defects (NTDs). Aberrant DNA methylation, excessive apoptosis, and oxidative stress have been implied as the mechanism underlying the association between PAH exposure and NTDs, respectively. However, the role of DNA methylation aberration of apoptotic initiator CASP8 (caspase-8, apoptosis-related cysteine peptidase) in the formation of NTDs in association with PAH exposure is not known. By combining a case-control study and mouse model, we aimed to explore the full spectrum of the links from PAH exposure, oxidative stress, CASP8 methylation change, caspase-8 activation, apoptosis, to NTD formation.ResultsHypomethylation of CASP8 promoter was noticed in the microarray profiled by Infinium HumanMethylation450 BeadChip using neural tissues from 10 terminated NTD fetuses and 8 terminated non-malformed fetuses (14 CpG sites, with β difference ranging between 8.8 and 26.3%), and was validated in a larger case-control sample performed with neural tissues from 80 NTD cases and 32 non-malformed fetuses, using the Sequenom MassARRAY system (7 CpG sites). Hypomethylation of CASP8 was a risk factor for NTDs (aOR = 1.11; 95% CI, 1.05-1.17) based on the logistic regression model. According to Pearson's correlation, methylation levels of CASP8 were inversely correlated with PAH concentrations in maternal serum and with oxidative stress markers in fetal neural tissues (p < 0.05). In the animal study, increased NTD rates (13.5% frequency), Casp8 hypomethylation, caspase-8 upregulation, increased caspase-8 cleavage, and excessive apoptosis were found in mouse embryos cultured with benz(a)pyrene (BaP) in vitro. Antioxidant N-acetyl-L-cysteine (NAC) and BaP co-treatment attenuated the changes found in BaP treatment group.ConclusionsHypomethylation of Casp8 promoter is associated with the formation of NTDs, and Casp8 hypomethylation may be induced by oxidative stress that resulted from exposure to PAHs.

Project description:Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative ("risk genotypes") and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms.

Dataset Information

Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

Publications

Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

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