Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis

<p>Neural tube defects (NTDs) are a spectrum of severe congenital malformations of fusion failure of the neural tube during early embryogenesis. Evidence on aberrant DNA methylation in NTD development remains scarce, especially when exposure to environmental pollutant is taken into consideration. DNA methylation profiling was quantified using the Infinium HumanMethylation450 array in neural tissues from 10 NTD cases and 8 non-malformed controls (stage 1). Subsequent validation was performed using a Sequenom MassARRAY system in neural tissues from 20 NTD cases and 20 non-malformed controls (stage 2). Correlation analysis of differentially methylated CpG sites in fetal neural tissues and polycyclic aromatic hydrocarbons concentrations in fetal neural tissues and maternal serum was conducted. Differentially methylated CpG sites of neural tissues were further validated in fetal mice with NTDs induced by benzo(a)pyrene given to pregnant mice. Differentially hypermethylated CpG sites in neural tissues from 17 genes and 6 pathways were identified in stage 1. Subsequently, differentially hypermethylated CpG sites in neural tissues from 6 genes (<i>BDKRB2, CTNNA1, CYFIP2, MMP7, MYH2</i>, and <i>TIAM2</i>) were confirmed in stage 2. Correlation analysis showed that methylated CpG sites in <i>CTNNA1</i> and <i>MYH2</i> from NTD cases were positively correlated to polycyclic aromatic hydrocarbon level in fetal neural tissues and maternal serum. The correlation was confirmed in NTD-affected fetal mice that were exposed to benzo(a)pyrene in utero. In conclusion, hypermethylation of the <i>CTNNA1</i> and <i>MYH2</i> genes in tight junction pathway is associated with the risk for NTDs, and the DNA methylation aberration may be caused by exposure to benzo(a)pyrene.</p

Maternal haemoglobin concentration and risk of preterm birth in a Chinese population

<p>The aim was to examine the relationship between maternal haemoglobin (Hb) concentrations and risk of preterm birth by secondary analysis of data from a randomised controlled trial. This analysis included 10,430 women who were at least 20 years old and no more than 20 weeks of gestation. Results revealed neither first- nor second-trimester Hb concentrations were associated with the risk of preterm births. However, the risk of preterm birth increased when the Hb level was low (<130 g/L) in the first but high (≥130 g/L) in the second trimester, regardless of supplement type (iron-containing: AOR: 2.26, 95% CI: 1.37–3.73; non-iron-containing: AOR: 2.16, 95% CI: 1.11–4.21). In conclusion, maternal Hb concentrations were not associated with the risk of preterm birth. A low-Hb level in the first trimester but coupled with a high Hb level in the second was associated with an elevated risk of preterm birth.Impact statement</p><p><b>What is already known on this subject:</b> The relationship between maternal Hb concentration and preterm birth remains inconclusive. Some studies have shown an association between a low- or a high-Hb level and an increased risk of preterm birth. Others have not found such an association. Yet others have shown a U-shaped relationship.</p><p><b>What do the results of this study add:</b> Overall, maternal Hb concentrations in first or second trimester were not statistically associated with the risk of preterm birth. However, women with a low Hb concentration in the first trimester together with a high Hb concentration in the second trimester had an increased risk of preterm birth, compared to women who had a higher Hb concentration in the first trimester that remained similar during the second trimester.</p><p><b>What are the implications are of these findings for clinical practice and/or further research:</b> Our finding helps identify mothers who are at risk of having a preterm delivery. Investigating the underlying clinical causes of the unfavourable change in Hb levels and close follow-up to these women may help improve birth outcomes.</p><p></p> <p><b>What is already known on this subject:</b> The relationship between maternal Hb concentration and preterm birth remains inconclusive. Some studies have shown an association between a low- or a high-Hb level and an increased risk of preterm birth. Others have not found such an association. Yet others have shown a U-shaped relationship.</p> <p><b>What do the results of this study add:</b> Overall, maternal Hb concentrations in first or second trimester were not statistically associated with the risk of preterm birth. However, women with a low Hb concentration in the first trimester together with a high Hb concentration in the second trimester had an increased risk of preterm birth, compared to women who had a higher Hb concentration in the first trimester that remained similar during the second trimester.</p> <p><b>What are the implications are of these findings for clinical practice and/or further research:</b> Our finding helps identify mothers who are at risk of having a preterm delivery. Investigating the underlying clinical causes of the unfavourable change in Hb levels and close follow-up to these women may help improve birth outcomes.</p

Metabonomic Profiling of Human Placentas Reveals Different Metabolic Patterns among Subtypes of Neural Tube Defects

Neural tube defects (NTDs) are one of the most common types of birth defects with a complex etiology. We have previously profiled serum metabolites of pregnant women in Lvliang prefecture, Shanxi Province of China, which revealed distinct metabolic changes in pregnant women with NTDs outcome. Here we present a metabonomics study of human placentas of 144 pregnant women with normal pregnancy outcome and 115 pregnant women affected with NTDs recruited from four rural counties (Pingding, Xiyang, Taigu, and Zezhou) of Shanxi Province, the area with the highest prevalence worldwide. A panel of 19 metabolites related to one-carbon metabolism was also quantitatively determined. We observed obvious differences in global metabolic profiles and one-carbon metabolism among three subtypes of NTDs, anencephaly (Ane), spina bifida (SB), and Ane complicated with SB (Ane & SB) via mass-spectrometry-based metabonomics approach. Disturbed carbohydrate, amino acid, lipid, and nucleic acid metabolism were identified. Placental transport of amino acids might be depressed in Ane and Ane & SB group. Deficiency of choline contributes to Ane and Ane & SB pathogenesis via different metabolic pathways. The formation of NTDs seemed to be weakly related to folates. The metabonomic analysis reveals that the physiological and biochemical processes of the three subtypes of NTDs might be different and the subtype condition should be considered for the future investigation of NTDs