title: Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis.
abstract: 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 (BDKRB2, CTNNA1, CYFIP2, MMP7, MYH2, and TIAM2) were confirmed in stage 2. Correlation analysis showed that methylated CpG sites in CTNNA1 and MYH2 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 CTNNA1 and MYH2 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.
authors.affiliation: a Institute of Reproductive and Child Health, School of Public Health, Peking University/Key Laboratory of Reproductive Health, National Health and Family Planning Commission of the People's Republic of China , Beijing , China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.affiliation: a Institute of Reproductive and Child Health, School of Public Health, Peking University/Key Laboratory of Reproductive Health, National Health and Family Planning Commission of the People's Republic of China , Beijing , China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Lin
authors.affiliation: a Institute of Reproductive and Child Health, School of Public Health, Peking University/Key Laboratory of Reproductive Health, National Health and Family Planning Commission of the People's Republic of China , Beijing , China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a Institute of Reproductive and Child Health, School of Public Health, Peking University/Key Laboratory of Reproductive Health, National Health and Family Planning Commission of the People's Republic of China , Beijing , China.
authors.forename: Tian
authors.initials: T
authors.lastname: Tian
authors.affiliation: a Institute of Reproductive and Child Health, School of Public Health, Peking University/Key Laboratory of Reproductive Health, National Health and Family Planning Commission of the People's Republic of China , Beijing , China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: a Institute of Reproductive and Child Health, School of Public Health, Peking University/Key Laboratory of Reproductive Health, National Health and Family Planning Commission of the People's Republic of China , Beijing , China.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Ren
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005333:Fetus / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009436:Neural Tube Defects / Q000235:genetics*; D011247:Pregnancy; D062725:Tight Junction Proteins / Q000235:genetics; D019108:Tight Junctions / Q000235:genetics*
chemical_list: D062725:Tight Junction Proteins
keywords: Benzo(a)pyrene; DNA methylation; neural tube defects; tight junction