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Background  Neural tube defects (NTDs) are common and severe congenital malformations.  Pax3  is an essential gene for neural tube closure in mice but it is unknown whether altered expression or methylation of  PAX3  contributes to human NTDs. We examined the potential role of hypermethylation of  Pax3  in the development of NTDs by analyzing human NTD cases and a mouse model in which NTDs were induced by benzo[a]pyrene (BaP), a widely studied polycyclic aromatic hydrocarbon (PAH).    Methods  We extracted methylation information of  PAX3  in neural tissues from array data of ten NTD cases and eight non-malformed controls. A validation study was then performed in a larger independent population comprising 73 NTD cases and 29 controls. Finally, we examined methylation patterns and expression of  Pax3  in neural tissues from mouse embryos of dams exposed to BaP or BaP and vitamin E.    Results  Seven CpG sites in  PAX3  were hypermethylated in NTD fetuses as compared to controls in the array data. In the validation phase, significantly higher methylation levels in the body region of  PAX3  were observed in NTD cases than in controls ( P  = 0.003). And mean methylation intensity in the body region of  PAX3  in fetal neural tissues was positively correlated with median concentrations of PAH in maternal serum. In the mouse model, BaP-induced NTDs were associated with hypermethylation of specific CpG sites within both the promoter and body region of  Pax3 . Supplementation with vitamin E via chow decreased the rate of NTDs, partly recovered the repressed total antioxidant capacity in mouse embryos exposed to BaP, and this was accompanied by the normalization of  Pax3  methylation level and gene expression.    Conclusion  Hypermethylation of  Pax3  may play a role in the development of NTDs; DNA methylation aberration may be caused by exposure to BaP, with possible involvement of oxidative stress.    Electronic supplementary material  The online version of this article (10.1186/s13148-019-0611-7) contains supplementary material, which is available to authorized users.

Aberrant methylation of Pax3 gene and neural tube defects in association with exposure to polycyclic aromatic hydrocarbons