Aberrant methylation of Pax3 gene and neural tube defects in association with exposure to polycyclic aromatic hydrocarbons.
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.
['Lin|Shanshan|S|', 'Ren|Aiguo|A|0000-0001-9115-5638', 'Wang|Linlin|L|', 'Santos|Chloe|C|', 'Huang|Yun|Y|', 'Jin|Lei|L|', 'Li|Zhiwen|Z|', 'Greene|Nicholas D E|NDE|']
D000818:Animals D016022:Case-Control Studies D018899:CpG Islands D019175:DNA Methylation D004195:Disease Models, Animal D005260:Female D005786:Gene Expression Regulation D006801:Humans D008297:Male D008423:Maternal Age D018811:Maternal Exposure D051379:Mice D009436:Neural Tube Defects D000072041:PAX3 Transcription Factor D011084:Polycyclic Aromatic Hydrocarbons D011247:Pregnancy D011401:Promoter Regions, Genetic D014810:Vitamin E
Methylation Pax3 gene Neural tube defects Polycyclic aromatic hydrocarbon Benzo[a]pyrene