Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Lin S

PROVIDER: S-EPMC6341549 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Lin Shanshan S Ren Aiguo A Wang Linlin L Santos Chloe C Huang Yun Y Jin Lei L Li Zhiwen Z Greene Nicholas D E NDE

Clinical epigenetics 20190121 1

<h4>Background</h4>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).<h4>Methods</ ...[more]

PMID: 30665459

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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:BackgroundEpigenetic dysregulation is one of the postulated underlying mechanisms of neural tube defects (NTDs). Polycyclic aromatic hydrocarbons (PAHs), a group of environmental pollutants that are reported as a risk factor of NTDs, may cause decreased genome-wide DNA methylation. With DNA extracted from neural tissues, this study identified gene(s) whose hypomethylation was related to elevated risk for NTDs and examined whether its hypomethylation is related to PAH exposure.ResultsUsing data profiled by Infinium HumanMethylation450 BeadChip array from 10 NTD cases and eight controls, ZIC4, CASP8, RAB32, RARA, and TRAF6 were identified to be the top five genes in NTD-related hypomethylated gene families. Among all identified genes, ZIC4 had the largest number of differently methylated CpG sites (n = 13) in the promoter region and 5' UTR. Significantly decreased methylation in the ZIC4 promoter region and 5' UTR was verified in an independent cohort of 80 cases and 32 controls (p < 0.001) utilizing the Sequenom EpiTYPER platform. Hypomethylation of ZIC4 was associated with a higher risk of NTDs [adjusted OR = 1.08; 95% confidence interval (CI): 1.03, 1.13] in a logistic regression model. Mean methylation levels in the promoter region and 5' UTR of ZIC4 tended to be inversely associated with levels of high-molecular-weight PAHs in fetal liver among NTD fetuses (β [95% CI]: -0.045 [-0.091, 0.001], p = 0.054). Six and three CpG sites in the ZIC4 promoter region and 5' UTR were inversely correlated with antioxidant indicators and protein oxidation markers (ρ: -0.45 to -0.75, p < 0.05) in fetal neural tissues, respectively. In a whole-embryo cultured mouse model, hypomethylation of the Zic4 promoter region and 5' UTR and upregulation of Zic4 were observed, coupled with increased NTD rates after BaP exposure. The antioxidant N-acetyl-L-cysteine normalized the changes observed in the BaP exposure group.ConclusionHypomethylation of the ZIC4 promoter region and 5' UTR may increase the risk for NTDs; oxidative stress is likely to play a role in the methylation change of Zic4 in response to PAH exposure in NTD formation.

Project description:BackgroundAging is related to an increased risk of morbidity and mortality and is affected by environmental factors. Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health outcomes; but the association of such exposure with DNA methylation aging, a novel aging marker, is unclear.ObjectivesOur aim was to investigate the association of PAH exposure with methylation aging.MethodsWe trained and validated a methylation age predictor suitable for Chinese populations using whole blood methylation data in 989 Chinese and 160 Caucasians. We defined two aging indicators: δage, as methylation age minus chronological age; and aging rate, the ratio of methylation to chronological age. The association of PAH exposure with aging indicators was evaluated using linear regressions in three panels of healthy Chinese participants (N=539, among the aforementioned 989 Chinese participants) whose exposure levels were assessed by 10 urinary monohydroxy-PAH metabolites.ResultsWe developed a methylation age predictor providing accurate predictions in both Chinese individuals and Caucasian persons (R=0.94-0.96, RMSE=3.8-4.3). Among the 10 urinary metabolites that we measured, 1-hydroxypyrene and 9-hydroxyphenanthrene were associated with methylation aging independently of other OH-PAHs and risk factors; 1-unit increase in 1-hydroxypyrene was associated with a 0.53-y increase in Δage [95% confidence interval (CI): 0.18, 0.88; false discovery rate (FDR) FDR=0.004] and 1.17% increase in aging rate (95% CI: 0.36, 1.98; FDR=0.02), whereas for 9-hydroxyphenanthrene, the increase was 0.54-y for Δage (95% CI: 0.17, 0.91; FDR=0.004), and 1.15% for aging rate (95% CI: 0.31, 1.99; FDR=0.02). The association direction was consistent across the three Chinese panels with the association magnitude correlating with the panels' exposure levels; the association was validated by methylation data of purified leukocytes. Several cytosine-phosphoguanines, including those located on FHL2 and ELOVL2, were found associated with both aging indicators and monohydroxy-PAH levels.ConclusionsWe developed a methylation age predictor specific for Chinese populations but also accurate for Caucasian populations. Our findings suggest that exposure to PAHs may be associated with an adverse impact on human aging and epigenetic alterations in Chinese populations. https://doi.org/10.1289/EHP2773.

Project description:BackgroundAlthough there is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) is linked with congenital heart defects (CHDs), few studies have examined the association in humans. We conducted a case-control study to examine the association between maternal exposure to PAHs and CHDs in offspring using data from the National Birth Defects Prevention Study (NBDPS) (1997-2011).MethodsWe obtained detailed information on maternal occupation during the month before to three months after conception. Expert raters, masked to case-control status, assessed job descriptions to assign categorical levels of exposure. Categories were quantitatively mapped to estimate cumulative exposure to PAHs, incorporating exposure intensity, frequency, work duration, and work hours. Quartiles were generated for cumulative maternal exposure to PAHs. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression for quartiles of PAH exposure and six CHD groupings (e.g. conotruncal) and specific subtypes (e.g. tetralogy of Fallot [ToF]). Final models were adjusted for maternal age, race/ethnicity, education, smoking, anticonvulsant use, folic acid supplementation, and study center.ResultsThere were 4,775 case and 7,734 control infants eligible for the study. The prevalence of occupational exposure to PAHs was 10.2% among both case and control mothers. In adjusted analysis, compared to mothers with no occupational PAH exposure, those in the highest quartile of exposure were more likely to have offspring in the conotruncal heart defects group (OR 1.41; 95% CI 1.00-2.00), and with ToF (OR 1.83; 95% CI 1.21-2.78).ConclusionsWomen in the highest quartile of estimated cumulative occupational PAH exposure during early pregnancy were more likely to have offspring with conotruncal heart defects, specifically ToF, compared to women with no occupational PAH exposure. Other comparisons between PAHs and other CHDs subgroups did not show any statistically precise associations.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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