Decreased global DNA hydroxymethylation in neural tube defects: Association with polycyclic aromatic hydrocarbons

Abstract

5-Hydroxymethylcytosine (5hmC), a distinct epigenetic marker that plays a role in DNA active demethylation, has been reported to be important for embryonic development and may respond to environmental exposure. No studies have evaluated the association between DNA hydroxymethylation and the risk for fetal neural tube defects (NTDs), with consideration of prenatal exposure to polycyclic aromatic hydrocarbons (PAHs), a risk factor for NTDs. We measured the global levels of 5hmC% in neural tissue from 92 terminated NTD cases and 33 terminated non-malformed fetuses. A lower level of 5hmC% was found in the NTD cases (median [interquartile range]: 0.25 [0.12-0.39]) compared to the controls (0.45 [0.19-1.00]). After adjusting for periconceptional folate supplementation, risk for NTDs increased with decreasing tertiles of 5hmC% (odds ratio: 7.89, 95% confidence interval: 2.32, 26.86, for the lowest tertile relative to the top tertile; p for trend = 0.002). Linear regression revealed that concentrations of highmolecular-weight PAHs (H_PAHs) in fetal liver tissue were negatively associated with log2transformed 5hmC%. Superoxide dismutase activity and 5hmC% were positively correlated in fetal neural tissue (r s = 0.64; p < 0.05). A mouse whole-embryo culture model was used for further validation. Decreased levels of 5hmC% and increased levels of reactive oxygen species were found in mouse embryos treated with BaP, a well-studied PAH. Taken together, levels of 5hmC% in fetal neural tissue were inversely associated with the risk for NTDs, and this association may be related to oxidative stress induced by exposure to PAHs.

Early-life oxidative stress due to air pollution. A scoping review focusing on identifying potential ‘-OMICS’ biomarkers from body fluids

“…The potential health effects of an increase in internal PAH metabolites have been reviewed [16,62]. Similar to our study, a meta-analysis [63] determined that, in addition to the total exposure level of PAH metabolites, the levels of 1-PYR, 2-NAP, 2-Fluo, 3-PHE, and 4-PHE were most commonly studied, and that the 1-PYR level is suitable for evaluating AP exposure in children and adolescents.…”

Neural Tube Defects and ZIC4 Hypomethylation in Relation to Polycyclic Aromatic Hydrocarbon Exposure

“…Moreover, OS may induce excessive S -adenosyl- L -methionine consumption which would cause a decrease in methyl donor and then block methylation reaction. Furthermore, the upregulation of the demethylation enzyme ten-eleven translocation may also play a role in OS-induced hypomethylation ( Chia et al, 2011 ; Huang et al, 2019a ). Although no other specific evidence for Zic4 methylation and OS is available in the literature, the negative correlation between markers of OS and ZIC4 methylation in fetuses, together with hypomethylated Zic 4 after BaP exposure rescued by NAC in mouse embryos, suggests that PAHs may mediate ZIC4 / Zic4 methylation via OS.…”

Tissue and sex-specific programming of DNA methylation by perinatal lead exposure: implications for environmental epigenetics studies

“…Although 5hmC is an intermediate in the DNA demethylation pathway, recent studies suggest that the genomic distribution, downstream targets, and functional roles of 5hmC are distinct from that of 5mC [3]. Environmental exposures may also lead to reprogramming of 5hmC, and these changes are associated with altered transcription and adverse health outcomes [4][5][6].…”