Abstract
BackgroundIn utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life.MethodsGenome-wide DNA methylation in cord blood from 64 subjects in the Taiwanese maternal infant and birth cohort was analyzed. Robust regressions were applied to assess the association of DNA methylation with in utero arsenic exposure. Multiple testing was adjusted by controlling false discovery rate (FDR) of 0.05. The DAVID bioinformatics tool was implemented for functional annotation analyses on the detected CpGs. The identified CpGs were further tested in an independent cohort. For the CpGs replicated in the independent cohort, linear mixed models were applied to assess the association of DNA methylation with low-density lipoprotein (LDL) at different ages (2, 5, 8, 11 and 14 years).ResultsIn total, 579 out of 385,183 CpGs were identified after adjusting for multiple testing (FDR = 0.05), of which ~60% were positively associated with arsenic exposure. Functional annotation analysis on these CpGs detected 17 KEGG pathways (FDR = 0.05) including pathways for cardiovascular diseases (CVD) and diabetes mellitus. In the independent cohort, about 46% (252 out of 553 CpGs) of the identified CpGs showed associations consistent with those in the study cohort. In total, 11 CpGs replicated in the independent cohort were in the pathways related to CVD and diabetes mellitus. Via longitudinal analyses, we found at 5 out of the 11 CpGs methylation was associated with LDL over time and interactions between DNA methylation and time were observed at 4 of the 5 CpGs, cg25189764 (coeff = 0.157, p-value = 0.047), cg04986899 (coeff. For interaction [coeff.int] = 0.030, p-value = 0.024), cg04903360 (coeff.int = 0.026, p-value = 0.032), cg08198265 (coeff.int = −0.063, p-value = 0.0021), cg10473311 (coeff.int = −0.021, p-value = 0.027).ConclusionIn utero arsenic exposure was associated with cord blood DNA methylation at various CpGs. The identified CpGs may help determine pathological epigenetic mechanisms linked to in utero arsenic exposure. Five CpGs (cg25189764, cg04986899, cg04903360, cg08198265 and cg10473311) may serve as epigenetic markers for changes in LDL later in life.
Highlights
In utero arsenic exposure may alter fetal developmental programming by altering Deoxyribonucleic acid (DNA) methylation, which may result in a higher risk of disease in later life
Given this observation and the connection of arsenic exposure with CVDs and diabetes noted in the literature [7, 8, 36, 37], findings from the pathway analyses, and findings in the replication study, we further investigated the Multiple CpG (CpGs) sites of the genes enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are potentially linked to cardiovascular diseases and diabetes in our Taiwan cohort
We found that in utero arsenic exposure was associated with cord blood DNA methylation
Summary
In utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life. Epidemiological studies have reported that gestational arsenic exposure is associated with increased risk of non-cancerous and cancerous diseases in adulthood [3, 4]. A number of studies have shown that early life arsenic exposure is associated with later cardiovascular diseases (CVDs) [5,6,7]. In utero exposure to low level arsenic in the womb and in adulthood was found to be associated with diabetes mellitus [8]
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