Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life

Environmental Health

Research

Carmen J. Marsit¹  Todd M. Everson¹  Margaret R. Karagas²  Akhilesh Kaushal³  Wilfried J. J. Karmaus³  Hongmei Zhang³  Shih-Fen Tsai⁴  Hui-Ju Wen⁴  Shu-Li Wang⁵ 

[1] Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA;Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA;Children’s Environmental Health & Disease Prevention Research Center at Dartmouth, Hanover, NH, USA;Division of Epidemiology, Biostatistics, and Environmental Health, University of Memphis, 38152, Memphis, TN, USA;National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan;National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan;School of Public Health, National Defense Medical Center, Taipei, Taiwan;Department of Public Health, China Medical University, Taichung, Taiwan;Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;

关键词: Arsenic;    DNA methylation;    CpG;    DAVID;    KEGG pathway;    Genome-wide;    Ldl;   

DOI  :  10.1186/s12940-017-0262-0

 received in 2016-12-22, accepted in 2017-05-22,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017