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. 2014 Aug;5(4):288-98.
doi: 10.1017/S2040174414000221.

Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys

K Broberg  1 , S Ahmed  1 , K Engström  2 , M B Hossain  1 , S Jurkovic Mlakar  3 , M Bottai  4 , M Grandér  1 , R Raqib  5 , M Vahter  1
Affiliations
Free PMC article

Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys

K Broberg et al. J Dev Orig Health Dis. 2014 Aug.
Free PMC article

Abstract

Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov-Smirnov test, P-value<10-15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (r S -values>-0.62), but in girls only 207 (41%) showed inverse correlation (r S -values>-0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.

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Figures

Fig. 1
Fig. 1
Distribution of the P-values for the coefficient associated with maternal urinary arsenic concentrations in early gestation from linear regression analysis of CpG methylation (n=482,421 sites) in cord blood. (a) Cord blood from girls, (b) Cord blood from boys.
Figure 2
Figure 2
Scatterplot of the fractions (0 to 1) of methylation of the CpG sites in cord blood and the concentrations of arsenic metabolites in maternal urine in early pregnancy (gestational week 8) for: (a) cg13659051 and (c) cg02975107, among top five CpG sites in boys; and (b) cg06411879 and (d) cg09606015, among top five CpG sites in girls. The associations are indicated by Lowess lines.
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