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.
Highlights
The environment of the developing child is an important determinant of disease susceptibility in later life.[1]
Women in the study sample were to a larger extent nulliparous, had higher SES and had children with somewhat higher birth weight, compared with the total cohort of 1729 pregnant women studied for arsenic exposure
In the regression analysis arsenic exposure variable was log2-transformed. aP-value adjusted for FDR. bAdjusted for mother’s age, body mass index, gestational age at birth, socioeconomic status, exact gestational weeks at urine collection. This first study of sex-differential genome-wide cord blood DNA methylation in relation to arsenic exposure provides strong evidence that maternal arsenic exposure in early gestation is associated with modified DNA methylation in the newborn child
Summary
The environment of the developing child is an important determinant of disease susceptibility in later life.[1]. Arsenic, which frequently occurs at elevated concentrations in drinking water worldwide, is a potent carcinogen, a general toxicant and an endocrine disrupter.[9,10] Besides the accumulating evidence for associations between in utero arsenic exposure and impaired fetal and child health and development,[11,12,13,14] both human and experimental animal studies indicate higher risk for cancer, cardiovascular effects and increased mortality later in childhood or adulthood when exposure starts prenatally or shortly after birth.[15,16,17,18,19,20] These results suggest persistent longterm effects of early-life changes, possibly through alterations of DNA methylation at the 5-methylcytosine position. Considering the increasing evidence for sexual dimorphism both for programming trajectories and in response
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