Sex-specific effects of early life cadmium exposure on DNA methylation and implications for birth weight

Abstract

Dietary cadmium exposure was recently found to alter DNA methylation in adults, but data on effects early in life are lacking. Our objective was to evaluate associations between prenatal cadmium exposure, DNA methylation and birth weight. In total 127 mother-child pairs from rural Bangladesh were studied. For comparison, we included 56 children at 4.5 y. Cadmium concentrations in mothers' blood (gestational week 14) and children's urine were measured by ICPMS. Global DNA methylation was analyzed by Infinium HumanMethylation450K BeadChip in cord blood and children's blood. Maternal cadmium exposure was associated with cord blood DNA methylation (p-value < 10 (-16) ). The association was markedly sex-specific. In boys, 96% of the top 500 CpG sites showed positive correlations (rS-values > 0.50), whereas most associations in girls were inverse; only 29% were positive (rS > 0.45). In girls we found overrepresentation of methylation changes in genes associated with organ development, morphology and mineralization of bone, whereas changes in boys were found in cell death-related genes. Several individual CpG sites that were positively associated with cadmium were inversely correlated with birth weight, although none statistically significant after correction for multiple comparisons. The associations were, however, fairly robust in multivariable-adjusted linear regression models. We identified CpG sites that were significantly associated with cadmium exposure in both newborns and 4.5-y-old children. In conclusion, cadmium exposure in early life appears to alter DNA methylation differently in girls and boys. This is consistent with previous findings of sex-specific cadmium toxicity. Cadmium-related changes in methylation were also related to lower birth weight.

Keywords: 450K; CpG; epigenetic; fetal development; gender; gene-environment interaction; growth.

Figure 1. The histograms show the frequency distribution of the p-values (x-axis) of the regression coefficients for cadmium from 482, 421 separate regression models, one for each CpG site, of DNA methylation in cord blood vs. cadmium in maternal blood for girls (A) and boys (B), respectively.

Figure 2.

Scatterplots depicting (A) fraction of DNA methylation in cord blood for the CpG site cg20309121 in RUNX1T1 vs. maternal blood Cd at GW14; and (B) fraction of DNA methylation for cg20309121 in peripheral blood from 4.5-y-old children vs. their urinary Cd; (C) fraction of DNA methylation in cord blood for cg09127607 in MYPN vs. maternal blood Cd at GW14; and (D) fraction of DNA methylation for cg09127607 in peripheral blood from 4.5-y-old children vs. their urinary Cd. Solid lines represent Lowess-moving average curves; dashed lines represent fitted curves from the multivariable-adjusted regression analyses defined in Table 3.