GSE123279
Effects of Cadmium Exposure on DNA Methylation at Imprinting Control Regions and Genome-Wide in Mothers and Newborn Children.
Background: Imprinted genes are defined by their preferential expression from one of the two parental alleles. This unique mode of gene expression is dependent on allele-specific DNA methylation profiles established at regulatory sequences called imprinting control regions. These loci are frequently used as biosensors to study how environmental exposures affect methylation and transcription. However, a critical unanswered question is whether they are more, less or equally sensitive to environmental stressors as the rest of the genome. Objectives: Using cadmium exposure in humans as a model, we determined the relative sensitivity of imprinting control regions to perturbation of methylation compared to similar, non-imprinted loci in the genome. Methods: We assayed DNA methylation genome-wide using bisulfite sequencing of newborn cord blood and maternal blood samples selected on the basis of maternal blood cadmium levels. Differentially methylated regions associated with cadmium exposure were identified. Results: In newborn cord blood and maternal blood, 641 and 1945 cadmium-associated differentially methylated regions were identified, respectively. These were strongly enriched at maternally-methylated imprinting control regions when compared to similar loci in newborn cord blood (P = 5.64E-8) and maternal blood (P = 6.22E-14), suggesting an increased sensitivity for imprinting control regions to cadmium. Genome-wide, methylation changes were enriched in maternal blood at genes implicated in body mass index (P = 2.0E-5), blood pressure (P = 3.8E-5) and body weight (P = 1.4E-3), with similar trends for metabolic and cardiovascular functions in cord blood, suggesting that epigenetic changes may contribute to the etiology of cadmium-associated diseases. Conclusions: We present the first global nucleotide-resolution DNA methylation profile associated with cadmium exposure in humans. We identify imprinting control regions as hotspots for perturbation by cadmium, possibly due to their unique modes of regulation, motivating further study of these loci to provide insight into the mechanisms of cadmium action. Overall design: We analyzed specimens from 20 pregnant women and 19 of their offspring. We selected 10 women with the highest blood Cd concentrations in the first trimester of pregnancy and 10 from the majority of women with blood concentrations close to zero.