Fetal exposure to phthalates and bisphenols and DNA methylation at birth: the Generation R Study

Abstract

Background: Phthalates and bisphenols are non-persistent endocrine disrupting chemicals that are ubiquitously present in our environment and may have long-lasting health effects following fetal exposure. A potential mechanism underlying these exposure-outcome relationships is differential DNA methylation. Our objective was to examine the associations of maternal phthalate and bisphenol concentrations during pregnancy with DNA methylation in cord blood using a chemical mixtures approach.

Methods: This study was embedded in a prospective birth cohort study in the Netherlands and included 306 participants. We measured urine phthalates and bisphenols concentrations in the first, second and third trimester. Cord blood DNA methylation in their children was processed using the Illumina Infinium HumanMethylation450 BeadChip using an epigenome-wide association approach. Using quantile g-computation, we examined the association of increasing all mixture components by one quartile with cord blood DNA methylation.

Results: We did not find evidence for statistically significant associations of a maternal mixture of phthalates and bisphenols during any of the trimesters of pregnancy with DNA methylation in cord blood (all p values > 4.01 * 10^-8). However, we identified one suggestive association (p value < 1.0 * 10^-6) of the first trimester maternal mixture of phthalates and bisphenols and three suggestive associations of the second trimester maternal mixture of phthalates and bisphenols with DNA methylation in cord blood.

Conclusions: Although we did not identify genome-wide significant results, we identified some suggestive associations of exposure to a maternal mixture of phthalates and bisphenols in the first and second trimester with DNA methylation in cord blood that need further exploration in larger study samples.

Keywords: Bisphenols; DNA methylation; Mixture; Phthalates; Prenatal.

Fig. 1

Manhattan plot of associations between a mixture of phthalates and bisphenols during first, second and third trimester with DNA methylation at birth. Manhattan plot of associations between a mixture of phthalates and bisphenols during first (A), second (B) and third (C) trimester with DNA methylation at birth in the total population. In all Manhattan plots, the x-axis represents the autosomal chromosomes, the y-axis represents the −log₁₀ of the p value and the dots represent CpGs

Fig. 2

Manhattan plot of associations between a mixture of phthalates and bisphenols during first, second and third trimester with DNA methylation at birth among boys. Manhattan plot of associations between a mixture of phthalates and bisphenols during first (A), second (B) and third (C) trimester with DNA methylation at birth among boys. In all Manhattan plots, the x-axis represents the autosomal chromosomes, the y-axis represents the −log₁₀ of the p value and the dots represent CpGs

Fig. 3

Manhattan plot of associations between a mixture of phthalates and bisphenols during first, second and third trimester with DNA methylation at birth among girls. Manhattan plot of associations between a mixture of phthalates and bisphenols during first (A), second (B) and third (C) trimester with DNA methylation at birth among girls. In all Manhattan plots, the x-axis represents the autosomal chromosomes, the y-axis represents the −log₁₀ of the p value and the dots represent CpGs

Fig. 4

Manhattan plot of associations between a mixture of phthalates and bisphenols averaged over pregnancy with DNA methylation at birth in the total population and among boys and girls specifically. Manhattan plot of associations between a mixture of phthalates and bisphenols averaged over pregnancy in the total population (A), among boys (B) and among girls (C) with DNA methylation at birth. In all Manhattan plots, the x-axis represents the autosomal chromosomes, the y-axis represents the −log₁₀ of the p value and the dots represent CpG