Prenatal phthalate exposure and altered patterns of DNA methylation in cord blood

Abstract

Epigenetic changes such as DNA methylation may be a molecular mechanism through which environmental exposures affect health. Phthalates are known endocrine disruptors with ubiquitous exposures in the general population including pregnant women, and they have been linked with a number of adverse health outcomes. We examined the association between in utero phthalate exposure and altered patterns of cord blood DNA methylation in 336 Mexican-American newborns. Concentrations of 11 phthalate metabolites were analyzed in maternal urine samples collected at 13 and 26 weeks gestation as a measure of fetal exposure. DNA methylation was assessed using the Infinium HumanMethylation 450K BeadChip adjusting for cord blood cell composition. To identify differentially methylated regions (DMRs) that may be more informative than individual CpG sites, we used two different approaches, DMRcate and comb-p. Regional assessment by both methods identified 27 distinct DMRs, the majority of which were in relation to multiple phthalate metabolites. Most of the significant DMRs (67%) were observed for later pregnancy (26 weeks gestation). Further, 51% of the significant DMRs were associated with the di-(2-ethylhexyl) phthalate metabolites. Five individual CpG sites were associated with phthalate metabolite concentrations after multiple comparisons adjustment (FDR), all showing hypermethylation. Genes with DMRs were involved in inflammatory response (IRAK4 and ESM1), cancer (BRCA1 and LASP1), endocrine function (CNPY1), and male fertility (IFT140, TESC, and PRDM8). These results on differential DNA methylation in newborns with prenatal phthalate exposure provide new insights and targets to explore mechanism of adverse effects of phthalates on human health. Environ. Mol. Mutagen. 58:398-410, 2017. © 2017 Wiley Periodicals, Inc.

PRDM8 exhibits antitumor activities toward hepatocellular carcinoma by targeting NAP1L1

“…PRDM8 has hypomethylated CpG islands in endometrial cancer . Association between in utero phthalate exposure and altered DNA methylation of PRDM8 has also been identified recently . Of note, expression of PRDM8 is down‐regulated in a subset of colorectal and gastric cancer cell lines, but the expression is not significantly restored by treating cells with 5‐aza‐2′‐deoxycytidine .…”

Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation

“…Solomon et al were recently the first to assess epigenome-wide effects in humans from prenatal phthalate exposure. Using the Infinium 450K BeadChip they identified 27 differentially methylated regions (DMRs) in infant cord blood of which more than half of the DMRs were associated with SDEHP and some DMRs were found in genes involved in endocrine function [52]. Taken together, the prenatal epigenomic landscape, from gene to genome-wide, appears to be sensitive to several different phthalates or phthalate mixtures.…”

Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data

“…Despite the range of biological and technical differences across the UCB references, combining references would yield a larger sample size, which we hypothesized would result in increased power and accuracy of the CP/QP model. One study effectively combined three reference datasets (de Goede, Bakulski and Gervin) for UCB deconvolution[28], though validating the specificity of a combined reference was not tested. Interestingly, although our analyses on combined data slightly improved accuracy and sensitivity of the deconvolution estimates, a clean reference reflecting cell type purity was much more important.…”