​The placenta plays a fundamental role in the Developmental Origins of Health and Disease (DOHaD)¹ concept. More than a simple transporter of nutriments and waste between mother and fetus, the placenta affects the programming and development of the fetal phenotype. Also, there is growing evidence that epigenetics plays an important role in this process. The placental epigenetic modifications occurring during pregnancy may be sensitive to a range of environmental factors. For example, several chemical products have been associated with developmental disorders, congenital abnormalities and childhood health issues.

Phthalates are chemical compounds that are used in a wide variety of consumer products such as cosmetics, food packaging, and the near entirety of products employing polyvinyl chloride (PVC). Certain phthalates have been shown to cross the placental barrier and possibly to cause changes to cellular homeostasis. A growing body of epidemiological evidence suggests that exposure to some phthalates during pregnancy may be associated with modifications to a range of placental epigenetic parameters, including placental DNA methylation. Epidemiological studies on those associations remain however relatively rare.

To contribute to a greater understanding of this issue, the Epigenetic and Environment Laboratory (CNRGH) participated in an international² study aimed at characterizing associations between placental DNA methylation and the concentrations of 11 phthalate-derived metabolites in urine samples from pregnant women. The samples used for the analysis, published in Environment International, were obtained from EDEN, a cohort of French mothers and children. Urine samples were obtained from 202 women at 22 to 29 weeks of pregnancy. Methylation rates were analyzed in DNA extracted from fetal-facing placental tissue sampled at delivery.

First, the researchers evaluated DNA methylation globally via an analysis of the repetitive nucleotide elements Alu and LINE-1. They then performed a more in-depth epigenome-wide association study³ using IlluminaHM450 BeadChips to characterize CpG site methylation (450,000 sites in all) and determine associations with phthalate metabolite concentrations. This enabled the identification of differentially methylated regions (DMRs; regions containing several significantly modified CpGs) associated with phthalate exposure.

Concerning the metabolites, the researchers noted that monobenzyl phthalate (MBzP) concentrations were associated with reduced methylation of the repetitive Alu sequences.

Also, numerous phthalates were associated with increased methylation in several DMRs, and two (MBzP and MEHP) with reduced methylation in three. The identified regions comprised 23 genes coding for heat shock proteins, transcription factors and nucleotide exchange factors among others.

Interestingly, four of these 23 genes had already been associated with maternal smoking, suggesting that the concerned genomic regions could be particularly sensitive to the effects of environmental contaminants.

This study is the first to provide a description of genome-wide placental DNA methylation modifications associated with phthalate exposure during pregnancy.

It suggests epigenetic mechanisms set off by phthalate exposure during pregnancy and potentially able to affect fetal development.

1 : The DOHaD concept builds upon the idea that prenatal gene-environment interactions may result in predisposition or resistance to adulthood pathologies.

2 :  With Grenoble Alpes University, Paris University, the National Center for Environmental Health (Atlanta, USA), and the Harvard T.H. Chan School of Public Health (Boston, USA).

3 : An epigenome-wide association study, frequently abbreviated as EWAS, examines the totality of quantifiable epigenetic marks in a genome, usually DNA methylation, over a range of individuals to determine any associations between epigenetic variants and identifiable phenotypes.