Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation

Abstract

Exposure to ambient air pollution during pregnancy has been associated with an increased risk of preeclampsia (PE). Some suggested mechanisms behind this association are changes in placental DNA methylation and gene expression. The objective of this study was to identify how early pregnancy exposure to ambient nitrogen oxides (NOx) among PE cases and normotensive controls influence DNA methylation (EPIC array) and gene expression (RNA-seq). The study included placentas from 111 women (29 PE cases/82 controls) in Scania, Sweden. First-trimester NOx exposure was assessed at the participants’ residence using a dispersion model and categorized via median split into high or low NOx. Placental gestational epigenetic age was derived from the DNA methylation data. We identified six differentially methylated positions (DMPs, q < 0.05) comparing controls with low NOx vs. cases with high NOx and 14 DMPs comparing cases and controls with high NOx. Placentas with female fetuses showed more DMPs (N = 309) than male-derived placentas (N = 1). Placentas from PE cases with high NOx demonstrated gestational age deceleration compared to controls with low NOx (p = 0.034). No differentially expressed genes (DEGs, q < 0.05) were found. In conclusion, early pregnancy exposure to NOx affected placental DNA methylation in PE, resulting in placental immaturity and showing sexual dimorphism.

A comprehensive review on endocrine toxicity of gaseous components and particulate matter in smog

“…These toxicants also cause alterations in the placenta’s DNA. Early pregnancy exposure to NO x changed the placental DNA methylation leading to placental immaturity ( 54 , 55 ). Chronic interaction with NO x is also linked with diabetes mellitus.…”

“…Moreover, other studies have revealed that the chronic exposure to air pollution may produce alterations in normal ovarian function e.g., estrogen-like effect or gene mutation, which can lead to ovarian cancer ( 66 ). Additionally, transplacental exposure to PM is connected to higher placental mutation rate and such epigenetic alterations may be a reason for placental carcinogenicity ( 55 ).…”

Childhood atopic disorders in relation to placental changes—A systematic review and meta‐analysis

“…17 One mechanism involved in fetal programming may be epigenetic changes, 7,8 which have been reported in placentas exposed to ambient air pollution and in placentas from women who live on farms. 18,19 Differences in cord blood cytokines and immune cells have also been found between neonates who later develop an allergic disease and healthy controls. For example, detectable levels of interleukin 4 and interferonγ in cord blood were associated with reduced incidences of asthma and atopy during childhood.…”

“…Another well‐studied prenatal exposure linked to an increased risk of atopic disorders in offspring, particularly wheezing and asthma, is maternal smoking during pregnancy 17 . One mechanism involved in fetal programming may be epigenetic changes, 7,8 which have been reported in placentas exposed to ambient air pollution and in placentas from women who live on farms 18,19 . Differences in cord blood cytokines and immune cells have also been found between neonates who later develop an allergic disease and healthy controls.…”

Integrated single-cell RNA-seq and DNA methylation reveal the effects of air pollution in patients with recurrent spontaneous abortion

“…In addition, alterations in placental DNA methylation of the LINE-1 and HSD11B2 genes might be involved in PM10-induced reproductive and developmental toxicity [ 28 ]. Furthermore, NO 2 exposure during early pregnancy influenced placental DNA methylation in preeclampsia and resulted in placental immaturity and sexual dimorphism [ 29 ]. In addition, the researcher found that the epigenetic modifiers such as TET2 and TET3 were upregulated in the placenta of patients with spontaneous abortion [ 30 ].…”