Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study,Environmental Health Perspectives

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Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2020-12-24 , DOI: 10.1289/ehp6888
Anne P Starling _{1,

2} , Cuining Liu ₃ , Guannan Shen ₃ , Ivana V Yang _{1,

4,

5} , Katerina Kechris _{3,

4} , Sarah J Borengasser ₆ , Kristen E Boyle ₆ , Weiming Zhang ₃ , Harry A Smith _{2,

3} , Antonia M Calafat ₇ , Richard F Hamman _{1,

2} , John L Adgate ₈ , Dana Dabelea _{1,

2,

6}

Affiliation

Abstract

Background:

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype.

Objectives:

We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators.

Methods:

Among 583 mother–infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate $open parenthesis false discovery rate close parenthesis less than 0.05$ and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjusted $lowercase italic p less than 0.05$ ). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin.

Results:

Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations ( $lowercase rho equals 0.28 to 0.76$ ). Methylation at one DMP (cg18587484), annotated to the gene TJAP1, was associated with perfluorooctanoate (PFOA) at $false discovery rate less than 0.05$ . Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth (RPTOR), lipid homeostasis (PON1, PON3, CIDEB, NR1H2), inflammation and immune activity (RASL11B, RNF39), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively ( $false discovery rate less than 0.1$ ).

Discussion:

DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888

中文翻译：

产前接触全氟烷基和多氟烷基物质、新生儿脐带血 DNA 甲基化和心脏代谢指标：健康开始研究

抽象的

背景：

全氟烷基物质和多氟烷基物质 (PFAS) 是在育龄妇女中广泛检测到的环境持久性化学物质。产前 PFAS 暴露与儿童不良健康结果相关。我们假设 DNA 甲基化变化可能是由产前 PFAS 暴露引起的，并且可能与后代心脏代谢表型有关。

目标：

我们估计了产前 PFAS 与脐带血 DNA 甲基化的关联。我们评估了选定位点的甲基化与新生儿心脏代谢指标的关联。

方法：

在前瞻性队列中的 583 对母婴中，对母体血清（中位妊娠 27 周）中的 5 种 PFAS 进行了定量。使用 Illumina HumanMmethylation450 阵列评估脐带血 DNA 甲基化。以错误发现率评估差异甲基化位置 (DMP) $open parenthesis false discovery rate close parenthesis less than 0.05$ 使用comb-p（Šidák调整的 $lowercase italic p less than 0.05$ ）。我们估计了候选 DMP 和 DMR 位点的甲基化与以下结果之间的关联：新生儿体重、肥胖和脐带血糖、胰岛素、血脂和瘦素。

结果：

母亲血清 PFAS 浓度低于美国普通人群女性的中位数。 PFAS 浓度之间观察到中度至高度的成对相关性（ $lowercase rho equals 0.28 to 0.76$ ）。注释为基因TJAP1的一个 DMP (cg18587484) 的甲基化与全氟辛酸 (PFOA) 相关 $false discovery rate less than 0.05$ 。 Comb-p 检测到每种 PFAS 中有 4 到 15 个 DMR。相关基因（一些在多种 PFAS 中常见）与生长 ( RPTOR )、脂质稳态（ PON1 、 PON3 、 CIDEB 、 NR1H2 ）、炎症和免疫活性（ RASL11B 、 RNF39 ）等功能有关。有提示性证据表明，两个 PFAS 相关位点（cg09093485、cg09637273）分别与脐带血甘油三酯和出生体重相关（ $false discovery rate less than 0.1$ ）。