Abstract

Background:

Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes.

Objective:

We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development.

Methods:

The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography–tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) $p<0.05$. Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted $p<0.2$.

Results:

We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2-ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs. Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites. Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively. Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations.

Discussion:

To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort. We identified numerous genes and lncRNAs associated with prenatal phthalate exposure. These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure. https://doi.org/10.1289/EHP8973

中文翻译：

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产前邻苯二甲酸盐暴露与胎盘转录组学景观之间关联的综合评估

摘要

背景：

邻苯二甲酸盐是常用的干扰内分泌的化学物质，在普通人群中无处不在。产前接触邻苯二甲酸酯可能会改变胎盘生理和胎儿发育，导致不良的围产期和儿童健康结果。

客观的：

我们检查了妊娠中期和晚期的产前邻苯二甲酸酯暴露与出生时胎盘转录组之间的关联，包括基因和长链非编码 RNA (lncRNA)，以深入了解胎儿发育过程中的潜在作用机制。

方法：

ECHO PATHWAYs 联盟使用高效液相色谱-串联质谱法对参加 CANDLE 研究（田纳西州谢尔比县）的 760 名女性的 21 种尿液邻苯二甲酸酯代谢物进行了量化。使用配对末端 RNA 测序获得胎盘转录组数据。线性模型被拟合以估计孕中期和晚期母体尿液邻苯二甲酸酯代谢物浓度与出生时胎盘基因表达之间的独立关联，并针对混杂变量进行了调整。基因被认为以 Benjamini-Hochberg 错误发现率 (FDR) 差异表达$p<0.05$. 邻苯二甲酸酯代谢物与生物途径之间的关联是使用独立的基因组测试确定的，并被认为随着 FDR 调整而显着改变$p<0.2$.

结果：

我们观察到孕中期邻苯二甲酸酯代谢物单（羧基异辛基）邻苯二甲酸酯（MCIOP）、单-2-乙基-5-羧基戊基邻苯二甲酸酯和单-2-乙基-5-氧代己基邻苯二甲酸酯与总共 18 个基因（包括 4 个 lncRNA）之间存在显着关联. 具体而言， NEAT1的胎盘表达与多种邻苯二甲酸酯代谢物相关。妊娠晚期 MCIOP 和邻苯二甲酸单异丁酯浓度分别与 18 个基因和两个基因的胎盘表达显着相关。27 种生物途径中的基因表达与邻苯二甲酸单甲酯、MCIOP 和邻苯二甲酸单乙酯浓度相关。

讨论：

据我们所知，这是对一个庞大且多样化的出生队列中出生时胎盘转录组与产前邻苯二甲酸盐暴露之间关系的首次全基因组评估。我们确定了许多与产前邻苯二甲酸盐暴露相关的基因和 lncRNA。这些关联反映了其他流行病学和体外分析的发现，并可能提供对子宫内受邻苯二甲酸盐暴露影响的生物学途径的深入了解。https://doi.org/10.1289/EHP8973