Perez Cynthia, Campbell Kyle, Barr Dana Boyd, Shankar Kartik, Sims Clark, Pearson Kevin J, Andres Aline, Everson Todd M
Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA.
USDA Agricultural Research Services, Responsive Agricultural Food Systems Research Unit, College Station, TX, USA.
medRxiv. 2025 Jun 24:2025.06.23.25330157. doi: 10.1101/2025.06.23.25330157.
Per- and polyfluoroalkyl substances (PFAS) are environmental toxicants associated with adverse neonatal outcomes. The exact mechanisms by which PFAS impairs neonatal health are undefined, but the placenta is a likely target.
We applied a systems biology approach to identify placental RNA co-expression modules (gene sets) associated with PFAS exposure and birth weight.
Placental tissue samples (n = 147) from the GLOWING study underwent RNA-sequencing, and PFAS concentrations were quantified using liquid chromatography-tandem mass spectrometry. We constructed a weighted gene co-expression network using Spearman correlations across 15,028 transcripts, identifying 20 gene modules. Linear regression models were used to examine associations between PFAS and module eigengenes, adjusting for potential confounders. Effect modification by fetal sex was also tested.
One module showed a negative association with perfluorononanoic acid (PFNA; β = -0.012, q = 0.009). This association was sex-specific, with the sexes exhibiting varied PFAS associations but similar directional effects. Genes within the PFNA-associated module were involved in histone modification (q ≤ 0.05) and were enriched for targets of the Vitamin D Receptor (VDR), a transcription factor previously linked to PFAS.
Our research indicates that prenatal exposure to PFNA influences placental gene expression differently based on sex, which may affect insulin growth factor signaling and histone modification. The presence of VDR in this module and the transcription enrichment analysis align with previous findings regarding PFAS and VDR interactions. This module related to PFNA could shed light on the molecular pathways connecting PFAS exposure to health outcomes in neonates.
全氟和多氟烷基物质（PFAS）是与不良新生儿结局相关的环境毒物。PFAS损害新生儿健康的确切机制尚不清楚，但胎盘可能是一个靶点。
我们应用系统生物学方法来识别与PFAS暴露和出生体重相关的胎盘RNA共表达模块（基因集）。
对来自GLOWING研究的胎盘组织样本（n = 147）进行RNA测序，并使用液相色谱-串联质谱法定量PFAS浓度。我们使用Spearman相关性在15,028个转录本上构建了一个加权基因共表达网络，识别出20个基因模块。使用线性回归模型来检验PFAS与模块特征基因之间的关联，并对潜在混杂因素进行调整。还测试了胎儿性别的效应修饰。
一个模块与全氟壬酸（PFNA）呈负相关（β = -0.012，q = 0.009）。这种关联具有性别特异性，不同性别表现出不同的PFAS关联，但方向效应相似。PFNA相关模块内的基因参与组蛋白修饰（q≤0.05），并且富含维生素D受体（VDR）的靶标，VDR是一种先前与PFAS相关的转录因子。
我们的研究表明，产前暴露于PFNA会根据性别不同地影响胎盘基因表达，这可能会影响胰岛素生长因子信号传导和组蛋白修饰。该模块中VDR的存在以及转录富集分析与先前关于PFAS和VDR相互作用的研究结果一致。这个与PFNA相关的模块可能会揭示将PFAS暴露与新生儿健康结局联系起来的分子途径。
