Lapehn Samantha, Parenti Mariana, Firsick Evan J, Khodasevich Dennis, Baker Brennan H, Day Drew B, MacDonald James W, Bammler Theo K, Kannan Kurunthachalam, Choi Hyo Young, Barrett Emily S, Howe Caitlin G, Carroll Kecia N, LeWinn Kaja Z, Zhao Qi, Cardenas Andres, Szpiro Adam A, Sathyanarayana Sheela, Paquette Alison G
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, United States.
Department of Epidemiology and Population Health, Stanford University, Stanford, CA 94305, United States.
Environ Int. 2025 Apr;198:109402. doi: 10.1016/j.envint.2025.109402. Epub 2025 Mar 19.
Prenatal exposure to organophosphate ester (OPE) chemicals, commonly used as flame retardants and plasticizers, has been associated with adverse birth outcomes. The placenta is a critical fetal organ and therefore may be involved in pathogenesis of birth outcomes. The goal of this study was to evaluate associations of 10 maternal urinary OPE metabolites, individually and as a mixture, with the placental transcriptome at birth in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Individual OPE metabolites were evaluated for associations with individual genes as well as co-expressed gene modules. Mixtures analysis was conducted using quantile g-computation. The analyses were performed with the entire data set (N = 737) as well as the sex-stratified subsets. Two genes (HAP1 and RAP1GAP) were associated with bis(1,3-dichloro-2-propyl) phosphate (BDCPP), and six genes were associated the mixture in the full data set. 3 genes were associated with diphenyl phosphate (DPHP) and 36 genes were associated with the mixture in a male stratified analysis. 2 genes were associated with DPHP, and 1 gene was associated with diethyl phosphate (DEP) in a female stratified analysis. Three gene modules were associated with BDCPP or diphenyl phosphate (DPHP) and one module was associated with the OPE mixture. 12 WGCNA modules were associated with individual OPE metabolites or the mixture in males, and 1 WGCNA module was associated with DEP in females. Five of the OPE-associated gene modules were enriched for a total of 17 KEGG pathways, and 11 modules were enriched with targets of 12 nuclear hormone receptor transcription factors. Overall, novel associations were identified between the placental transcriptome and OPE metabolites, individually and in mixture, including differences based on fetal sex. These findings highlight the need for additional research on mechanisms of OPE-associated gene expression changes in the placenta and associated health outcomes.
产前暴露于通常用作阻燃剂和增塑剂的有机磷酸酯（OPE）化学品与不良出生结局相关。胎盘是一个关键的胎儿器官，因此可能参与出生结局的发病机制。本研究的目的是在影响儿童早期神经认知发育和学习的状况（CANDLE）研究中，评估10种母体尿液OPE代谢物单独及作为混合物与出生时胎盘转录组的关联。评估了个体OPE代谢物与单个基因以及共表达基因模块的关联。使用分位数g计算进行混合物分析。分析是在整个数据集（N = 737）以及按性别分层的子集中进行的。在完整数据集中，两个基因（HAP1和RAP1GAP）与双（1,3 - 二氯 - 2 - 丙基）磷酸酯（BDCPP）相关，六个基因与混合物相关。在男性分层分析中，3个基因与磷酸二苯酯（DPHP）相关，36个基因与混合物相关。在女性分层分析中，2个基因与DPHP相关，1个基因与磷酸二乙酯（DEP）相关。三个基因模块与BDCPP或磷酸二苯酯（DPHP）相关，一个模块与OPE混合物相关。12个WGCNA模块在男性中与个体OPE代谢物或混合物相关，1个WGCNA模块在女性中与DEP相关。与OPE相关的基因模块中有五个总共富集了17条KEGG通路，11个模块富集了12种核激素受体转录因子的靶标。总体而言，在胎盘转录组与OPE代谢物单独及混合之间发现了新的关联，包括基于胎儿性别的差异。这些发现凸显了对胎盘OPE相关基因表达变化机制及相关健康结局进行更多研究的必要性。
