Seattle Children's Research Institute, Seattle, WA, USA; University of Washington, Seattle, WA, USA.
Seattle Children's Research Institute, Seattle, WA, USA.
Environ Int. 2023 Feb;172:107763. doi: 10.1016/j.envint.2023.107763. Epub 2023 Jan 18.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants originating from petrogenic and pyrogenic sources. PAH compounds can cross the placenta, and prenatal PAH exposure is linked to adverse infant and childhood health outcomes.
In this first human transcriptomic assessment of PAHs in the placenta, we examined associations between prenatal PAH exposure and placental gene expression to gain insight into mechanisms by which PAHs may disrupt placental function.
The ECHO PATHWAYS Consortium quantified prenatal PAH exposure and the placental transcriptome from 629 pregnant participants enrolled in the CANDLE study. Concentrations of 12 monohydroxy-PAH (OH-PAH) metabolites were measured in mid-pregnancy urine using high performance liquid chromatography tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate covariate-adjusted associations between maternal urinary OH-PAHs and placental gene expression. We performed sex-stratified analyses to evaluate whether associations varied by fetal sex. Selected PAH/gene expression analyses were validated by treating HTR-8/SVneo cells with phenanthrene, and quantifying expression via qPCR.
Urinary concentrations of 6 OH-PAHs were associated with placental expression of 8 genes. Three biological pathways were associated with 4 OH-PAHs. Placental expression of SGF29 and TRIP13 as well as the vitamin digestion and absorption pathway were positively associated with multiple metabolites. HTR-8/SVneo cells treated with phenanthrene also exhibited 23 % increased TRIP13 expression compared to vehicle controls (p = 0.04). Fetal sex may modify the relationship between prenatal OH-PAHs and placental gene expression, as more associations were identified in females than males (45 vs 28 associations).
Our study highlights novel genes whose placental expression may be disrupted by OH-PAHs. Increased expression of DNA damage repair gene TRIP13 may represent a response to double-stranded DNA breaks. Increased expression of genes involved in vitamin digestion and metabolism may reflect dietary exposures or represent a compensatory mechanism to combat damage related to OH-PAH toxicity. Further work is needed to study the role of these genes in placental function and their links to perinatal outcomes and lifelong health.
多环芳烃（PAHs）是源自石油和热解源的普遍存在的污染物。PAH 化合物可以穿过胎盘，产前 PAH 暴露与婴儿和儿童健康不良结局有关。
在这项对胎盘内 PAHs 的首次人类转录组评估中，我们研究了产前 PAH 暴露与胎盘基因表达之间的关联，以深入了解 PAHs 可能破坏胎盘功能的机制。
ECHO PATHWAYS 联盟在 CANDLE 研究中量化了 629 名孕妇的产前 PAH 暴露和胎盘转录组。使用高效液相色谱串联质谱法测量妊娠中期尿液中 12 种单羟基-PAH（OH-PAH）代谢物的浓度。使用配对末端 RNA 测序获得胎盘转录组数据。使用线性模型估计母体尿液 OH-PAH 与胎盘基因表达之间的协变量调整关联。我们进行了性别分层分析，以评估关联是否因胎儿性别而异。通过用菲处理 HTR-8/SVneo 细胞，并通过 qPCR 定量表达，验证了选定的 PAH/基因表达分析。
尿液中 6 种 OH-PAH 的浓度与 8 种基因在胎盘中的表达有关。有 3 个生物学途径与 4 种 OH-PAH 有关。SGF29 和 TRIP13 的胎盘表达以及维生素消化和吸收途径与多种代谢物呈正相关。与载体对照相比，用菲处理的 HTR-8/SVneo 细胞的 TRIP13 表达增加了 23%（p=0.04）。胎儿性别可能会改变产前 OH-PAHs 与胎盘基因表达之间的关系，因为在女性中比男性中鉴定出更多的关联（45 个与 28 个关联）。
我们的研究强调了胎盘表达可能被 OH-PAHs 破坏的新基因。DNA 损伤修复基因 TRIP13 的表达增加可能代表双链 DNA 断裂的反应。参与维生素消化和代谢的基因表达增加可能反映了饮食暴露或代表了一种补偿机制，以对抗与 OH-PAH 毒性相关的损伤。需要进一步研究这些基因在胎盘功能及其与围产期结局和终身健康的联系中的作用。
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