摘要
妊娠期间暴露于颗粒物（PM）会增加儿童患哮喘的风险。然而，胎盘机制尚未阐明。本研究旨在通过胎盘表观遗传失调评估妊娠期PM暴露与哮喘易感性的相关机制。我们分析了两个独立的韩国出生队列的数据(COCOA， 684名儿童；PSKC， 818明)。在7岁时通过乙酰甲胆碱激发试验评估医师诊断的哮喘和支气管高反应性（BHR）。我们使用回归模型估算了妊娠期间直径< 10 μm的PM暴露（PM10）。在COCOA研究中，我们对40例胎盘样本进行了全基因组甲基化分析，并分析了基因表达水平。在COCOA研究中，妊娠期PM10高暴露增加了当前发生哮喘和BHR的风险(aOR 2.36, 95% CI 1.06-5.22；aOR 2.14, 95% CI 1.40-3.27)和PSKC的当前哮喘（aOR 2.62, 95% CI 1.35-5.09）。参与神经元分化增殖的基因和Notch信号通路的基因在PM10高暴露哮喘儿童中发生明显的高甲基化。这些通路中8个基因（PAX6、REST、OLIG2、GLI1、ZBTB7A、NOTCH4、NOTCH1和NOTCH3）的甲基化和表达水平与临床参数相关。这可能通过基于基因或CpG的甲基化程度的预测模型有效地预测PM相关哮喘（AUC分别为0.96和0.93）。妊娠期PM10暴露通过胎盘DNA高甲基化、神经元分化和增殖以及Notch信号通路影响子代哮喘的发生发展。
PM exposure during pregnancy affects childhood asthma via placental epigenetic changes: neuronal differentiation and proliferation and Notch signaling pathways
Hyo-Bin Kim, Si Hyeon Lee, Dae Yeol Yang, Seung-Hwa Lee, Jeong-Hyun Kim, Hwan-Cheol Kim, Kil Yong Choi, So-Yeon Lee, Song-I Yang, Dong In Suh, Youn Ho Shin, Kyung Won Kim, Kangmo Ahn, Suk-Joo Choi, Ja-Young Kwon, Soo Hyun Kim, Jong Kwan Jun, Mi-Young Lee, Hye-Sung Won, Kwoneel Kim, Soo-Jong Hong
Abstract
Particulate matter (PM) exposure during pregnancy increases the risk of developing asthma in children. However, the placental mechanisms have yet to be elucidated. This study aims to evaluate the mechanisms associated with PM exposure during pregnancy and asthma susceptibility via placental epigenetic dysregulation. We analyzed data from two independent Korean birth cohorts (COCOA, 684 children; PSKC, 818 children). Physician-diagnosed current asthma and bronchial hyperresponsiveness (BHR) via methacholine challenge tests were evaluated at age seven. We estimated PM exposure with a diameter < 10 μm (PM10) during pregnancy using land-use regression models. We performed genome-wide methylation profiling in the placenta of 40 samples in the COCOA study and analyzed the gene expression levels. High PM10exposure during pregnancy increased the risk of developing current asthma and BHR in the COCOA study (aOR 2.36, 95% CI 1.06-5.22; aOR 2.14, 95% CI 1.40-3.27, respectively) and current asthma in the PSKC (aOR 2.62, 95% CI 1.35-5.09). The genes involved in neuronal differentiation and proliferation and Notch signaling pathways were significantly hypermethylated in children with high PM10-exposed asthma. The methylation and expression levels of eight genes (PAX6, REST, OLIG2, GLI1, ZBTB7A, NOTCH4, NOTCH1, and NOTCH3) in these pathways correlated with clinical parameters. This may effectively predict PM-related asthma through a prediction model using degrees of gene-based or CpG-based methylation (AUC = 0.96 and 0.93, respectively). PM10exposure during pregnancy impacts asthma development in offspring via placental DNA hypermethylation via neuronal differentiation and proliferation and Notch signaling pathways.
妊娠期间暴露于颗粒物（PM）会增加儿童患哮喘的风险。然而，胎盘机制尚未阐明。本研究旨在通过胎盘表观遗传失调评估妊娠期PM暴露与哮喘易感性的相关机制。我们分析了两个独立的韩国出生队列的数据(COCOA， 684名儿童；PSKC， 818明)。在7岁时通过乙酰甲胆碱激发试验评估医师诊断的哮喘和支气管高反应性（BHR）。我们使用回归模型估算了妊娠期间直径< 10 μm的PM暴露（PM10）。在COCOA研究中，我们对40例胎盘样本进行了全基因组甲基化分析，并分析了基因表达水平。在COCOA研究中，妊娠期PM10高暴露增加了当前发生哮喘和BHR的风险(aOR 2.36, 95% CI 1.06-5.22；aOR 2.14, 95% CI 1.40-3.27)和PSKC的当前哮喘（aOR 2.62, 95% CI 1.35-5.09）。参与神经元分化增殖的基因和Notch信号通路的基因在PM10高暴露哮喘儿童中发生明显的高甲基化。这些通路中8个基因（PAX6、REST、OLIG2、GLI1、ZBTB7A、NOTCH4、NOTCH1和NOTCH3）的甲基化和表达水平与临床参数相关。这可能通过基于基因或CpG的甲基化程度的预测模型有效地预测PM相关哮喘（AUC分别为0.96和0.93）。妊娠期PM10暴露通过胎盘DNA高甲基化、神经元分化和增殖以及Notch信号通路影响子代哮喘的发生发展。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Environ Pollut. 2024 Dec 4:125471. doi: 10.1016/j.envpol.2024.125471.)
(Environ Pollut. 2024 Dec 4:125471. doi: 10.1016/j.envpol.2024.125471.)
PM exposure during pregnancy affects childhood asthma via placental epigenetic changes: neuronal differentiation and proliferation and Notch signaling pathways
Hyo-Bin Kim, Si Hyeon Lee, Dae Yeol Yang, Seung-Hwa Lee, Jeong-Hyun Kim, Hwan-Cheol Kim, Kil Yong Choi, So-Yeon Lee, Song-I Yang, Dong In Suh, Youn Ho Shin, Kyung Won Kim, Kangmo Ahn, Suk-Joo Choi, Ja-Young Kwon, Soo Hyun Kim, Jong Kwan Jun, Mi-Young Lee, Hye-Sung Won, Kwoneel Kim, Soo-Jong Hong
Abstract
Particulate matter (PM) exposure during pregnancy increases the risk of developing asthma in children. However, the placental mechanisms have yet to be elucidated. This study aims to evaluate the mechanisms associated with PM exposure during pregnancy and asthma susceptibility via placental epigenetic dysregulation. We analyzed data from two independent Korean birth cohorts (COCOA, 684 children; PSKC, 818 children). Physician-diagnosed current asthma and bronchial hyperresponsiveness (BHR) via methacholine challenge tests were evaluated at age seven. We estimated PM exposure with a diameter < 10 μm (PM10) during pregnancy using land-use regression models. We performed genome-wide methylation profiling in the placenta of 40 samples in the COCOA study and analyzed the gene expression levels. High PM10exposure during pregnancy increased the risk of developing current asthma and BHR in the COCOA study (aOR 2.36, 95% CI 1.06-5.22; aOR 2.14, 95% CI 1.40-3.27, respectively) and current asthma in the PSKC (aOR 2.62, 95% CI 1.35-5.09). The genes involved in neuronal differentiation and proliferation and Notch signaling pathways were significantly hypermethylated in children with high PM10-exposed asthma. The methylation and expression levels of eight genes (PAX6, REST, OLIG2, GLI1, ZBTB7A, NOTCH4, NOTCH1, and NOTCH3) in these pathways correlated with clinical parameters. This may effectively predict PM-related asthma through a prediction model using degrees of gene-based or CpG-based methylation (AUC = 0.96 and 0.93, respectively). PM10exposure during pregnancy impacts asthma development in offspring via placental DNA hypermethylation via neuronal differentiation and proliferation and Notch signaling pathways.
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