Abstract：
BACKGROUND: Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented.
OBJECTIVE: Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth.
METHODS: We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth.
RESULTS: We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation.
CONCLUSIONS: Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth.
OBJECTIVE: Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth.
METHODS: We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth.
RESULTS: We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation.
CONCLUSIONS: Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth.
摘要：
背景：有机磷酸酯（OPEs）暴露可能会影响后代健康。然而,潜在的机制没有得到很好的记录。
目的：基于出生队列研究，我们的目的是调查妊娠OPEs暴露之间的关联，过氧化物酶体增殖物激活受体(PPAR)信号通路相关基因的胎盘DNA甲基化水平,和胎儿的生长。
方法：我们测量了733对母子对的母体尿液样本中8种OPE代谢物的浓度和新生儿人体测量。在327个胎盘样本中，我们评估了参与PPARs信号通路并在胎盘中表达的14个基因的DNA甲基化水平.多元线性回归模型用于检查OPEs暴露与胎盘DNA甲基化的相关性。新生儿人体测量法测量OPEs和胎盘DNA甲基化。进行了因果介导分析，以检查胎盘DNA甲基化在OPEs暴露与胎儿生长之间的途径中的潜在介导作用。
结果：我们观察到OPEs暴露的一般模式与候选基因的超甲基化有关，在几个OPEs与RXRA的统计上显着的关联中，ACAA1、ACADL、ACADM,PLTP,和NR1H3甲基化。Further,妊娠暴露于BCIPP，DPP,BBOEP,∑NCl-OPEs,和∑OPEs倾向于与较低的人体测量值相关，在臂围上观察到更显著的关联，腹部和背部皮褶厚度。值得注意的是,RXRA,ACAA1,ACOX1,CPT2,ACADM,和NR1H3甲基化倾向于与较低的新生儿人体测量相关，尤其是腹部和背部皮褶厚度。此外，调解分析表明，DPP对背部皮褶厚度的总影响的19.42％是由RXRA甲基化的变化介导的，RXRA甲基化有显著的间接作用。
结论：妊娠OPEs暴露可破坏PPARAR信号通路相关基因的胎盘DNA甲基化水平，这可能有助于OPEs对胎儿生长的影响。
目的：基于出生队列研究，我们的目的是调查妊娠OPEs暴露之间的关联，过氧化物酶体增殖物激活受体(PPAR)信号通路相关基因的胎盘DNA甲基化水平,和胎儿的生长。
方法：我们测量了733对母子对的母体尿液样本中8种OPE代谢物的浓度和新生儿人体测量。在327个胎盘样本中，我们评估了参与PPARs信号通路并在胎盘中表达的14个基因的DNA甲基化水平.多元线性回归模型用于检查OPEs暴露与胎盘DNA甲基化的相关性。新生儿人体测量法测量OPEs和胎盘DNA甲基化。进行了因果介导分析，以检查胎盘DNA甲基化在OPEs暴露与胎儿生长之间的途径中的潜在介导作用。
结果：我们观察到OPEs暴露的一般模式与候选基因的超甲基化有关，在几个OPEs与RXRA的统计上显着的关联中，ACAA1、ACADL、ACADM,PLTP,和NR1H3甲基化。Further,妊娠暴露于BCIPP，DPP,BBOEP,∑NCl-OPEs,和∑OPEs倾向于与较低的人体测量值相关，在臂围上观察到更显著的关联，腹部和背部皮褶厚度。值得注意的是,RXRA,ACAA1,ACOX1,CPT2,ACADM,和NR1H3甲基化倾向于与较低的新生儿人体测量相关，尤其是腹部和背部皮褶厚度。此外，调解分析表明，DPP对背部皮褶厚度的总影响的19.42％是由RXRA甲基化的变化介导的，RXRA甲基化有显著的间接作用。
结论：妊娠OPEs暴露可破坏PPARAR信号通路相关基因的胎盘DNA甲基化水平，这可能有助于OPEs对胎儿生长的影响。
