Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea; Institute of Environmental Technology, Department of Environmental Engineering, Seoul National University of Science & Technology, Seoul 01811, Republic of Korea.
Center for Environmental Health Sciences, Biomedical and Pharmaceutical Sciences, College of Health Professions and Biomedical Sciences, University of Montana, Missoula, MT, 59812, USA.
Environ Int. 2019 Sep;130:104956. doi: 10.1016/j.envint.2019.104956. Epub 2019 Jul 1.
Exposure to persistent organic pollutants (POPs) during pregnancy is associated with a disruption in thyroid hormone balance. The placenta serves as an important environment for fetal development and also regulates thyroid hormone supply to the fetus. However, epigenetic changes of thyroid regulating genes in placenta have rarely been studied. This study was conducted to evaluate the association between several POP concentrations in maternal serum and DNA methylation of thyroid hormone-related genes in the placenta. The placenta samples were collected from 106 Korean mother at delivery, and the promoter methylation of the placental genes was measured by a bisulfite pyrosequencing. The deiodinase type 3 (DIO3), monocarboxylate transporter 8 (MCT8), and transthyretin (TTR) genes were selected as the target genes as they play an important role in the regulation of fetal thyroid balance. Because people are exposed to multiple chemicals at the same time, a multiple-POP model using principal component analysis (PCA) was applied to evaluate the association between the multiple POPs exposure and the epigenetic change in placenta. In addition, a single-POP model which includes one chemical each in the statistical model for association was conducted. Based on the single-POP models, serum concentrations of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and brominated diphenyl ether-47 (BDE-47) were significantly associated with an increase in placental DIO3 methylation, but only among female infants. Among male infants, a positive association between serum p,p'-DDT and MCT8 methylation level was found. According to the multiple-POP models, serum DDTs were positively associated with DIO3 methylation in the placenta of female infants, while a positive association with MCT8 methylation was observed in those of the male infants. Our observation showed that in utero exposure to DDTs may influence the DNA methylation of DIO3 and MCT8 genes in the placenta, in a sexually dimorphic manner. These alterations in placental epigenetic regulation may in part explain the thyroid hormone disruption observed among the newborns or infants followed by in utero exposure to POPs.
孕期暴露于持久性有机污染物（POPs）会导致甲状腺激素平衡紊乱。胎盘是胎儿发育的重要环境，也调节着向胎儿供应甲状腺激素。然而，胎盘调节甲状腺基因的表观遗传变化很少被研究。本研究旨在评估母体血清中几种 POP 浓度与胎盘甲状腺激素相关基因 DNA 甲基化之间的关系。在分娩时从 106 名韩国母亲收集胎盘样本，并通过亚硫酸氢盐焦磷酸测序测量胎盘基因的启动子甲基化。选择脱碘酶 3（DIO3）、单羧酸转运蛋白 8（MCT8）和转甲状腺素蛋白（TTR）基因作为靶基因，因为它们在调节胎儿甲状腺平衡中发挥重要作用。由于人们同时暴露于多种化学物质，因此应用主成分分析（PCA）的多 POP 模型来评估多种 POP 暴露与胎盘表观遗传变化之间的关系。此外，还进行了一个单 POP 模型，其中每个统计模型中包含一种化学物质，用于关联分析。基于单 POP 模型，p,p'-二氯二苯二氯乙烯（p,p'-DDE）和溴代二苯醚-47（BDE-47）血清浓度与胎盘 DIO3 甲基化增加显著相关，但仅在女婴中如此。在男婴中，发现血清 p,p'-DDT 与 MCT8 甲基化水平呈正相关。根据多 POP 模型，母体血清 DDTs 与女婴胎盘 DIO3 甲基化呈正相关，而在男婴中则与 MCT8 甲基化呈正相关。我们的观察表明，宫内暴露于滴滴涕可能以性别二态的方式影响胎盘 DIO3 和 MCT8 基因的 DNA 甲基化。这些胎盘表观遗传调节的改变可能部分解释了在宫内暴露于 POPs 后观察到的新生儿或婴儿的甲状腺激素紊乱。
