Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China (Fudan University), China; Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China.
Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China; Division of Health Risk Factors Surveillance and Control, Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China.
Environ Int. 2019 Dec;133(Pt B):105255. doi: 10.1016/j.envint.2019.105255. Epub 2019 Oct 23.
Polybrominated diphenyl ethers (PBDEs) are environmental chemicals with harmful effects on pregnancy, but their effects on adverse developmental outcomes are not fully understood. The placental DNA methylation is strongly influenced by prenatal environmental factors and has been linked to fetal growth.
To evaluate the association between in utero PBDEs exposure, placental DNA methylation changes (growth regulatory genes), and pathophysiology of fetal growth (birth outcomes, fetal growth retardation) in a population-based pregnancy cohort study.
This was a nested case-control study within the prospective Wenzhou Birth Cohort including 130 fetal growth retardation (FGR) cases and 130 healthy controls and their mothers recruited from June 2016 to June 2017. FGR was diagnosed based on the comprehensive evaluation of ultrasound results at 24, 28, and 32 weeks of gestation. Neonatal birth measurements were obtained from medical records. Gestational exposure to 19 PBDEs, including 13 lower BDE congeners (BDE-17-190) and 6 higher brominated BDE congeners (BDE-196-209), were determined by gas chromatography tandem mass spectrometry in the umbilical cord blood. Placental DNA methylation changes of one repetitive element (LINE1) and two candidate genes (HSD11B2, IGF2) were characterized by quantitative polymerase chain reaction-pyrosequencing. Multiple linear regression and logistic regression models were used to examine the associations among PBDEs exposure, fetal growth indicators, and DMR (differential methylation region) methylation fractions. Sobel tests were conducted to assess DNA methylation as a mediator in multivariate models.
After excluding women who withdrew from the study or were lost to follow-up or failed to provide placenta or umbilical cord blood, 249 mother-newborn pairs (124 FGR cases, 125 controls) were included in the final analysis. Elevated BDE-206 (OR: 1.569, 95% CIs: 1.053-2.338), BDE-17-190 (OR: 2.860, 95% CIs: 1.233-6.634), BDE-196-209 (OR: 1.688, 95% CIs: 1.024-2.783) and ∑PBDEs (OR: 2.387, 95% CIs: 1.220-4.668) concentrations were associated with increased risk of FGR in newborns. FGR birth was also associated with increased DNA methylation of HSD11B2 (OR: 1.145, 95% CIs: 1.032-1.270) and decreased DNA methylation of IGF2 (OR: 0.892, 95% CIs: 0.845-0.941). In addition, BDE-17-190 showed significant associations with DNA methylation of HSD11B2 and IGF2 (β: 1.127, 95% CIs: 0.069-2.186; β: -3.452, 95% CIs: -5.512-1.392), indicating placental DNA methylation changes of HSD11B2 and IGF2 were related to both lower BDE congeners exposure and fetal growth. Further mediation analyses showed that IGF2 methylation mediated about 40% of the effects of BDE-17-190 in umbilical cord blood on neonatal FGR.
We report an inverse association between in utero exposures to PBDEs and fetal growth and provide evidence supporting epigenetic gene plasticity in these associations. Changes in placental DNA methylation might be part of the underlying biological pathway between prenatal PBDEs exposure and adverse fetal growth.
多溴联苯醚（PBDEs）是对妊娠有害的环境化学物质，但它们对不良发育结果的影响尚不完全清楚。胎盘的 DNA 甲基化强烈受产前环境因素的影响，并与胎儿生长有关。
在一项基于人群的妊娠队列研究中，评估宫内 PBDEs 暴露、胎盘 DNA 甲基化变化（生长调节基因）与胎儿生长（出生结局、胎儿生长迟缓）的病理生理学之间的关系。
这是温州出生队列前瞻性研究中的一个嵌套病例对照研究，包括 130 例胎儿生长迟缓（FGR）病例和 130 例健康对照及其母亲，于 2016 年 6 月至 2017 年 6 月招募。根据 24、28 和 32 周妊娠超声结果的综合评估诊断 FGR。新生儿出生测量值从病历中获得。通过气相色谱串联质谱法在脐带血中测定 19 种 PBDEs（包括 13 种低溴代 BDE 同系物（BDE-17-190）和 6 种高溴代 BDE 同系物（BDE-196-209））的暴露情况。通过定量聚合酶链反应-焦磷酸测序法描述 LINE1 一个重复元件和 HSD11B2、IGF2 两个候选基因的胎盘 DNA 甲基化变化。采用多元线性回归和逻辑回归模型，研究 PBDEs 暴露、胎儿生长指标和 DMR（差异甲基化区）甲基化分数之间的关系。Sobel 检验用于评估多变量模型中的 DNA 甲基化作为中介。
在排除了退出研究或失访或未能提供胎盘或脐带血的女性后，共有 249 对母婴（124 例 FGR 病例，125 例对照）纳入最终分析。BDE-206（OR：1.569，95%CI：1.053-2.338）、BDE-17-190（OR：2.860，95%CI：1.233-6.634）、BDE-196-209（OR：1.688，95%CI：1.024-2.783）和∑PBDEs（OR：2.387，95%CI：1.220-4.668）浓度与新生儿 FGR 风险增加相关。FGR 分娩还与 HSD11B2 的 DNA 甲基化增加（OR：1.145，95%CI：1.032-1.270）和 IGF2 的 DNA 甲基化减少（OR：0.892，95%CI：0.845-0.941）相关。此外，BDE-17-190 与 HSD11B2 和 IGF2 的 DNA 甲基化均呈显著相关（β：1.127，95%CI：0.069-2.186；β：-3.452，95%CI：-5.512-1.392），表明 HSD11B2 和 IGF2 胎盘 DNA 甲基化变化与低溴代 BDE 同系物暴露和胎儿生长均有关。进一步的中介分析表明，脐带血中 BDE-17-190 与新生儿 FGR 之间的关联有大约 40%是通过 IGF2 甲基化介导的。
我们报告了宫内 PBDEs 暴露与胎儿生长之间的负相关关系，并提供了支持这些关联中表观遗传基因可塑性的证据。胎盘 DNA 甲基化的变化可能是产前 PBDEs 暴露与不良胎儿生长之间潜在的生物学途径的一部分。
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