Departments of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan.
Clin Epigenetics. 2021 Apr 7;13(1):74. doi: 10.1186/s13148-021-01063-z.
Prenatal smoking exposure has been associated with childhood attention-deficit/hyperactivity disorder (ADHD). However, the mechanism underlying this relationship remains unclear. We assessed whether DNA methylation differences may mediate the association between prenatal smoking exposure and ADHD symptoms at the age of 6 years.
We selected 1150 mother-infant pairs from the Hokkaido Study on the Environment and Children's Health. Mothers were categorized into three groups according to plasma cotinine levels at the third trimester: non-smokers (≤ 0.21 ng/mL), passive smokers (0.21-11.48 ng/mL), and active smokers (≥ 11.49 ng/mL). The children's ADHD symptoms were determined by the ADHD-Rating Scale at the age of 6 years. Maternal active smoking during pregnancy was significantly associated with an increased risk of ADHD symptoms (odds ratio, 1.89; 95% confidence interval, 1.14-3.15) compared to non-smoking after adjusting for covariates. DNA methylation of the growth factor-independent 1 transcriptional repressor (GFI1) region, as determined by bisulfite next-generation sequencing of cord blood samples, mediated 48.4% of the total effect of the association between maternal active smoking during pregnancy and ADHD symptoms. DNA methylation patterns of other genes (aryl-hydrocarbon receptor repressor [AHRR], cytochrome P450 family 1 subfamily A member 1 [CYP1A1], estrogen receptor 1 [ESR1], and myosin IG [MYO1G]) regions did not exert a statistically significant mediation effect.
Our findings demonstrated that DNA methylation of GFI1 mediated the association between maternal active smoking during pregnancy and ADHD symptoms at the age of 6 years.
产前吸烟暴露与儿童注意缺陷多动障碍（ADHD）有关。然而，这种关系的机制尚不清楚。我们评估了 DNA 甲基化差异是否可能介导产前吸烟暴露与 6 岁时 ADHD 症状之间的关联。
我们从北海道环境与儿童健康研究中选择了 1150 对母婴对。根据妊娠晚期血浆可替宁水平，母亲被分为三组：不吸烟者（≤0.21ng/mL）、被动吸烟者（0.21-11.48ng/mL）和主动吸烟者（≥11.49ng/mL）。6 岁时通过 ADHD-Rating Scale 确定儿童的 ADHD 症状。与不吸烟相比，母亲在怀孕期间主动吸烟与 ADHD 症状的风险增加显著相关（优势比，1.89；95%置信区间，1.14-3.15），调整了协变量后。通过对脐带血样本进行亚硫酸氢盐下一代测序，确定生长因子独立 1 转录抑制因子（GFI1）区域的 DNA 甲基化，介导了母亲在怀孕期间主动吸烟与 ADHD 症状之间关联的总效应的 48.4%。其他基因（芳香烃受体抑制剂 [AHRR]、细胞色素 P450 家族 1 亚家族 A 成员 1 [CYP1A1]、雌激素受体 1 [ESR1]和肌球蛋白 IG [MYO1G]）区域的 DNA 甲基化模式没有产生统计学上显著的中介效应。
我们的研究结果表明，GFI1 的 DNA 甲基化介导了母亲在怀孕期间主动吸烟与 6 岁时 ADHD 症状之间的关联。
