BACKGROUND Fetal epigenetic programming plays a critical role in development. DNA methyltransferase 3 alpha (DNMT3A), which is involved in de novo DNA methylation (DNAm), is a prime candidate gene as a mediator between prenatal exposures and birth outcomes. We evaluated the relationships between in utero arsenic (As) exposure, birth outcomes, and DNMT3A DNAm. METHODS In a prospective Bangladeshi birth cohort, cord blood DNAm of three DNMT3A CpGs was measured using bisulfite pyrosequencing. Maternal toenail As concentrations at birth were measured to estimate in utero exposure. Among vaginal births (N = 413), structural equation models (SEMs) were used to evaluate relationships between DNMT3A methylation, log2 (toenail As), birth weight, and gestational age. RESULTS In an adjusted SEM including birth weight and gestational age, maternal toenail As levels were associated with DNMT3A DNAm (B = 0.40; 95% CI: 0.15, 0.66) and gestational age (B = -0.19 weeks; 95% CI: 0.36, -0.03). DNMT3A DNAm was associated with gestational age (B = -0.10 weeks; 95% CI: 0.16, -0.04) and birth weight (B = -11.0 g; 95% CI: 21.5, 0.4). There was an indirect effect of As on gestational age mediated through DNMT3A DNAm (B = -0.04; 95% CI: 0.08, -0.01), and there were indirect effects of maternal toenail As levels on birth weight through pathways including gestational age (B = -14.4 g; 95% CI: 29.2, -1.9), DNMT3A DNAm and gestational age (B = -3.1 g; 95% CI: 6.6, -0.8), and maternal weight gain and gestational age (B = -5.1 g; 95% CI: 9.6, -1.5). The total effect of a doubling in maternal toenail As concentration is a decrease in gestational age of 2.1 days (95% CI: 0.9, 3.3) and a decrease in birth weight of 29 g (95% CI: 14, 46). CONCLUSIONS DNMT3A plays a critical role in fetal epigenetic programming. In utero arsenic exposure was associated with greater methylation of CpGs in DNMT3A which partially mediated associations between prenatal As exposure and birth outcomes. Additional studies are needed to verify this finding.

中文翻译：

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DNMT3A的脐血DNA甲基化介导子宫内砷暴露与出生结局之间的关联：孟加拉国一个预期出生队列的结果。

背景技术胎儿表观遗传编程在发育中起关键作用。DNA甲基转移酶3α（DNMT3A）参与了从头DNA甲基化（DNAm），是一个重要的候选基因，可作为出生前暴露与出生结局之间的介体。我们评估了子宫内砷（As）暴露，出生结局与DNMT3A DNAm之间的关系。方法在一个预期的孟加拉国出生队列中，使用亚硫酸氢盐焦磷酸测序法测定了三个DNMT3A CpG的脐血DNAm。测量出生时母亲的趾甲As浓度以估计子宫内暴露。在阴道分娩中（N = 413），使用结构方程模型（SEM）评估DNMT3A甲基化，log2（趾甲As），出生体重和胎龄之间的关系。结果在调整后的SEM中（包括出生体重和胎龄），母体趾甲水平与DNMT3A DNAm（B = 0.40; 95％CI：0.15，0.66）和胎龄（B = -0.19周; 95％CI：0.36，-0.03）有关。DNMT3A DNAm与胎龄（B = -0.10周; 95％CI：0.16，-0.04）和出生体重（B = -11.0 g; 95％CI：21.5，0.4）相关。通过DNMT3A DNAm介导的砷对胎龄的间接影响（B = -0.04; 95％CI：0.08，-0.01），并且通过包括胎龄的途径，母体趾甲砷水平对出生体重的间接影响（B = -14.4 g； 95％CI：29.2，-1.9），DNMT3A DNAm和胎龄（B = -3.1 g； 95％CI：6.6，-0.8）以及孕妇体重增加和胎龄（B = -5.1 g） ； 95％CI：9.6，-1.5）。母体趾甲浓度增加一倍的总效果是使胎龄减少2.1天（95％CI：0.9、3）。3），出生体重下降了29 g（95％CI：14、46）。结论DNMT3A在胎儿表观遗传程序中起着至关重要的作用。子宫内砷暴露与DNMT3A中CpGs的更大甲基化有关，这部分介导了产前砷暴露与出生结局之间的关联。需要进一步的研究以验证这一发现。