Prenatal antidepressant exposure associated with CYP2E1 DNA methylation change in neonates
Prenatal antidepressant exposure associated with CYP2E1 DNA methylation change in neonates
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DOI：
10.1080/15592294.2015.1026031
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发表时间：
2015-05-04
期刊：
影响因子：
3.7
通讯作者：
Hensch, Takao K.
中科院分区：
文献类型：
--
作者：
Gurnot, Cecile;Martin-Subero, Ignacio;Hensch, Takao K.
一些但并非全部新生儿会受到产前接触血清素再摄取抑制剂抗抑郁药 (SRI) 和母亲情绪障碍的影响。区分这两种暴露的影响具有挑战性，并提出了药理学、遗传或表观遗传因素是否可以解释所报告结果的范围的关键问题。使用无偏差的 DNA 甲基化阵列测量和详细的候选基因方法，我们检查了产前 SRI 暴露是否与新生儿 DNA 甲基化变化相关，以及这些变化是否与出生结果的差异相关。产前 SRI 暴露首先与主要在 CYP2E1 处的 DNA 甲基化状态增加相关（β（未暴露）= 0.06，β（SRI 暴露）= 0.30，FDR = 0）；然而，这一发现无法与产前母亲抑郁情绪的潜在影响区分开来。然后，在扩大的队列中对 CYP2E1 调节区进行焦磷酸测序，发现较高的 DNA 甲基化状态（16 个 CpG 位点的平均值 (P < 0.01) 和每个特定 CpG 位点的平均值 (P < 0.05)）仅在 SRI 暴露的新生儿中与妊娠第三个月较低的母亲抑郁情绪症状相关，这表明母亲情绪与 SRI 暴露存在相互作用。此外，在被检测的 CYP2E1 区域中，CpG2 (P = 0.04)、CpG9 (P = 0.04) 和 CpG10 (P = 0.02) 的 DNA 甲基化水平较高，与出生体重增加相关，与产前母亲情绪、SRI 药物暴露或出生时孕龄无关。产前 SRI 抗抑郁药物暴露和母亲抑郁情绪与新生儿 CYP2E1 DNA 甲基化状态的改变有关，而这反过来又似乎与出生体重有关。
Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these 2 exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(beta(Non-exposed) = 0.06, beta(SRI-exposed) = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status-both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05)-was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 DNA methylation status, which, in turn, appeared to be associated with birth weight.