BC Children's Hospital Research Institute (BCCHR), 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Sci Rep. 2022 Dec 30;12(1):22576. doi: 10.1038/s41598-022-26071-8.
Selective serotonin reuptake inhibitors (SSRIs) for treatment of prenatal maternal depression have been associated with neonatal neurobehavioral disturbances, though the molecular mechanisms remain poorly understood. In utero exposure to SSRIs may affect DNA methylation (DNAme) in the human placenta, an epigenetic mark that is established during development and is associated with gene expression. Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip; clinical assessments of maternal mood and SSRI treatment records were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression was defined using a mean maternal Hamilton Depression score > 8 to indicate symptomatic depressed mood ("maternally-depressed"), and we further classified cases into SSRI-exposed, maternally-depressed (n = 14); SSRI-exposed, not maternally-depressed (n = 6); SSRI non-exposed, maternally-depressed (n = 20); and SSRI non-exposed, not maternally-depressed (n = 24). For replication, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n = 17 SSRI-exposed, n = 17 SSRI non-exposed). No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, in a model adjusted for mean maternal Hamilton Depression score, or in a model restricted to maternally-depressed cases with and without SSRI exposure. However, at a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four were covered by the replication cohort measured by the 450K array, but none replicated. No CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n = 31; males n = 33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment, as compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively-recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.
选择性 5-羟色胺再摄取抑制剂（SSRIs）用于治疗产前产妇抑郁症与新生儿神经行为障碍有关，尽管其分子机制仍知之甚少。宫内暴露于 SSRIs 可能会影响人类胎盘的 DNA 甲基化（DNAme），这是一种在发育过程中建立的表观遗传标记，与基因表达有关。从 64 个人类胎盘中提取绒毛膜绒毛样本，并使用 Illumina MethylationEPIC BeadChip 进行分析；在妊娠期间的多个时间点收集了对产妇情绪的临床评估和 SSRI 治疗记录。病例分布为 20 例 SSRI 暴露病例和 44 例 SSRI 未暴露病例。使用平均产妇汉密尔顿抑郁评分 > 8 来定义产妇抑郁，以表示有症状的抑郁情绪（“产妇抑郁”），我们进一步将病例分为 SSRI 暴露、产妇抑郁（n = 14）；SSRI 暴露，无产妇抑郁（n = 6）；SSRI 未暴露，产妇抑郁（n = 20）；和 SSRI 未暴露，无产妇抑郁（n = 24）。为了进行复制，从另一个独立队列中获得了 34 例额外病例的 Illumina 450K DNAme 图谱（n = 17 例 SSRI 暴露，n = 17 例 SSRI 未暴露）。在调整了平均产妇汉密尔顿抑郁评分的模型中，或在仅包括有和没有 SSRI 暴露的产妇抑郁病例的模型中，SSRI 暴露与未暴露的胎盘之间没有 CpG 差异甲基化（FDR < 0.05）。然而，在放宽 FDR < 0.25 的阈值下，有五个 CpG 差异甲基化（|Δβ| > 0.03）与 SSRI 暴露状态有关。其中四个由复制队列中的 450K 阵列测量，但没有一个得到复制。与没有抑郁的病例相比，产妇抑郁病例之间没有 CpG 差异甲基化（FDR < 0.25）。在 SSRI 暴露与未暴露病例的性别分层分析中（女性 n = 31；男性 n = 33），在放宽的 FDR < 0.25 截止值下，女性有三个额外的 CpG 差异甲基化，但男性没有。与没有 SSRI 暴露的胎盘相比，我们没有观察到母体 SSRI 治疗暴露的胎盘 DNAme 的大规模改变。我们也没有发现母体抑郁暴露与非抑郁暴露的胎盘 DNAme 改变的证据。这项在前瞻性招募的队列中进行的新工作，具有临床医生确定的 SSRI 暴露和情绪评估，将受益于未来的复制。
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