Department of Physiology, University of Toronto, Toronto, ON, Canada.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
Transl Psychiatry. 2022 Mar 31;12(1):132. doi: 10.1038/s41398-022-01902-4.
Antenatal corticosteroids (ACS) are used to treat women at risk of preterm birth to improve neonatal survival. Though affected children may be at long-term risk of neurobehavioural disorders, the driving mechanisms remain unknown. Animal studies have shown that ACS exposure can lead to overlapping changes in DNA methylation between the blood and the brain, identifying gene pathways for neurodevelopment, which highlights the potential to examine peripheral blood as a surrogate for inaccessible human brain tissue. We hypothesized that differential methylation will be identified in blood of term-born neonates following ACS. Mother-infant dyads that received ACS were retrospectively identified through the Ontario Birth Study at Sinai Health Complex and matched to untreated controls for maternal age, BMI, parity and foetal sex (n = 14/group). Genome-wide methylation differences were examined at single-nucleotide resolution in DNA extracted from dried bloodspot cards using reduced representative bisulfite sequencing approaches. 505 differentially methylated CpG sites (DMCs) were identified, wherein 231 were hypermethylated and 274 were hypomethylated. These sites were annotated to 219 genes, of which USP48, SH3PXD2A, NTM, CAMK2N2, MAP6D1 were five of the top ten genes with known neurological function. Collectively, the set of hypermethylated genes were enriched for pathways of transcription regulation, while pathways of proteasome activity were enriched among the set of hypomethylated genes. This study is the first to identify DNA methylation changes in human neonatal blood following ACS. Understanding the epigenetic changes that occur in response to ACS will support future investigations to delineate the effects of prenatal glucocorticoid exposure on human development.
产前皮质类固醇（ACS）用于治疗有早产风险的妇女，以提高新生儿的存活率。尽管受影响的儿童可能长期存在神经行为障碍的风险，但驱动机制尚不清楚。动物研究表明，ACS 暴露会导致血液和大脑之间的 DNA 甲基化发生重叠变化，确定了神经发育的基因途径，这突出了将外周血作为无法触及的人脑组织替代物进行检查的潜力。我们假设 ACS 后足月出生的新生儿血液中会出现差异甲基化。通过 Sinai Health Complex 的安大略出生研究回顾性地确定了接受 ACS 的母婴对，并按母亲年龄、BMI、产次和胎儿性别与未接受治疗的对照组相匹配（每组 n=14）。使用减少的代表性亚硫酸氢盐测序方法，在从干血斑卡中提取的 DNA 上以单核苷酸分辨率检查全基因组甲基化差异。鉴定出 505 个差异甲基化 CpG 位点（DMC），其中 231 个呈高甲基化，274 个呈低甲基化。这些位点被注释到 219 个基因，其中 USP48、SH3PXD2A、NTM、CAMK2N2、MAP6D1 是具有已知神经功能的十大基因中的五个。总的来说，高甲基化基因集富集了转录调控途径，而低甲基化基因集富集了蛋白酶体活性途径。这项研究首次在 ACS 后人类新生儿血液中鉴定出 DNA 甲基化变化。了解 ACS 引起的表观遗传变化将支持未来的研究，以阐明产前糖皮质激素暴露对人类发育的影响。
