Department of Biology, Western University, 1151 Richmond St, London, Ontario, N6A 5B7, Canada.
McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD, 21205, USA.
J Neurodev Disord. 2020 May 16;12(1):15. doi: 10.1186/s11689-020-09316-3.
Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the USA and Canada. Children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood.
We model FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We use RNA-seq followed by clustering of expression profiles through weighted gene co-expression network analysis (WGCNA) to analyze transcriptomic changes that result from the treatments. We use reverse transcription qPCR to validate these changes in the mouse hippocampus.
We report an association between adult hippocampal gene expression and prenatal ethanol exposure followed by postnatal separation stress that is related to behavioral changes. Expression profile clustering using WGCNA identifies a set of transcripts, module 19, associated with anxiety-like behavior (r = 0.79, p = 0.002) as well as treatment group (r = 0.68, p = 0.015). Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation (q = 2e-12, p = 0.004, respectively).
Together, transcriptional control in the hippocampus is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.
胎儿酒精谱系障碍（FASD）在美国和加拿大的人群中较为常见，发病率为 1-5%。被诊断为 FASD 的儿童不太可能与亲生父母在一起，他们在童年时期会经历早期母婴分离和寄养安置。
我们通过产前酒精暴露在小鼠中模拟 FASD，并通过母婴分离进一步诱导早期生活压力。我们使用 RNA-seq 进行分析，然后通过加权基因共表达网络分析（WGCNA）对表达谱进行聚类，以分析由这些处理引起的转录组变化。我们使用逆转录 qPCR 在小鼠海马体中验证这些变化。
我们报告了成年海马体基因表达与产前乙醇暴露后再加上产后分离应激之间的关联，这种关联与行为变化有关。使用 WGCNA 进行表达谱聚类，确定了一组与焦虑样行为相关的转录本，模块 19（r = 0.79，p = 0.002）以及与处理组相关的转录本，模块 19（r = 0.68，p = 0.015）。该模块中的基因与转录调控和其他与神经发育相关的途径有关的基因重叠。有趣的是，该模块的一个成员，Polr2a，聚合酶（RNA）II（DNA 指导）多肽 A，在产前乙醇和产后应激的组合下在 RNA-Seq 实验和 qPCR 验证中下调（q = 2e-12，p = 0.004）。
总的来说，海马体中的转录控制被认为是一种潜在的潜在机制，通过环境损伤导致焦虑样行为。需要进一步的研究来阐明所涉及的机制，并利用这一认识来制定针对出生时患有 FASD 的儿童的早期诊断和改善策略。
