School of Public Health, Xinxiang Medical University, Xinxiang, People's Republic of China.
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
Hum Exp Toxicol. 2020 May;39(5):748-761. doi: 10.1177/0960327119899996. Epub 2020 Jan 21.
2,3,7,8-Tetrachlorodibenzo--dioxin (TCDD) is a ubiquitous environmental pollutant and also a strong teratogen for cleft palate (CP). But up to now, the underlying molecular mechanisms of TCDD-induced CP are largely unknown. More recently, accumulating evidences are revealing important roles of long noncoding RNAs (lncRNAs) in all kinds of diseases including CP. However, the role and molecular mechanism of lncRNAs in TCDD-induced CP are still largely unexplored. Thus, identification of differentially expressed lncRNA (DEL) might help figuring out the mechanism of CP induced by TCDD. In this study, a CP offspring model of C57BL/6 female mice was generated by TCDD (64 µg/kg body weight) induce on embryo day 10 (E10). The incidence rate of CP was 100% in the TCDD group (105) after cervical dislocation on E16. Then, the high-throughput RNA sequencing (RNA-seq) was established to search a comprehensive profile of the lncRNAs. In addition, a coexpression network of lncRNA and messenger RNA (mRNA) was performed to discern potential mechanism. The result showed that 26,246 novel lncRNAs and 9635 known lncRNAs were screened out, and 413 lncRNA transcripts and 65 mRNA transcripts were identified as being significantly different between the CP group and control group. Notably, we found that there are seven lncRNAs that can target Smad1 and Smad5, which are key molecules of bone morphogenetic protein (BMP) signaling pathway, which suggested that they may be concerned with BMP signaling in TCDD-induced CP. In addition, some lncRNAs targeted the important molecules of Hippo and Wnt signaling pathways. These results suggested that characteristic lncRNA alterations may play a critical role in TCDD-induced CP, which provided a theoretical basis for further research.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种普遍存在的环境污染物，也是腭裂（CP）的强致畸物。但到目前为止，TCDD 诱导 CP 的潜在分子机制在很大程度上尚不清楚。最近，越来越多的证据表明，长非编码 RNA（lncRNA）在包括 CP 在内的各种疾病中发挥着重要作用。然而，lncRNA 在 TCDD 诱导 CP 中的作用和分子机制在很大程度上仍未得到探索。因此，鉴定差异表达的 lncRNA（DEL）可能有助于阐明 TCDD 诱导 CP 的机制。在这项研究中，通过 TCDD（64μg/kg 体重）诱导胚胎第 10 天（E10），建立了 C57BL/6 雌性小鼠 CP 后代模型。E16 时经颈椎脱位，TCDD 组（105 只）CP 的发生率为 100%。然后，建立了高通量 RNA 测序（RNA-seq）来搜索 lncRNA 的综合图谱。此外，进行了 lncRNA 和信使 RNA（mRNA）的共表达网络分析，以辨别潜在的机制。结果表明，筛选出 26246 个新的 lncRNA 和 9635 个已知的 lncRNA，CP 组和对照组之间有 413 个 lncRNA 转录本和 65 个 mRNA 转录本被鉴定为差异显著。值得注意的是，我们发现有 7 个 lncRNA 可以靶向骨形态发生蛋白（BMP）信号通路的关键分子 Smad1 和 Smad5，这表明它们可能与 TCDD 诱导的 CP 中的 BMP 信号有关。此外，一些 lncRNA 靶向 Hippo 和 Wnt 信号通路的重要分子。这些结果表明，特征性 lncRNA 改变可能在 TCDD 诱导的 CP 中发挥关键作用，为进一步研究提供了理论依据。
