Regenerative Biology Laboratory, Morgridge Institute for Research, Madison, Wisconsin 53707.
Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin 53706.
Toxicol Sci. 2017 Sep 1;159(1):251-265. doi: 10.1093/toxsci/kfx129.
Lead (Pb) is a well-known toxicant, especially for the developing nervous system, albeit the mechanism is largely unknown. In this study, we use time series RNA-seq to conduct a genome-wide survey of the transcriptome response of human embryonic stem cell-derived neural progenitor cells to lead treatment. Using a dynamic time warping algorithm coupled with statistical tests, we find that lead can either accelerate or decelerate the expression of specific genes during the time series. We further show that lead disrupts a neuron- and brain-specific splicing factor NOVA1 regulated splicing network. Using lead induced transcriptome change signatures, we predict several known and novel disease risks under lead exposure. The findings in this study will allow a better understanding of the mechanism of lead toxicity, facilitate the development of diagnostic biomarkers and treatment for lead exposure, and comprise a highly valuable resource for environmental toxicology. Our study also demonstrates that a human (embryonic stem) cell-derived system can be used for studying the mechanism of toxicants, which can be useful for drug or compound toxicity screens and safety assessment.
铅（Pb）是一种众所周知的有毒物质，尤其是对发育中的神经系统，尽管其机制在很大程度上尚不清楚。在这项研究中，我们使用时间序列 RNA-seq 对人胚胎干细胞衍生的神经祖细胞对铅处理的转录组反应进行全基因组调查。我们使用动态时间 warping 算法结合统计检验，发现铅可以在时间序列中加速或减速特定基因的表达。我们进一步表明，铅会破坏神经元和大脑特异性剪接因子 NOVA1 调节的剪接网络。我们使用铅诱导的转录组变化特征来预测在铅暴露下的几种已知和新的疾病风险。本研究的结果将有助于更好地了解铅毒性的机制，促进铅暴露的诊断生物标志物和治疗方法的开发，并为环境毒理学提供一个非常有价值的资源。我们的研究还表明，人类（胚胎干细胞）衍生系统可用于研究有毒物质的机制，这对于药物或化合物毒性筛选和安全性评估可能是有用的。
