Toxicogenomics of the flame retardant tris (2-butoxyethyl) phosphate in HepG2 cells using RNA-seq
Toxicogenomics of the flame retardant tris (2-butoxyethyl) phosphate in HepG2 cells using RNA-seq
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DOI：
10.1016/j.tiv.2017.10.011
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发表时间：
2018-02-01
影响因子：
3.2
通讯作者：
Husson, Steven J.
中科院分区：
文献类型：
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作者：
Krivoshiev, Boris V.;Beemster, Gerrit T. S.;Husson, Steven J.
三(2-丁氧基乙基)磷酸(TBOEP)是一种大量生产的化合物，既可用作阻燃剂，又可用作增塑剂。它具有持久性和生物蓄积性，但对其毒理作用模式知之甚少。这种洞察力可能有助于在补充现有检测策略的证据权重方法中进行风险评估。我们使用RNA测序方法作为一种公正和灵敏的工具来探索亚细胞毒性浓度的TBOEP对人肝细胞癌细胞系HepG2转录组的潜在负面健康影响，所使用的最低浓度可能与人类生理水平相关。过度表达和基因集浓缩分析符合得很好，表明TBOEP处理导致与蛋白质和能量代谢相关的基因上调，以及DNA复制。细胞和大分子代谢的这种增加可以解释较低的TBOEP浓度下线粒体活性的增加。此外，TBOEP还影响了多种生物过程，其中最显著的是一般应激反应，即伤口愈合。最后，TBOEP显示了类固醇激素的生物合成以及免疫反应的激活、调节和增强，这与其他研究一致。因此，这项研究是第一次研究人类细胞中对TBOEP反应的全基因组范围内基因转录的变化。
Tris (2-butoxyethyl) phosphate (TBOEP) is a compound produced at high volume that is used as both a flame retardant and a plasticizer. It is persistent and bioaccumulative, yet little is known of its toxicological modes of action. Such insight may aid risk assessment in a weight-of-evidence approach supplementing current testing strategies. We used an RNA sequencing approach as an unbiased and sensitive tool to explore potential negative health effects of sub-cytotoxic concentrations of TBOEP on the transcriptome of the human liver hepatocellular carcinoma cell line, HepG2, with the lowest concentration used potentially holding relevance to human physiological levels. Over-representation and gene set enrichment analysis corresponded well and revealed that TBOEP treatments resulted in an upregulation of genes involved in protein and energy metabolism, along with DNA replication. Such increases in cell and macromolecule metabolism could explain the increase in mitochondrial activity at lower TBOEP concentrations. In addition, TBOEP affected a wide variety of biological processes, the most notable one being the general stress response, wound healing. Finally, TBOEP showed effects on steroid hormone biosynthesis and activation, regulation, and potentiation of immune responses, in agreement with other studies. As such, this study is the first study investigating genome-wide changes in gene transcription in response to TBOEP in human cells.