Chem Res Toxicol. 2019 Oct 21;32(10):2078-2085. doi: 10.1021/acs.chemrestox.9b00249. Epub 2019 Sep 6.
Hexavalent chromium [Cr(VI)] compounds that are generated during industrial processes are widely recognized as highly toxic and carcinogenic. It has been reported that exposure to Cr(VI) can produce some chromium intermediates and reactive oxygen species (ROS), which causes DNA damages, genetic instability, and eventually leads to the elevated risk of various diseases including cancers. In recent years, it has been proposed that epigenetic-based mechanisms may involve in the toxic heavy metals-induced cytotoxicity and mutagenicity besides the genetic-based mechanisms. However, whether Cr(VI) could impose its cytotoxic effect through dysregulating the RNA epigenetic modifications remains poorly defined. We systematically investigated the effects of Cr(VI) exposure on 14 kinds of modifications in mRNA of HEK293T cells. We found that Cr(VI) exposure can induce an obvious decrease of inosine in mRNA. In addition, we observed that the expression level of the adenosine deaminase acting on RNA (ADAR1) was significantly decreased upon Cr(VI) exposure, which could be responsible for the induced decrease of inosine in mRNA by Cr(VI) exposure. Together, we demonstrated that Cr(VI) could interrupt A-to-I RNA editing in mRNA, which may eventually lead to the cytotoxicity and mutagenicity.
六价铬[Cr(VI)]化合物在工业过程中产生，被广泛认为是高度有毒和致癌的。据报道，接触 Cr(VI)会产生一些铬中间体和活性氧物种(ROS)，导致 DNA 损伤、遗传不稳定性，最终导致各种疾病（包括癌症）的风险增加。近年来，人们提出，除了遗传机制外，基于表观遗传的机制可能参与了毒性重金属诱导的细胞毒性和致突变性。然而，Cr(VI)是否可以通过调节 RNA 表观遗传修饰来发挥其细胞毒性作用仍未得到明确界定。我们系统地研究了 Cr(VI)暴露对 HEK293T 细胞中 14 种 mRNA 修饰的影响。我们发现，Cr(VI)暴露可诱导 mRNA 中肌苷明显减少。此外，我们观察到 Cr(VI)暴露后腺苷脱氨酶作用于 RNA（ADAR1）的表达水平显著下降，这可能是 Cr(VI)暴露诱导 mRNA 中肌苷减少的原因。总之，我们证明了 Cr(VI)可以中断 mRNA 中的 A-to-I RNA 编辑，这可能最终导致细胞毒性和致突变性。
