Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Rd., Nanjing, Jiangsu, 210023, China.
Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Rd., Nanjing, Jiangsu, 210023, China.
Chemosphere. 2022 Dec;308(Pt 2):136343. doi: 10.1016/j.chemosphere.2022.136343. Epub 2022 Sep 7.
Cytotoxicity of non-polar narcotic chemicals can be predicted by quantitative structure activity relationship (QSAR) models, but the polar narcotic chemicals' actual cytotoxicity exceeds the predicted values by their chemical structures. This discrepancy indicates that the molecular mechanism by which polar narcotic chemicals exert their toxicity is unclear. Taking advantage of Saccharomyces cerevisiae (yeast) functional genome-wide heterozygous essential gene knockout mutants, we here have identified the specific molecular fingerprints of two main chemical structure groups (phenols and anilines) of polar narcotic chemicals (dichlorophen (DCP), 4-chlorophenol (4-CP), 2, 4, 6-trichlorophenol (TCP), 3, 4-dichloroaniline (DCA) and N-methylaniline (NMA)) and one non-polar narcotic chemical 2, 2, 2-trichloroethanol (TCE). Especially, we identify 33, 57, 54, 46, 59 and 53 responsive strains through exposure to TCE, DCP, 4-CP, TCP, DCA and NMA with three test concentrations, respectively, revealing that these polar narcotic chemicals have more responsive strains than the non-polar narcotic chemical. Remarkably, we find that the molecular fingerprints of polar narcotic chemicals in different chemical structure groups are obviously varied, particularly phenols and anilines have their own specific molecular fingerprints. Interestingly, our results demonstrate that the molecular toxicity mechanisms of anilines are associated with DNA replication, but phenols are related with pathway of RNA degradation. Additionally, we find that the two knockout strains (SME1 and DIS3) and the three knockout strains (TSC11, RSP5 and HSF1) can specifically respond to exposure to phenols and anilines, respectively. Thus, they may be served as potential biomarkers to distinguish phenols from anilines. Collectively, our works demonstrate that the functional genomic platform of yeast essential gene mutants can not only act as an effective tool to identify key specific molecular fingerprints for polar narcotic chemicals, but also help to understand the molecular mechanisms of polar narcotic chemicals.
非极性麻醉化学品的细胞毒性可以通过定量构效关系（QSAR）模型来预测，但极性麻醉化学品的实际细胞毒性超过了其化学结构的预测值。这种差异表明，极性麻醉化学品发挥毒性的分子机制尚不清楚。利用酿酒酵母（酵母）功能基因组全杂合必需基因敲除突变体，我们在这里确定了极性麻醉化学品（二氯苯（DCP）、4-氯苯酚（4-CP）、2,4,6-三氯苯酚（TCP）、3,4-二氯苯胺（DCA）和 N-甲基苯胺（NMA））和一种非极性麻醉化学品 2,2,2-三氯乙醇（TCE）的两种主要化学结构基团（酚类和苯胺类）的特定分子指纹。特别是，我们通过分别暴露于 TCE、DCP、4-CP、TCP、DCA 和 NMA 的三种测试浓度，鉴定了 33、57、54、46、59 和 53 个响应株，表明这些极性麻醉化学品比非极性麻醉化学品具有更多的响应株。值得注意的是，我们发现不同化学结构基团的极性麻醉化学品的分子指纹明显不同，特别是酚类和苯胺类具有各自特定的分子指纹。有趣的是，我们的结果表明苯胺类的分子毒性机制与 DNA 复制有关，而酚类与 RNA 降解途径有关。此外，我们发现两个敲除株（SME1 和 DIS3）和三个敲除株（TSC11、RSP5 和 HSF1）分别可以特异性地响应暴露于酚类和苯胺类。因此，它们可能被用作区分酚类和苯胺类的潜在生物标志物。总之，我们的工作表明，酵母必需基因突变体的功能基因组平台不仅可以作为识别极性麻醉化学品关键特定分子指纹的有效工具，还可以帮助理解极性麻醉化学品的分子机制。
