State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University , Nanjing 210089, People's Republic of China.
Environ Sci Technol. 2014 May 20;48(10):5929-37. doi: 10.1021/es5003023. Epub 2014 May 5.
Results of previous studies have indicated that 6-HO-BDE-47, the addition of the hydroxyl (HO) group to the backbone of BDE-47, significantly increased the toxicity of the chemical compared to its postulated precursor analogues, BDE-47 and 6-MeO-BDE-47. However, whether such a result is conserved across polybrominated diphenyl ether (PBDE) congeners was unknown. Here, cytotoxicity of 32 PBDE analogues (17 HO-PBDEs and 15 MeO-PBDEs) was further tested and the underlying molecular mechanism was investigated. A total of 14 of the 17 HO-PBDEs inhibited growth of Escherichia coli during 4 or 24 h durations of exposure, but none of the MeO-PBDEs was cytotoxic at the concentrations tested. 6-HO-BDE-47 and 2-HO-BDE-28 were most potent with 4 h median effect concentrations (EC50) of 12.13 and 6.25 mg/L, respectively, which trended to be lesser with a longer exposure time (24 h). Expression of 30 modulated and validated genes by 6-HO-BDE-47 in a previous study was also observed after exposure to other HO-PBDE analogues. For instance, uhpT was upregulated by 13 HO-PBDEs, and three rRNA operons (rrnA, rrnB, and rrnC) were downregulated by 8 HO-PBDEs. These unanimous responses suggested a potential common molecular signaling modulated by HO-PBDEs. To explore new information on mechanisms of action, this work was extended by testing the increased susceptibility of 182 mutations of transcriptional factors (TFs) and 22 mutations as genes modulated by 6-HO-BDE-47 after exposure to 6-HO-BDE-47 at the 4 h IC50 concentration. Although a unanimous upregulation of uhpT was observed after exposure to HO-PBDEs, no significant shift in sensitivity was observed in uhpT-defective mutants. The 54 genes, selected by cut-offs of 0.35 and 0.65, were determined to be responsible for "organic acid/oxoacid/carboxylic acid metabolic process" pathways, which supported a previous finding.
先前的研究结果表明，6-羟基-BDE-47（BDE-47 主链上加羟基（HO）基团）与推测的前体类似物 BDE-47 和 6-MeO-BDE-47 相比，显著增加了该化学物质的毒性。然而，这种结果是否在多溴二苯醚（PBDE）同系物中得到保留尚不清楚。在这里，进一步测试了 32 种 PBDE 类似物（17 种 HO-PBDEs 和 15 种 MeO-PBDEs）的细胞毒性，并研究了潜在的分子机制。在 4 小时或 24 小时的暴露期间，17 种 HO-PBDEs 中有 14 种抑制了大肠杆菌的生长，但在测试浓度下，没有一种 MeO-PBDEs 具有细胞毒性。6-羟基-BDE-47 和 2-羟基-BDE-28 的效力最强，4 小时半数效应浓度（EC50）分别为 12.13 和 6.25mg/L，随着暴露时间的延长（24 小时），其趋势略有下降。先前研究中 6-羟基-BDE-47 表达的 30 个调节和验证基因在暴露于其他 HO-PBDE 类似物后也被观察到。例如，13 种 HO-PBDEs 上调了 uh pT，而 8 种 HO-PBDEs 下调了三个 rRNA 操纵子（rrnA、rrnB 和 rrnC）。这些一致的反应表明，HO-PBDEs 可能存在潜在的共同分子信号转导。为了探索作用机制的新信息，这项工作通过测试在 4 小时 IC50 浓度下暴露于 6-羟基-BDE-47 后，182 种转录因子（TFs）突变和 22 种作为 6-羟基-BDE-47 调节基因的突变对 182 种突变的敏感性增加，从而得到扩展。尽管暴露于 HO-PBDEs 后观察到 uh pT 的一致上调，但在 uh pT 缺陷突变体中未观察到敏感性显著变化。通过 0.35 和 0.65 的截止值选择的 54 个基因被确定为负责“有机酸/氧化酸/羧酸代谢过程”途径的基因，这支持了先前的发现。
