State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China.
Collaborative Innovation Center for Regional Environmental Quality, China.
Sci Rep. 2016 Sep 20;6:33718. doi: 10.1038/srep33718.
Previous studies have identified a phenomenon in which the concentration-response curves (CRCs) for mixtures cross the curves for concentration addition model when predicting or judging joint toxic actions. However, mechanistic investigations of this phenomenon are extremely limited. In this study, a similar phenomenon was observed when we determined the joint toxic actions of sulfonamides (SAs) and erythromycin (ERY) on Escherichia coli (E. coli), which we named the "cross-phenomenon", and it was characterized by antagonism in the low-concentration range, addition in the medium-concentration range, and synergism in the high-concentration range. The mechanistic investigation of the cross-phenomenon was as follows: SAs and ERY could form a double block to inhibit the bacterial growth by exhibiting a synergistic effect; however, the hormetic effect of SAs on E. coli led to antagonism in the low-concentration range, resulting from the stimulation of sdiA mRNA expression by SAs, which increased the expression of the efflux pump (AcrAB-TolC) to discharge ERY. Furthermore, this cross-phenomenon was observed to be a time-dependent process induced by the increase of both the concentration and extent of stimulation of sdiA mRNA with exposure time. This work explains the dose-dependent and time-dependent cross-phenomenon and provides evidence regarding the interaction between hormesis and cross-phenomenon.
先前的研究已经发现了一种现象，即在预测或判断混合物的联合毒性作用时，混合物的浓度-反应曲线 (CRC) 会与浓度加和模型的曲线交叉。然而，对这种现象的机制研究非常有限。在本研究中，当我们确定磺胺类药物 (SAs) 和红霉素 (ERY) 对大肠杆菌 (E. coli) 的联合毒性作用时，观察到了类似的现象，我们将其命名为“交叉现象”，其特征是在低浓度范围内拮抗，在中浓度范围内加和，在高浓度范围内协同。对交叉现象的机制研究如下：SAs 和 ERY 可以通过协同作用形成双重阻断来抑制细菌生长；然而，SAs 对 E. coli 的兴奋效应导致在低浓度范围内拮抗，这是由于 SAs 刺激 sdiA mRNA 的表达，增加了外排泵 (AcrAB-TolC) 的表达，从而排出 ERY。此外，这种交叉现象被观察到是一个随着暴露时间的增加而由 sdiA mRNA 的浓度和刺激程度增加引起的时间依赖性过程。这项工作解释了剂量依赖性和时间依赖性的交叉现象，并提供了关于兴奋效应和交叉现象之间相互作用的证据。
