Abstract
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.
Highlights
Indiscriminate use of chemicals and ineffective supervision have led to human beings to become exposed to an environment that contains complicated chemical mixtures rather than single chemicals, some of which seriously threatens human health and economic development[1,2]
When using the concentration addition (CA) model to predict or judge joint toxic action, some studies have found that the joint toxic action of several mixtures varied with the dose in a given organism[11,12,13,14,15], which is different from the results obtained using toxic indexes such as toxic unit (TU), because these toxic indexes only determine the joint toxic action of combined chemicals at a fixed concentration point that is always set at median effective concentration (EC50), indicating a fixed joint toxic action
Using molecular docking studies of the LuxR protein and sulfonamides (SAs), the hormetic effect of SAs on Photobacterium phosphoreum was investigated in our previous study, and the mechanistic hypothesis could be described briefly as follows: SAs at low concentrations could bind to the LuxR protein, and the resulting complexes promoted the expression of the LuxR protein[18]
Summary
Indiscriminate use of chemicals and ineffective supervision have led to human beings to become exposed to an environment that contains complicated chemical mixtures rather than single chemicals, some of which seriously threatens human health and economic development[1,2]. A similar phenomenon was observed in our preliminary experiment in which the CRCs for the joint effects of sulfachloropyridazine (SCP) and erythromycin (ERY) on Escherichia coli (E. coli) crossed the curves for the CA model, leading to a heterogeneous pattern of joint toxic action, which we named the “cross-phenomenon”. This observation raises an important issue that we will examine in the current study: why do joint toxic actions vary with the dose of a mixture?. Using molecular docking studies of the LuxR protein and sulfonamides (SAs), the hormetic effect of SAs on Photobacterium phosphoreum was investigated in our previous study, and the mechanistic hypothesis could be described briefly as follows: SAs at low concentrations could bind to the LuxR protein, and the resulting complexes promoted the expression of the LuxR protein[18]
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