Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products
Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products
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DOI：
10.1016/j.watres.2015.12.047
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发表时间：
2016-03-15
期刊：
影响因子：
12.8
通讯作者：
Escher, Beate I.
中科院分区：
文献类型：
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作者：
Stalter, Daniel;O'Malley, Elissa;Escher, Beate I.
为了更好地了解消毒副产物反应毒性分子机制的共性和差异，对50种消毒副产物进行了9种代表细胞毒性途径不同阶段的体外细胞生物测定。大肠杆菌测试电池显示，%的化合物对蛋白质/多肽具有反应性。98%的受试者激活了Nrf2介导的氧化应激反应，68%的受试者对基因毒性效应产生了适应性应激反应，如肿瘤抑制蛋白P53的激活所表明的那样。在大肠杆菌检测中，所有DBP对DNA都有反应，激活P53也会诱导氧化应激，证实了后者可能触发DBP的致癌作用。作为反应性参数的最低空位分子轨道ELumo的能量与三卤代甲烷(r(2)=0.98)和卤代乙酰胺(r(2)=0.58)的氧化应激诱导呈线性相关，表明这些DBPs的效力与亲电性有关。然而，卤代乙酸类(HAAs)和卤代乙腈类化合物的描述能力较差(r(2)<；0.06)。对于HAAs，我们还通过在两参数多元线性回归模型中包括酸度常数和ELumo来解释物种形成。这使r(2)增加到>；0.80，表明哈斯的效力与亲电性和物种形成有关。基于氧化应激反应的激活和大多数受试DBPs的软亲电特性，我们假设对于大多数受试DBPs来说，间接遗传毒性(例如，通过氧化应激诱导和/或酶抑制)比直接DNA损伤更可信。这些结果不仅提供了对DBPs细胞效应的机理了解，而且效应浓度也可用于评估DBPs在水样中的混合效应。(C)2016爱思唯尔有限公司。保留所有权利。
A set of nine in vitro cellular bioassays indicative of different stages of the cellular toxicity pathway was applied to 50 disinfection by-products (DBPs) to obtain a better understanding of the commonalities and differences in the molecular mechanisms of reactive toxicity of DBPs. An Eschericia coli test battery revealed reactivity towards proteins/peptides for 64% of the compounds. 98% activated the NRf2-mediated oxidative stress response and 68% induced an adaptive stress response to genotoxic effects as indicated by the activation of the tumor suppressor protein p53. All DBPs reactive towards DNA in the E. coli assay and activating p53 also induced oxidative stress, confirming earlier studies that the latter could trigger DBP's carcinogenicity. The energy of the lowest unoccupied molecular orbital ELumo as reactivity descriptor was linearly correlated with oxidative stress induction for trihalomethanes (r(2) = 0.98) and haloacetamides (r(2) = 0.58), indicating that potency of these DBPs is connected to electrophilicity. However, the descriptive power was poor for haloacetic acids (HAAs) and haloacetonitriles (r(2) < 0.06). For HAAs, we additionally accounted for speciation by including the acidity constant with ELumo in a two-parameter multiple linear regression model. This increased r(2) to >0.80, indicating that HAAs' potency is connected to both, electrophilicity and speciation. Based on the activation of oxidative stress response and the soft electrophilic character of most tested DBPs we hypothesize that indirect genotoxicity e.g., through oxidative stress induction and/or enzyme inhibition is more plausible than direct DNA damage for most investigated DBPs. The results provide not only a mechanistic understanding of the cellular effects of DBPs but the effect concentrations may also serve to evaluate mixture effects of DBPs in water samples. (C) 2016 Elsevier Ltd. All rights reserved.