Procházka Erik, Escher Beate I, Plewa Michael J, Leusch Frederic D L
Smart Water Research Centre, Australian Rivers Institute, School of Environment, Griffith University , Gold Coast, Queensland 4222, Australia.
Cell Toxicology, Helmholtz Centre for Environmental Research-UFZ , 04318 Leipzig, Germany.
Chem Res Toxicol. 2015 Oct 19;28(10):2059-68. doi: 10.1021/acs.chemrestox.5b00283. Epub 2015 Sep 18.
The process of disinfecting drinking water inadvertently leads to the formation of numerous disinfection byproducts (DBPs). Some of these are mutagenic, genotoxic, teratogenic, and cytotoxic, as well as potentially carcinogenic both in vivo and in vitro. We investigated the in vitro biological activity of five DBPs: three monohaloacetic acids (monoHAAs) [chloroacetic acid (CAA), bromoacetic acid (BAA), and iodoacetic acid (IAA)] and two novel halobenzoquinones (HBQs) [2,6-dichloro-p-benzoquinone (DCBQ) and 2,6-dibromo-p-benzoquinone]. We focused particularly on cytotoxicity and induction of two adaptive stress response pathways: the oxidative stress responsive Nrf2/ARE and DNA-damage responsive p53 pathways. All five DBPs were cytotoxic to the Caco-2 cell line after a 4 h exposure, and all DBPs induced both of the adaptive stress response pathways, Nrf2/ARE and p53, in the micromolar range, as measured by two β-lactamase-based reporter gene assays. The decreasing order of potency for all three endpoints for the five DBPs was IAA ∼ BAA > DCBQ ∼ DBBQ > CAA. Induction of oxidative stress was previously proposed to be the molecular initiating event (MIE) for both classes of DBPs. However, comparing the levels of activation of the two pathways uncovered that the Nrf2/ARE pathway was the more sensitive endpoint for HAAs, whereas the p53 pathway was more sensitive in the case of HBQs. Therefore, the DNA damage-responsive p53 pathway may be an important piece of information to fill in a gap in the adverse outcome pathway framework for the assessment of HBQs. Finally, we cautiously compared the potential risk of the two novel HBQs using a benchmarking approach to that of the well-studied CAA, which suggested that their relative risk may be lower than that of BAA and IAA.
饮用水消毒过程会意外导致大量消毒副产物（DBPs）的形成。其中一些具有致突变性、基因毒性、致畸性和细胞毒性，并且在体内和体外都具有潜在致癌性。我们研究了五种消毒副产物的体外生物活性：三种一卤乙酸（monoHAAs）[氯乙酸（CAA）、溴乙酸（BAA）和碘乙酸（IAA）]以及两种新型卤代苯醌（HBQs）[2,6 - 二氯对苯醌（DCBQ）和2,6 - 二溴对苯醌]。我们特别关注细胞毒性以及两种适应性应激反应途径的诱导：氧化应激反应性Nrf2/ARE途径和DNA损伤反应性p53途径。在暴露4小时后，所有五种消毒副产物对Caco - 2细胞系均具有细胞毒性，并且通过两种基于β - 内酰胺酶的报告基因测定法测量，所有消毒副产物在微摩尔范围内均诱导了适应性应激反应途径Nrf2/ARE和p53。五种消毒副产物在所有三个终点的效力递减顺序为IAA ∼ BAA > DCBQ ∼ DBBQ > CAA。先前有人提出氧化应激的诱导是这两类消毒副产物的分子起始事件（MIE）。然而，比较这两种途径的激活水平发现，Nrf2/ARE途径是一卤乙酸更敏感的终点，而在卤代苯醌的情况下p53途径更敏感。因此，DNA损伤反应性p53途径可能是填补卤代苯醌评估不良结局途径框架空白的重要信息。最后，我们使用基准方法谨慎地比较了两种新型卤代苯醌与研究充分的氯乙酸的潜在风险，这表明它们的相对风险可能低于溴乙酸和碘乙酸。
