Pals Justin A, Wagner Elizabeth D, Plewa Michael J, Xia Menghang, Attene-Ramos Matias S
Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States; Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States.
Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States; Safe Global Water Institute, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
J Environ Sci (China). 2017 Aug;58:224-230. doi: 10.1016/j.jes.2017.04.027. Epub 2017 May 9.
Haloacetamides (HAMs) are cytotoxic, genotoxic, and mutagenic byproducts of drinking water disinfection. They are soft electrophilic compounds that form covalent bonds with the free thiol/thiolate in cysteine residues through an S2 reaction mechanism. Toxicity of the monohalogenated HAMs (iodoacetamide, IAM; bromoacetamide, BAM; or chloroacetamide, CAM) varied depending on the halogen substituent. The aim of this research was to investigate how the halogen atom affects the reactivity and toxicological properties of HAMs, measured as induction of oxidative/electrophilic stress response and genotoxicity. Additionally, we wanted to determine how well in silico estimates of electrophilic softness matched thiol/thiolate reactivity and in vitro toxicological endpoints. Each of the HAMs significantly induced nuclear Rad51 accumulation and ARE signaling activity compared to a negative control. The rank order of effect was IAM>BAM>CAM for Rad51, and BAM≈IAM>CAM for ARE. In general, electrophilic softness and in chemico thiol/thiolate reactivity provided a qualitative indicator of toxicity, as the softer electrophiles IAM and BAM were more thiol/thiolate reactive and were more toxic than CAM.
卤代乙酰胺（HAMs）是饮用水消毒产生的具有细胞毒性、遗传毒性和致突变性的副产物。它们是软亲电化合物，通过S2反应机制与半胱氨酸残基中的游离硫醇/硫醇盐形成共价键。单卤代HAMs（碘乙酰胺，IAM；溴乙酰胺，BAM；或氯乙酰胺，CAM）的毒性因卤素取代基而异。本研究的目的是研究卤素原子如何影响HAMs的反应活性和毒理学性质，以氧化/亲电应激反应的诱导和遗传毒性来衡量。此外，我们想确定亲电软度的计算机模拟估计与硫醇/硫醇盐反应活性和体外毒理学终点的匹配程度。与阴性对照相比，每种HAMs均显著诱导核Rad51积累和ARE信号活性。Rad51的效应排序为IAM>BAM>CAM，ARE的效应排序为BAM≈IAM>CAM。一般来说，亲电软度和化学环境中的硫醇/硫醇盐反应活性提供了毒性的定性指标，因为较软的亲电试剂IAM和BAM与硫醇/硫醇盐的反应性更强，毒性也比CAM更大。
