Monohalogenated acetamide-induced cellular stress and genotoxicity are related to electrophilic softness and thiol/thiolate reactivity

• Published in: Journal of environmental sciences (China) 2017-08, Vol.58 (8), p.224-230
• Main Authors: Pals, Justin A., Wagner, Elizabeth D., Plewa, Michael J., Xia, Menghang, Attene-Ramos, Matias S.
• Format: Article
• Language: English
• Subjects: Acetamides - toxicity; byproducts; chemical bonding; cysteine; cytotoxicity; Disinfectants - toxicity; Disinfection; DNA Damage; Drinking Water; Drinking water disinfection byproducts; genotoxicity; Haloacetamide; halogens; hardness; Lewis acids; Mutagens; Oxidation-Reduction; Oxidative Stress; reaction mechanisms; Soft electrophile; stress response; Sulfhydryl Compounds - toxicity; thiols; Toxicity; Water Pollutants, Chemical - toxicity; 卤代; 柔软性; 氯乙酰胺; 硫醇盐; 细胞毒性; 诱导; 遗传毒性; 醇反应
• ISSN: 1001-0742; 1878-7320
• DOI: 10.1016/j.jes.2017.04.027

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 S_N2 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.