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J Environ Sci (China). 2017 Aug;58:224-230. doi: 10.1016/j.jes.2017.04.027. Epub 2017 May 9.

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

Author information

1
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.
2
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.
3
National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, MD, United States.
4
Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States. Electronic address: attene@gwu.edu.

Abstract

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 SN2 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.

KEYWORDS:

DNA damage; Drinking water disinfection byproducts; Haloacetamide; Oxidative stress; Soft electrophile; Toxicity

PMID:
28774613
PMCID:
PMC6239421
DOI:
10.1016/j.jes.2017.04.027
[Indexed for MEDLINE]
Free PMC Article

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