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

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 Rad 51 accumulation and ARE signaling activity compared to a negative control. In each case the rank order of effect was IAM > BAM > CAM for Rad 51, 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.

Genotoxicity Assessment of Drinking Water Disinfection Byproducts by DNA Damage and Repair Pathway Profiling Analysis

“…For the three haloamides tested, PELI max could be predicted by ATS3p (an autocorrelation descriptor of centered Broto-Moreau autocorrelation weighted by polarizabilities) with R 2 = 0.9345 (P=0.1645), and PELI1.5 could be predicted by G (Gibbs free energy) with R 2 = 0.9943 (P= 0.0482). The correlation of E lomo to toxicity of haloacetic acids is consistent with other published studies 4,16,25,67 The QSAR modeling exercise of the DBPs suggested that chemical properties of the molecules, for example, topological and quantum chemical properties, correlate with the genotoxicity of DBPs. In addition, the correlation of different descriptors implicated different mechanism(s).…”

“…3,13 Genotoxicity mechanisms of DBPs are also strongly related to their structures. For example, for halogenated DBPs, oxidative stress-induced DNA damage [14][15][16][17][18][19][20][21] and DNA alkylation [22][23][24][25] are two major mechanisms. Halonitriles may also induce genomic damage by cell cycle disruption and the induction of hyperploidy.…”

How Much of the Total Organic Halogen and Developmental Toxicity of Chlorinated Drinking Water Might Be Attributed to Aromatic Halogenated DBPs?

“…The ROS generation by xenobiotics may pose oxidative damage to essential biomolecules and cause functional deficits of cells, which may lead to cell death and even some adverse outcomes such as cancer with the absence of compensatory mechanisms. 47,48 The oxidative stress has been reported to relate to the genotoxicity and mutagenicity induced by mono-HAAs through inhibiting glycolysis by ROS. 47,78 Halophenols have been reported to generate phenoxy radical intermediates and halobenzoquinones during metabolism, and halobenzoquinones can induce ROS production in cells.…”

Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) after Exposure to Selected Drinking Water Disinfection By-Products

“…2016), including the subsequent generation of ROS (Pals et al. 2013, 2017). Based on concurrent up-regulation of nuclear factor kappa B (Nf- k B) and mitogen-activated protein kinase (MAPK) pathways, we speculate that this could involve downstream activation of Toll-like receptors (TLRs) (van der Veen et al.…”