Mustard gas surrogate, 2-chloroethyl ethylsulfide (2-CEES), induces centrosome amplification and aneuploidy in human and mouse cells

Abstract

Mustard gas is a simple molecule with a deadly past. First used as a chemical weapon in World War I, its simple formulation has raised concerns over its use by terrorist organizations and unstable governments. Mustard gas is a powerful vesicant and alkylating agent that causes painful blisters on epithelial surfaces and increases the incidence of cancer in those exposed. The mechanism of mustard gas toxicity and tumorigenesis is not well understood but is thought to be mediated by its ability to induce oxidative stress and DNA damage. Interestingly, several proteins that have been shown to either be targets of mustard gas or mediate mustard gas toxicity have also been shown to regulate centrosome duplication. Centrosomes are small nonmembrane-bound organelles that direct the segregation of chromosomes during mitosis through the formation of the bipolar mitotic spindle. Cells with more or less than two centrosomes during mitosis can segregate their chromosomes unequally, resulting in chromosome instability, a common phenotype of cancer cells. In our studies, we show that subtoxic levels of 2-chloroethyl ethylsulfide (2-CEES), a mustard gas analog, induce centrosome amplification and chromosome instability in cells, which may hasten the mutation rate necessary for tumorigenesis. These data may explain why those exposed to mustard gas exhibit higher incidences of cancer than unexposed individuals of the same cohort.

Effective removal of chemical warfare agent simulants using water stable metal–organic frameworks: mechanistic study and structure–property correlation

“…It is vital to develop methods or materials to detoxify or remove the chemical warfare agents. 3,4 Sulfur mustard can be detoxied by dehydrohalogenation, hydrolysis or oxidation. Dehydrohalogenation and hydrolysis suffer difficulties due to slow kinetics, the low solubility of sulfur mustard in water and the formation of toxic products.…”

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

“…Interestingly, after cutaneous exposure, SM induced DNA adducts could also be detected systemically in many internal organs, such as brain, lung, kidney, and spleen (Batal et al, 2014). In contrast to bi functional agents, mono functional agents, such as CEES, can only form monoadducts, with N7 ethylthioethyl guanine (N7 ETE Gua) being the most abundant base damage, however still sufficient to induce genomic instability in human cells (Batal et al, 2014;Bennett et al, 2014). In addition, it has been reported that several hours after treatment, mustard agents induce oxidative stress via mitochondrial dysfunction, induction of ROS/RNS generating genes, and GSH depletion on a cellular level or via the recruitment of ROS/RNS generating immune cells on a tissue level, which also leads to the generation of oxidative DNA damage Jain et al, 2011;Steinritz et al, 2014).…”

Whole genome expression analysis in primary bronchial epithelial cells after exposure to sulphur mustard

“…This should be investigated further as it has important consequences in terms of the ability of SM to induce aneuploidy/mutagenesis/carcinogenesis. Interestingly, a study published during the preparation of this manuscript demonstrated that a monofunctional analogue of SM (2-chloroethyl ethyl sulphide) was able to induce centromere amplification and aneuploidy in human and mouse cells (Bennett et al, 2014). As mentioned earlier, the microarray analysis identified changes in multiple genes involved in cellular replication.…”