Sulphur mustard induces progressive toxicity and demyelination in brain cell aggregate culture

Sawyer, Thomas W.; Wang, Yushan; Song, Yanfeng; Villanueva, Mercy; Jiménez, Andrés

doi:10.1016/j.neuro.2021.03.004

Cited by 3 publications

(2 citation statements)

References 60 publications

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“…Neurological complications after SM poisoning encompassed sensory nerve impairments [50], motor nerve disturbances [51], retinal abnormalities [52], chronic neuropathic symptoms [53], and mental health problems such as anxiety, depression, or cognitive decline [54] and persisted even decades after exposure [55]. Neurotoxicity in vitro has been demonstrated upon SM [56] and HN2 exposure [57], and multiple evidences exist from in vivo studies. For example, chronic SM exposure resulted in neurobehavioral impairments, oxidative stress, and apoptosis in the brains of male Swiss Albino mice [58].…”

Section: Discussionmentioning

confidence: 99%

Life-Cycle-Dependent Toxicities of Mono- and Bifunctional Alkylating Agents in the 3R-Compliant Model Organism C. elegans

Ruszkiewicz,

Endig,

Güver

et al. 2023

Cells

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Caenorhabditis elegans (C. elegans) is gaining recognition and importance as an organismic model for toxicity testing in line with the 3Rs principle (replace, reduce, refine). In this study, we explored the use of C. elegans to examine the toxicities of alkylating sulphur mustard analogues, specifically the monofunctional agent 2-chloroethyl-ethyl sulphide (CEES) and the bifunctional, crosslinking agent mechlorethamine (HN2). We exposed wild-type worms at different life cycle stages (from larvae L1 to adulthood day 10) to CEES or HN2 and scored their viability 24 h later. The susceptibility of C. elegans to CEES and HN2 paralleled that of human cells, with HN2 exhibiting higher toxicity than CEES, reflected in LC50 values in the high µM to low mM range. Importantly, the effects were dependent on the worms’ developmental stage as well as organismic age: the highest susceptibility was observed in L1, whereas the lowest was observed in L4 worms. In adult worms, susceptibility to alkylating agents increased with advanced age, especially to HN2. To examine reproductive effects, L4 worms were exposed to CEES and HN2, and both the offspring and the percentage of unhatched eggs were assessed. Moreover, germline apoptosis was assessed by using ced-1p::GFP (MD701) worms. In contrast to concentrations that elicited low toxicities to L4 worms, CEES and HN2 were highly toxic to germline cells, manifesting as increased germline apoptosis as well as reduced offspring number and percentage of eggs hatched. Again, HN2 exhibited stronger effects than CEES. Compound specificity was also evident in toxicities to dopaminergic neurons–HN2 exposure affected expression of dopamine transporter DAT-1 (strain BY200) at lower concentrations than CEES, suggesting a higher neurotoxic effect. Mechanistically, nicotinamide adenine dinucleotide (NAD+) has been linked to mustard agent toxicities. Therefore, the NAD+-dependent system was investigated in the response to CEES and HN2 treatment. Overall NAD+ levels in worm extracts were revealed to be largely resistant to mustard exposure except for high concentrations, which lowered the NAD+ levels in L4 worms 24 h post-treatment. Interestingly, however, mutant worms lacking components of NAD+-dependent pathways involved in genome maintenance, namely pme-2, parg-2, and sirt-2.1 showed a higher and compound-specific susceptibility, indicating an active role of NAD+ in genotoxic stress response. In conclusion, the present results demonstrate that C. elegans represents an attractive model to study the toxicology of alkylating agents, which supports its use in mechanistic as well as intervention studies with major strength in the possibility to analyze toxicities at different life cycle stages.

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Section: Discussionmentioning

confidence: 99%

Life-Cycle-Dependent Toxicities of Mono- and Bifunctional Alkylating Agents in the 3R-Compliant Model Organism C. elegans

Ruszkiewicz,

Endig,

Güver

et al. 2023

Cells

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“…The bisulfite level in cells is an essential index which links to cardiovascular diseases, neurological disorders, stroke, and lung and brain cancer development. 19,20 Although various fluorescent probes [21][22][23][24][25][26][27][28][29][30] have been developed for bisulfite detection and live cell imaging recently, most of them require tedious synthetic routes, combined with dangerous and toxic chemicals, while some of them require the use of precious metals. 31,32 These factors introduce unnecessary safety risks and increase the costs.…”

mentioning

confidence: 99%

One-pot synthesis to prepare lignin/photoacid nanohybrids for multifunctional biosensors and photo-triggered singlet oxygen generation

et al. 2022

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Clinical and experimental research progress on neurotoxicity of sulfur mustard and its possible mechanisms

Jiang¹,

Zhang

Shen

et al. 2023

Toxicology

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Sulphur mustard induces progressive toxicity and demyelination in brain cell aggregate culture

Cited by 3 publications

References 60 publications

Life-Cycle-Dependent Toxicities of Mono- and Bifunctional Alkylating Agents in the 3R-Compliant Model Organism C. elegans

Life-Cycle-Dependent Toxicities of Mono- and Bifunctional Alkylating Agents in the 3R-Compliant Model Organism C. elegans

One-pot synthesis to prepare lignin/photoacid nanohybrids for multifunctional biosensors and photo-triggered singlet oxygen generation

Clinical and experimental research progress on neurotoxicity of sulfur mustard and its possible mechanisms

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