A review of chemical warfare agents linked to respiratory and neurological effects experienced in Gulf War Illness

Cruz-Hernandez, Angela; Roney, Andrew; Goswami, Dinesh G.; Tewari‐Singh, Neera; Brown, Jared M.

doi:10.1080/08958378.2022.2147257

Cited by 5 publications

(2 citation statements)

References 170 publications

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“…Previous studies showed SM neurotoxicity in various experimental models as well as cognitive and emotional disorders in veterans exposed to this compound, as recently reviewed in [49]. 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.…”

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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“…Evidence of sarin exposure suggests that long-term adverse effects can occur, even at nonconvulsive and clinically asymptomatic doses, leading to cognitive and neurobehavioral dysfunction in victims. Gulf War veterans exposed to low levels of sarin performed worse than unexposed veterans on tests of visuospatial memory and visuospatial ability [ 8 ]. During the sarin gas attack on the Tokyo subway, firefighters and medical workers who responded to the disaster also experienced a chronic decline in memory [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Whole-Transcriptome Analysis of Repeated Low-Level Sarin-Exposed Rat Hippocampus and Identification of Cerna Networks to Investigate the Mechanism of Sarin-Induced Cognitive Impairment

Shi

Liu

Jin

et al. 2023

Biology

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Sarin is a potent organophosphorus nerve agent that causes cognitive dysfunction, but its underlying molecular mechanisms are poorly understood. In this study, a rat model of repeated low-level sarin exposure was established using the subcutaneous injection of 0.4 × LD50 for 21 consecutive days. Sarin-exposed rats showed persistent learning and memory impairment and reduced hippocampal dendritic spine density. A whole-transcriptome analysis was applied to study the mechanism of sarin-induced cognitive impairment, and a total of 1035 differentially expressed mRNA (DEmRNA), including 44 DEmiRNA, 305 DElncRNA, and 412 DEcircRNA, were found in the hippocampus of sarin-treated rats. According to Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and Protein–Protein Interaction (PPI) analysis, these DERNAs were mainly involved in neuronal synaptic plasticity and were related to the pathogenesis of neurodegenerative diseases. The circRNA/lncRNA–miRNA–mRNA ceRNA network was constructed, in which Circ_Fmn1, miR-741-3p, miR-764-3p, miR-871-3p, KIF1A, PTPN11, SYN1, and MT-CO3 formed one circuit, and Circ_Cacna1c, miR-10b-5p, miR-18a-5p, CACNA1C, PRKCD, and RASGRP1 constituted another circuit. The balance between the two circuits was crucial for maintaining synaptic plasticity and may be the regulatory mechanism by which sarin causes cognitive impairment. Our study reveals the ceRNA regulation mechanism of sarin exposure for the first time and provides new insights into the molecular mechanisms of other organophosphorus toxicants.

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Leveraging 3D-printed microfluidic micromixers for the continuous manufacture of melatonin loaded SNEDDS with enhanced antioxidant activity and skin permeability

Ongoren,

Kara,

Casettari

et al. 2024

International Journal of Pharmaceutics

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A review of chemical warfare agents linked to respiratory and neurological effects experienced in Gulf War Illness

Cited by 5 publications

References 170 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

Whole-Transcriptome Analysis of Repeated Low-Level Sarin-Exposed Rat Hippocampus and Identification of Cerna Networks to Investigate the Mechanism of Sarin-Induced Cognitive Impairment

Leveraging 3D-printed microfluidic micromixers for the continuous manufacture of melatonin loaded SNEDDS with enhanced antioxidant activity and skin permeability

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