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Dynamic cytotoxic profiles of sulfur mustard in human dermal cells determined by multiparametric high-content analysis.

ABSTRACT: Sulfur mustard (SM) is a well known chemical warfare agent that poses a major threat to military personnel and also populace. It targets multiple macromolecules, and its toxic effects are mediated by complex mechanisms. However, the sequence and manner of SM-induced cellular and molecular events underpinning the pathological processes are not fully elucidated. Effective therapeutic agents against SM poisoning are also lacking. The present study aimed to determine the dynamic cytotoxic profiles of SM in primary cultured human epidermal keratinocytes-fetal (HEK-f) and human dermal fibroblasts-adult (HDF-a) by establishing a high content analysis (HCA)-based multiparametric toxicity assay panel. SM was found to produce multiple, concentration-dependent cellular responses, including abnormal cellular morphology, cycle arrest, apoptosis, necrosis, mitochondrial membrane potential imbalance, increased membrane permeability, oxidative stress, DNA damage, and lysosome impairment. Time-course analysis indicated that the cellular and molecular responses related to the highly reactive targets of SM, such as glutathione depletion, reactive oxygen species release, DNA and lysosomal damage, and actin microfilament architecture modification, were congenerous initial events for SM injury. Moreover, this study demonstrated a novel finding that SM induced autophagy, and it was closely related to lysosome alterations in both cell types. Higher susceptibility of HEK-f cells to SM was associated with early lysosomal damage and decreased autophagy activity. Multiparametric HCA also revealed the concentration-dependent cytoprotective effect of hydroxychloroquine in HDF-a cells. The above results provided overall and objective evidence for elucidating the cytotoxic mechanism of SM, and also a good scientific base for further research on countermeasures against SM injury.

SUBMITTER: Long L

PROVIDER: S-EPMC6062398 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Dynamic cytotoxic profiles of sulfur mustard in human dermal cells determined by multiparametric high-content analysis.

Long Long L Li Wei W Chen Wei W Li Fei-Fei FF Li Hua H Wang Li-Li LL

Toxicology research 20160111 2

Sulfur mustard (SM) is a well known chemical warfare agent that poses a major threat to military personnel and also populace. It targets multiple macromolecules, and its toxic effects are mediated by complex mechanisms. However, the sequence and manner of SM-induced cellular and molecular events underpinning the pathological processes are not fully elucidated. Effective therapeutic agents against SM poisoning are also lacking. The present study aimed to determine the dynamic cytotoxic profiles o ...[more]

PMID: 30090372

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Project description:Sulfur mustard (SM) is a potent vesicant that targets epithelial cells and tissues. Most vesicant research has been performed using bona fide SM; however, some studies have used simulants, most notably half mustard (2-chloroethyl ethylsulfide; CEES) and nitrogen mustard (mechlorethamine; NM). Although CEES and NM have similarities to SM and can cause vesication, there are distinct differences in the chemical structures and physical properties of these compounds that may impact their toxic effects. Microarray analysis of cultured primary human epidermal keratinocytes (HEK) exposed to each of these vesicants was performed to directly compare the transcriptional responses induced by these vesicants. HEK were exposed in triplicate to concentrations ranging from 0-1000 µM for SM and NM and 0-4000 µM for CEES. Cells were harvested at 1, 2, 4, 8, 16, and 24 h and the RNA isolated for microarray analysis. Transcriptional responses were phenotypically anchored to cell morphology. The dataset was filtered by exposure and timepoint, and an analysis of variance was performed using dose as the factor. The top 500 genes ranked by p-value were analyzed using gene ontology algorithms to identify biological pathways significantly affected by each vesicant. At 2 h post-exposure, p53 signaling, Erk/MAPK signaling, and BMP signaling were significantly affected by all three vesicants. At 4 h post-exposure, p53 signaling , B cell activating factor, and glucocorticoid receptor signaling were significantly affected by all three vesicants. At 8 h post-exposure, there were no significant pathways commonly affected by all three vesicants. These results suggest that, although there are similarities in the transcriptional responses to each of these vesicants, the transcriptional responses appear to differ over time. Thus, extrapolation of results obtained with one vesicant to other vesicants may be complex and may have important implications for the development of vesicant therapeutics.

Dataset Information

Dynamic cytotoxic profiles of sulfur mustard in human dermal cells determined by multiparametric high-content analysis.

Publications

Dynamic cytotoxic profiles of sulfur mustard in human dermal cells determined by multiparametric high-content analysis.

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