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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.

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