Mediation of Sulfur Mustard Cellular Toxicity by ATP: A Possible Mechanism of Action of Sulfur Mustard Toxicity
Abstract
Exposure to HD of a selected number of phylogenetically different cell types (human skin keratinocytes, J774 cells, CRO-K1 cells, thymocytes and chick neurons) resulted in concentration-dependent cytotoxicity. HD induced apoptosis was shown to be common to all cell types tested as illustrated by annexin staining, production of DNA fragments, soluble DNA assay, morphology (acridine/ethidium bromide staining) and positive TUNEL reaction. Apoptosis was prevalent at lower concentrations, while necrosis was relatively more evident at higher HD concentrations. Calcium levels were elevated in HD exposed human keratinocytes, J774 cells and CHO-K1 cells at concentrations of HD that ultimately caused cell death. HD induced cytotoxicity (apoptosis) was unaffected by manipulation of calcium levels prior to exposure, suggesting no cause-effect relationship in keratinocytes. The role of calcium in other cell types is currently being examined. Studies using molecular and immunohistochemical techniques to identify ATP receptor types in HD sensitive cells revealed novel findings, including the presence of P2X1 and P2X7 receptors on vas deferens, and on immature thymocytes. ATP induced calcium influx in synaptosomes was demonstrated following activation of a novel CNS P2X7 receptor. HD did not potentiate this influx. The effects of caspase inhibitors and the role of cytoprotective genes in HD toxicity are currently being investigated.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 1999
- Accession Number
- ADA378733
Entities
People
- Murray G. Hamilton
- Paul M. Lundy
- Thomas W. Sawyer