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pubmed:abstractText |
JP-8 is a kerosene-based fuel widely used by the U.S. military. Various models of human occupational and animal exposure to JP-8 have demonstrated the potential for local and systemic toxicity but the mechanisms involved are unknown. The purpose of our investigation was to study the molecular mechanisms of JP-8 toxicity by using an in vitro model. JP-8 exposure in a rat lung alveolar type II epithelial cell line (RLE-6TN) induces biochemical and morphological markers of apoptotic cell death: caspase-3 activation, poly(ADP-ribose) polymerase (PARP) cleavage, chromatin condensation, membrane blebbing, cytochrome c release from mitochondria, and genomic DNA cleavage into both oligonucleosomal (DNA ladder) and high-molecular-weight (HMW) fragments. The human histiocytic lymphoma cell line (U937) also responds to JP-8 with caspase-3 activation, cleavage of caspase substrates, including PARP, DNA-PK, and lamin B1, and degradation of genomic DNA with the production of HMW fragments. Caspase-3 activation and PARP cleavage also occur in the acute T-cell leukemia cell line (Jurkat) following treatment with JP-8. Furthermore, Jurkat cells stably transfected with a plasmid encoding the antiapoptotic protein Bcl-x(L) or pretreated with the pan-caspase inhibitor Boc-d-fmk, are relatively resistant to the cytotoxic effects of JP-8 compared to control cells. Finally, we demonstrate that PARP cleavage occurs in primary mouse thymocytes exposed to JP-8. In conclusion, our data support the hypothesis that apoptotic cell death is responsible at least partially for the cytotoxic effects of JP-8 and suggest that inhibition of the apoptotic cascade might reduce JP-8 toxicity.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
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