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TOXICOLOGY

Evidence That 1,1-Dichloroethylene Induces Apoptotic Cell Death in Murine Liver

Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada

1,1-Dichloroethylene (DCE) causes dysfunction of hepatic mitochondria. As mitochondria have been implicated in apoptosis through opening of the permeability transition pore (PTP), we have undertaken studies to test the hypothesis that DCE induces apoptosis, in addition to necrosis, in murine liver. Our primary objective was to identify the biochemical events associated with DCE-induced apoptosis. Female CD-1 mice were treated with a mildly hepatotoxic dose of DCE (125 mg/kg, i.p.). Using the fluorescent dye JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide), decreased hepatic mitochondrial membrane potential was detected at 2 h. Western blotting of liver cytosolic proteins showed greater immunoreactivity for cytochrome c in fractions from mice treated with DCE for 4 h than in controls. Furthermore, caspase-9 activity was significantly increased 6 h after DCE exposure. Immunohistochemical studies with an antibody to activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were used to detect apoptotic cells. In both experiments, positive reactivities were observed in centrilobular hepatocytes 12 and 24 h after DCE. Additionally, centrilobular hepatocytes showing morphological criteria of apoptosis were observed at 24 h. Apoptosis and all apoptotic events were inhibited by pretreatment for 20 min with cyclosporine A (CyA) (50 mg/kg), a specific inhibitor of the mitochondrial PTP. To determine a major role for mitochondrial permeability transition (MPT) in DCE hepatotoxicity, serum alanine aminotransferase (ALT) activity was evaluated. ALT activity was significantly elevated 2 to 24 h after DCE, and CyA failed to inhibit this activity. These data suggested that DCE produces apoptosis by inducing MPT, causing release of cytochrome c into the cytosol and caspase activation.

Address correspondence to: Dr. Poh-Gek Forkert, Department of Anatomy and Cell Biology, Queen's University, Kingston, ON, Canada K7L 3N6. E-mail: forkertp{at}post.queensu.ca

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