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TOXICOLOGY

1,1-Dichloroethylene-Induced Mitochondrial Damage Precedes Apoptotic Cell Death of Bronchiolar Epithelial Cells in Murine Lung

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

1,1-Dichloroethylene (DCE) causes pulmonary injury that is characterized by necrosis of bronchiolar Clara cells. Mitochondria have been identified as an early target in the toxic response. Because mitochondria have been implicated in both necrotic and apoptotic cell death, we have undertaken studies to test the hypothesis that DCE induces apoptosis, in addition to necrosis, in murine lung. A primary objective is to identify the biochemical events associated with pulmonary apoptosis. Groups of female CD-1 mice were treated with DCE (75 mg/kg i.p.) or corn oil. Using an antibody directed against DCE-cysteine conjugates, adducts were detected primarily in association with mitochondria in the apices of bronchiolar Clara cells. Furthermore, morphological studies demonstrated early mitochondrial alterations in Clara cells that included severe swelling and disruption of cristae. Western blotting of lung cytosolic proteins showed greater immunoreactivity for cytochrome c in fractions from mice treated with DCE for 4 h than in controls. Immunohistochemical studies with an antibody to activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick-end labeling were used to detect apoptotic cells. In both experiments, positive reactivities were observed in the bronchiolar epithelium at 12 and 24 h after DCE treatment, whereas reactivities were absent in tissues from control animals. Finally, bronchiolar epithelial cells showing morphological criteria of apoptosis (chromatin condensation and margination) were observed at 24 h after 75 and 125 mg/kg DCE. Apoptotic-like cells were more abundant in larger bronchioles. These data suggested that DCE produces pulmonary bronchiolar apoptosis by inducing mitochondrial perturbations, 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: forkert{at}post.queensu.ca

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