1,1-Dichloroethylene-induced alterations in glutathione and covalent binding in murine lung: morphological,...

Non-ciliated Clara cells of the pulmonary bronchiolar epithelium are preferentially damaged by administration of 1,1-dichloroethylene (1,1-DCE) to mice. In this study, an in vivo system was utilized to investigate the dose-dependent effects of 1,1-DCE (75, 125, 175, and 225 mg/kg) on covalent binding and on reduced glutathione (GSH) in murine lung. Treatment of mice with each dose level of 1,1-DCE elicited significant decreases in GSH content and resulted in covalent binding of [14C]1,1-DCE in a dose-dependent manner. Histochemical staining for GSH in lungs of control mice revealed positive cellular sites in alveolar septa and bronchiolar epithelium, with the highest staining intensities in Clara cells. Staining was reduced after exposure to 75 and 125 mg/kg 1,1-DCE, and at higher doses it was abolished in alveolar septa and retained in bronchiolar epithelium, albeit at considerably reduced intensities. Heterogeneity with respect to staining intensities was consistently observed in the Clara cell population in both control and 1,1-DCE-treated mice. Progressive increases in covalent binding and decreases in GSH content correlated with increasing severities of Clara cell injury. These results show a dose dependence in regard to the magnitudes of [14C]1,1-DCE binding, the alterations in cellular GSH, and the severities of Clara cell necrosis.