Mechanistic Evaluation of Trichloroethene-Mediated Autoimmune Hepatitis-Like Disease In Female MRL+/+ Mice

Environmental and occupational exposure to trichloroethene (TCE) is associated with autoimmune diseases (ADs). However, the mechanisms of TCE-mediated ADs are not fully elucidated. Previous investigations showed that chronic low dose exposure of autoimmune-prone female MRL+/+ mice to TCE resulted in development of autoimmune hepatitis-like disease (AIHLD). To elucidate the mechanisms involved in the development of AIHLD, we treated female MRL+/+ mice with TCE (0.5 mg/ml) via drinking water for 24, 36 and 48 weeks. Exposure to TCE resulted in increased lymphocytic infiltration and periportal hepatocellular necrosis in the livers of mice exposed for 48 weeks. Significantly increased apoptotic cells were observed in the livers after 24 weeks of TCE exposure as analyzed by TUNEL assay. Staining of Kupffer cells with RM-4 monoclonal antibody showed a decrease in number of Kupffer cells at 36 and 48 weeks of TCE exposure which may cause delayed/reduced clearance of apoptotic bodies. These observations led us to hypothesize that compromised Kupffer cell function may cause impaired clearance of apoptotic bodies, leading to secondary necrosis and inflammation. To test this hypothesis, we treated HepG2 cells with various concentrations of TCE and time periods. TCE treatment of HepG2 cells at 12mM and higher concentrations led to their decreased viability after 24h. When TCE-treated HepG2 cells were co-cultured with untreated RAW cells, the phagocytic function of RAW cells was reduced accompanied by increased secretion of tumor necrosis factor alpha. These results suggest that increased apoptosis and decreased phagocytic function of Kupffer cells may probably lead to accumulation of apoptotic bodies and secondary necrosis and the resulting inflammation could be a plausible mechanism of TCE-induced AIHLD.