Investigation of the Hepatotoxic and Immunotoxic Effects of the PeroxisomeProliferation Perflurodecanoic Acid

摘要

The effects of perfluorodeconoic acid (PFDA) on humoral, cellular, and innateimmunity in Fischer 344 rats was studied at 8 days and 30 days following a single intraperitoneal injection at doses of mg/kg body weight. Effects of in vitro PFDA treatment were also determined. PFDA was found to significantly decrease IgG2 alpha production at 8 days following PFDA treatment and to cause a trend of decreased DIFI responsiveness, reflecting inhibitory effects on humoral and cellular mediated immunity. Innate immunity was assessed by natural killer cell function and macrophage function. A significant increase in Mc activity was observed at 50 mg/kg PFDA at 30 but not at 8 days following PFDA treatment. PFDA also suppressed the oxidative burst of macrophages (8 days after PFDA treatment at 20 mg/kg) and phagocytosis. Various mechanisms were examined to account for the observed immunosuppression. The evidence suggests that PFDA suppressed IgG2 alpha production (8 days) and DTH responsiveness through combined underlying mechanisms of cytotoxicity, decreased IL-1 and IL-2 production, increased POE production, and decreased MHC II expression. Inhibition of phagocytosis and respiratory burst may have resulted from membrane alterations, disrupted energy production, and/or disrupted NADPH oxidase activity. Increased Mc activity (50 mg/kg, 30 days) appeared to be due to drug-induced anorexia since similar affects were observed in pair-fed-animals. An attempt was also made to use fluorescent indicator dyes and antibodies to measure peroxisome formation in livers of PFDA-treated rats. Neither effort proved to be very successful. The dye lacked specificity and the antibodies developed against enoyl CoA hydratase, a peroxisomal enzyme, were too weak to demonstrate reactivity following 2D gel electrophoresis.