Dose-response hepatotoxicity of the peroxisome proliferator, perfluorodecanoic acid and the relationship to phospholipid metabolism in rats

Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator that caus es hepatotoxicity but lacks tumor-promoting activity in rats. We previously showed that a single dose of PFDA at 50 mg/kg (similar to LD50) causes an elevation in liver phosphocholine (PCho) and other effects related to phosp holipid metabolism. In this study. we examined metabolic effects in the dos e range 2-50 mg/kg in rats. At doses less than or equal to 20 mg/kg, PFDA i s significantly less hepatotoxic than the LD50, as manifested by electron m icroscopy and measurements of daily food consumption and body weight. At 50 mg/kg rat serum tumor necrosis factor (TNF)-alpha concentration was increa sed 8-fold, while at 15 mg/kg there was no apparent increase in this cytoki ne. This lower dose, however, induces metabolic effects similar to those se en at the LD50. Liver fatty acyl-CoA oxidase activity showed a dose-depende nt increase from 5-25 mg/kg PFDA. Treatments at 15 and 50 mg/kg caused a si gnificant increase in liver phosphatidylcholine (28 and 66%) and phosphatid ylethanolamine (31 and 74%). Both doses caused a significant increase in li ver PCho but did not affect liver ATP levels, as manifested in P-31 nuclear magnetic resonance (NMR) spectra from rat livers in vivo. These data sugge st that the increase in liver [PCho] observed following PFDA exposure in ra ts represents a specific metabolic response, rather than a broad-range hepa totoxic effect. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.