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 causes hepatotoxicity but lacks tumor-promoting activity in rats. We previously showed that a single dose of PFDA at 50 mg/kg (∼LD 50) causes an elevation in liver phosphocholine (PCho) and other effects related to phospholipid m...

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Published in:Toxicology (Amsterdam) 1999-06, Vol.134 (2), p.179-195
Main Authors: Adinehzadeh, Mehdi, Reo, Nicholas V., Jarnot, Bruce M., Taylor, Catherine A., Mattie, David R.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Chemical and industrial products toxicology. Toxic occupational diseases
Hepatotoxicity
Medical sciences
Perfluorodecanoic acid
Peroxisome proliferator
Toxicology
Various organic compounds
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Summary:Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator that causes hepatotoxicity but lacks tumor-promoting activity in rats. We previously showed that a single dose of PFDA at 50 mg/kg (∼LD 50) causes an elevation in liver phosphocholine (PCho) and other effects related to phospholipid metabolism. In this study, we examined metabolic effects in the dose range 2–50 mg/kg in rats. At doses ≤20 mg/kg, PFDA is significantly less hepatotoxic than the LD 50, as manifested by electron microscopy and measurements of daily food consumption and body weight. At 50 mg/kg rat serum tumor necrosis factor (TNF)-α concentration was increased 8-fold, while at 15 mg/kg there was no apparent increase in this cytokine. This lower dose, however, induces metabolic effects similar to those seen at the LD 50. Liver fatty acyl-CoA oxidase activity showed a dose-dependent increase from 5–25 mg/kg PFDA. Treatments at 15 and 50 mg/kg caused a significant increase in liver phosphatidylcholine (28 and 66%) and phosphatidylethanolamine (31 and 74%). Both doses caused a significant increase in liver PCho but did not affect liver ATP levels, as manifested in 31P nuclear magnetic resonance (NMR) spectra from rat livers in vivo. These data suggest that the increase in liver [PCho] observed following PFDA exposure in rats represents a specific metabolic response, rather than a broad-range hepatotoxic effect.
ISSN:0300-483X
1879-3185
DOI:10.1016/S0300-483X(99)00038-4