US EPA

673550 

Journal Article 

Effects of peroxisome proliferators on rat liver phospholipids: sphingomyelin degradation may be involved in hepatotoxic mechanism of perfluorodecanoic acid 

Adinehzadeh, M; Reo, NV 

1998 

Yes 

Chemical Research in Toxicology
ISSN: 0893-228X
EISSN: 1520-5010 

American Chemical Society 

11 

5 

428-440 

English 

9585473 

10.1021/tx970155t 

WOS:000073747000005 

https://search.proquest.com/docview/79868314?accountid=171501
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Perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), clofibrate, di(2-ethylhexyl)phthalate (DEHP), and Wy-14,643 represent a class of compounds known as peroxisome proliferators (PPs). Such compounds induce biogenesis of liver peroxisomes and cause a varying degree of hepatotoxicity and carcinogenesis in rodents. We examined the effects of these PPs on rat hepatic lipids and phospholipid profiles using phosphorus-31 NMR spectroscopy. All PPs caused a 25-57% increase in hepatic phospholipid content, while all but clofibrate increased the total lipid content by 26-156%. Treatments also influenced the composition of liver phospholipids. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEth) contents were significantly increased in all treatment groups. Most notably, PFDA caused the largest increase in PtdCho and PtdEth content (ca. 70%), while PFOA and Wy-14,643 were the only test compounds that influenced the PtdCho:PtdEth ratio. PFDA also caused an ca. 30% decrease in sphingomyelin (SphM) from 24 to 120 h postdose. SphM is a key lipid in signal transduction processes involved in apoptosis. Hydrolysis of SphM can be mediated through the action of tumor necrosis factor (TNF-alpha). We measured the TNF-alpha concentrations in rat sera at 24 h post-PFDA-exposure and found an 8-fold increase relative to vehicle-treated controls. These data demonstrate that an increase in the serum TNF-alpha level correlates with the time frame for the observed reduction in hepatic SphM. PFOA, a structurally similar compound, had no effect on hepatic SphM content, nor did it affect the serum TNF-alpha concentration. These effects may be related to differences in the tumorigenicity associated with these compounds. We postulate that PFDA activates the SphM signal transduction pathway via the release of TNF-alpha. This then stimulates cytotoxic responses and processes of apoptosis and may suppress cell proliferative and mitogenic responses. 

Decanoic Acids; Fluorocarbons; Phospholipids; Sphingomyelins; Tumor Necrosis Factor-alpha; perfluorodecanoic acid; 335-76-2; Index Medicus; Tumor Necrosis Factor-alpha -- metabolism; Animals; Magnetic Resonance Spectroscopy; Rats, Inbred F344; Lipids -- chemistry; Lipid Metabolism; Microbodies -- drug effects; Liver -- metabolism; Decanoic Acids -- toxicity; Liver -- drug effects; Fluorocarbons -- toxicity; Sphingomyelins -- metabolism; Chemical and Drug Induced Liver Injury -- metabolism; Phospholipids -- metabolism