The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-Coenzyme A 1 Desaturase and Mixed Function Oxidase Activities in Rats

The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-CoenzymeA Desaturase and Mixed Function Oxidase Activities in Rats.VANRAFELGHAM, M. J., AND ANDERSON, M. E. (1988). Fundam. Appl.Toxicol. 11, 503-510. Perfluorodecanoic acid (PFDA) causes adioxin-lilce toxic syndrome and alters the hepatic oleate/stearateratio in rats. The acute toxic effects of a single ip dose (50mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixedfunction oxidases were studied in male Fischer-344 rats, 14days after dosing. PFDA causes a marked decrease in food intakein rats, resulting in severe body weight loss with delayed lethality(2-3 weeks after dosing). To distinguish the effects of hypophagiafrom those caused by PFDA, pair-fed control rats were used inaddition to ad libitum-fed controls. Stearoyl-CoA desaturaseactivity, responsible for the conversion of stearoyl-CoA tooleoyl-CoA, was absent in both PFDA dosed rats and their pair-fedcontrols at Day 14. Electron transfer through the desaturasesystem was significantly reduced in PFDA-treated rats only,and in these rats there was a significant reduction in microsomalcytochrome an important component of this electron transfersystem. Pentobarbital sleeping times were significantly prolongedin both the PFDA-dosed and pairfed rats, as compared with thead libitumfed controls. This effect was more pronounced in PFDA-dosedrats. Waking plasma pentobarbital concentration was similarin all treatment groups. Hepatic microsomal cytochrome PASOcontent was unaffected. Aminopyrine N-de-methylase activitywas greatly reduced in PFDA-dosed rats. Although pairfed controlsalso had reduced demethylase activity, it was not as pronouncedas in PFDA-dosed rats, and was probably due to the fasted conditionof these animals. Although the mechanism of action of PFDA isnot known, it is possible that PFDA affects microsomal enzymesby altering the structure and/or function of the membranes inwhich they are located, through effects on lipid metabolism.     

Pathological and Hepatic Ultrastructural Effects of a Single Dose of Perfluoro-n-decanoic Acid in the Rat, Hamster, Mouse, and Guinea Pig

In rats, the liver is the primary target organ of perfluoro-n-decanoicacid (PFDA) toxicity. Therefore, the effects of PFDA on hepaticultrastructure were studied in rats. Pathological changes inducedby PFDA in hamsters, mice, and guinea pigs were also examined.PFDA caused a severe reduction in body weight in all four speciesstudied. A reduction in food intake was observed in rats andhamsters. However, hamsters continued to consume food at a reducedlevel, while rats stopped eating for a 5 to 6-day period about6 days after dosing. The PFDA-induced pathological changes inthe hamsters, mice, and guinea pigs resembled those seen inrats to varying degrees. As in the rat, PFDA caused a markedliver enlargement in mice and hamsters and a moderate swellingin guinea pigs. This hepatomegaly was ascribed primarily toindividual cell swelling. Thymic atrophy was noted in PFDA-treatedhamsters, mice, and guinea pigs. Seminiferous tubular degenerationobserved in hamsters and guinea pigs, but not in mice, was notas severe as in the rat, where in some cases frank necrosishas been seen. Ultrastructural changes in the livers of allPFDA-treated animals, regardless of species, included disruptionof the rough endo plasmic reticulum, rounding and swelling ofthe mitochondria with related structural alter ations, and mildto extensive proliferation of peroxisomes. This peroxisome proliferativeresponse was greatest in mice and almost absent in guinea pigs.Accumulation of lipid droplets in liver cells due to PFDA treatmentwas more pronounced in hamsters and guinea pigs than in ratsand mice. PFDA-induced hepatomegaly with a concomitant increasein peroxisomes in several rodent species may be associated withan impairment of normal lipid metabolism in the liver by PFDA.