TOXICOLOGY OF PERFLUORINATED FATTY ACID-LIPID CONJUGATES

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Perfluorinated fatty acids, represented by perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA), are a new class of peroxisome proliferators. Like other classes (hypolipidemic drugs and phthalate esters) they produce a marked pleiotropic response in rodent liver. No information exists on the metabolic fate of PFOA or PFDA, their effects on hepatic fatty acid oxidation, or mechanisms by which they perturb normal lipid metabolism. In rats PFDA is more biologically potent than PFOA, but the cause is unknown. The hepatocarcinogenic potential of these agents is also not known. Perfluorinated fatty acids are potentially important chemicals to study because they (1) have widespread commercial usage, (2) are a new class of peroxisome proliferators that might not be hepatocarcinogenic, (3) might serve as probes for studying normal lipid metabolism, and (4) might be useful prototypes for studying xenobiotic-lipid conjugation. The latter research area, now in a state of infancy, is important toxicologically because the formation of xenobiotic-lipid conjugates might increase the persistence of a xenobiotic in the body (by its incorporation into a lipid storage form) or the xenobiotic-lipid conjugate itself might cause toxicity. The hypothesis will be tested that PFDA is more persistent in the rat than PFOA because it is esterified into acylglcerols (lipid storage form) while PFOA is almost entirely excluded from esterification. Lipophilic conjugates of each compound will be separated, identified and quantified. In perfused rat liver, metabolism of PFOA and PFDA and its effects on oxidation of medium and long-chain fatty acids will be studied. It will be ascertained whether effects of PFOA and PFDA on hepatic lipid metabolism result from depletion of free coenzyme A (CoA) or, more likely, formation of PFOA and PFDA-CoA thioesters as toxic lipophilic conjugates. In primary rat hepatocyte cultures, interrelationships between induction of fatty acyl-CoA oxidase and lauric acid hydroxylase, and inhibition of medium and long-chain fatty acid oxidation, will be examined. PFOA and PFDA will be evaluated in rats for hepatocarcinogenic potential. Until now, no peroxisome proliferator has been identified which does not cause hepatocellular carcinomas in rats and mice in long-term studies. Perfluorinated fatty acids might be the exception as recent findings suggest that PFOA is not hepatocarcinogenic. By evaluating if PFDA and PFOA act as initiators and/or promoters of rat hepatocarcinogenesis, the putative role of peroxisome proliferation in liver cancer might be better understood.