ToxSci Advance Access originally published online on April 30, 2009
Toxicological Sciences 2009 111(1):89-99; doi:10.1093/toxsci/kfp093
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Structure-Activity Relationships and Human Relevance for Perfluoroalkyl Acid–Induced Transcriptional Activation of Peroxisome Proliferation in Liver Cell Cultures
Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, Minnesota 55812
1 To whom correspondence should be addressed at Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, 1035 University Drive, Duluth, MN 55812. Fax: 218-726-8014. E-mail: kwallace{at}d.umn.edu.
Received February 25, 2009; accepted April 15, 2009
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Abstract |
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Perfluoroalkyl acids (PFAAs) are widely distributed and environmentally persistent agents whose potential toxicity is not yet fully characterized. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid elicit a number of potential toxicities in rodents, the most prevalent of which are governed by activation of the peroxisome proliferator-activated receptor alpha (PPAR
). The purpose of this investigation was twofold: (1) To conduct a structure-activity relationship study of the transcriptional activation of peroxisome proliferation in primary rat liver cell cultures for PFAA-related carboxylic and sulfonic acids of varying carbon chain length and (2) to explore whether this activity can be translated to human liver cells in culture. Exposure to PFOA caused a dose-dependent stimulation of the expression of acyl-CoA oxidase (Acox), Cte/Acot1, and Cyp4a1/11 transcripts that are indicative of peroxisome proliferation in primary rat hepatocytes. PFOA concentrations of 30µM and above caused cell injury characterized by the expression of Ddit3. Perfluorobutanoic acid (PFBA), on the other hand, stimulated Acox, Cte/Acot1, and Cyp4a1/11 gene expression in primary rat hepatocytes only at concentrations of 100µM and above. Neither PFOA nor PFBA at concentrations up to 200µM stimulated PPAR-related gene expression in either primary or HepG2 human liver cells. These data demonstrate that (1) PFFAs cause a concentration- and chain length-dependent increase in expression of gene targets related to cell injury and PPAR activation in primary rat hepatocytes, (2) the sulfonates are less potent than the corresponding carboxylates in stimulating PPAR-related gene expression in rat hepatocytes, and (3) stimulation of PPAR-mediated gene transcription is a mechanism that is not shared by human liver cells, adding further substantiation that PPAR-dependent liver toxicity in rodents does not extrapolate to assessing human health concerns.
Key Words: PFOA; PFOS; hepatocytes; gene expression; transcription; peroxisome proliferation; PPAR.