Structure-Activity Relationships and Human Relevance for Perfluoroalkyl Acid-Induced Transcriptional Activation of Peroxisome Proliferation in Liver Cell Cultures

Bjork, James A.; Wallace, Kendall B.

doi:10.1093/toxsci/kfp093

Cited by 137Per- and polyfluoroalkyl substances researchPeroxisome Proliferator-Activated ReceptorsToxic Organic Pollutants Impact

Structure-Activity Relationships and Human Relevance for Perfluoroalkyl Acid-Induced Transcriptional Activation of Peroxisome Proliferation in Liver Cell Cultures

Bjork, James A., Wallace, Kendall B.·2009·Toxicological Sciences

DOI 10.1093/toxsci/kfp093

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Abstract

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 (PPARalpha). 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 30 microM 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 100 microM and above. Neither PFOA nor PFBA at concentrations up to 200 microM stimulated PPARalpha-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 PPARalpha activation in primary rat hepatocytes, (2) the sulfonates are less potent than the corresponding carboxylates in stimulating PPARalpha-related gene expression in rat hepatocytes, and (3) stimulation of PPARalpha-mediated gene transcription is a mechanism that is not shared by human liver cells, adding further substantiation that PPARalpha-dependent liver toxicity in rodents does not extrapolate to assessing human health concerns.

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PPARα-mediated liver toxicity observed in rodents cannot be directly extrapolated to assess human health implications.
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Authors: Bjork, J. A., & Wallace, K. B.
Affiliations: University of Minnesota (US)
ORCID: Bjork, James A.
Wallace, Kendall B.
Venue: Toxicological Sciences
Publisher: Oxford University Press (OUP)
Published: 2009-04-30
Volume: 111
Issue: 1
Pages: 89-99
ISSN: 1096-0929 (ISSN-L)
1096-6080
DOI: 10.1093/toxsci/kfp093
OpenAlex: W2125775820
Cited by: 137
References: 48
Citations by year: 2026: 10 · 2025: 6 · 2024: 10 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 7 · 2016: 3 · 2015: 10 · 2014: 11 · 2013: 10 · 2012: 10
FWCI: 8.10
Type: journal article
Language: en
Open access: closed
Locations: Toxicological Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Keywords: perfluoroalkyl acids, perfluorooctanoic acid, perfluorobutanoic acid, PPARα, peroxisome proliferation, structure-activity relationship, hepatotoxicity, acyl-CoA oxidase, DDIT3, species differences in toxicity, chain length dependence
MeSH terms: Animals, Cell Line, Cells, Cultured, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Fluorocarbons, Humans, Liver, RNA, Structure-Activity Relationship, Transcriptional Activation, DNA Primers, Peroxisome Proliferators, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Cytochrome P-450 CYP4A, Acyl-CoA Oxidase, PPAR alpha, Rats

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Structure-Activity Relationships and Human Relevance for Perfluoroalkyl Acid-Induced Transcriptional Activation of Peroxisome Proliferation in Liver Cell Cultures

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