Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα
Open accessAbstract
Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) alpha, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARalpha transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARalpha), Pparalpha-null mice and humanized PPARalpha (hPPARalpha) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARalpha mice. APFO increased mRNA and/or protein levels of PPARalpha target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARalpha mice, but not in Pparalpha-null or hPPARalpha mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARalpha mice. Taken together, human PPARalpha may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans.
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Activation of PPARα target genes by APFO is prominently observed in the liver of mice with mouse PPARα, whereas such effects are notably absent in mice lacking PPARα or possessing human PPARα.
“Specifically, activation of PPARα target genes by ammonium perflurooctanate (APFO) is prominently observed in the liver of mice with mouse PPARα, whereas such effects are notably absent in mice lacking PPARα or possessing human PPARα [34].”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [34]
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References 41 · Cited by 57
Research works printed but not linked: 1
- Kennedy GL Jr. Butenhoff JL Olsen GW O’Connor JC Seacat AM Perkins RG Biegel LB Murphy SR Farrar DG The toxicology of perfluorooc-tanoate Crit. Rev. Toxicol 2004 34 351 384 15328768
- Authors
- Nakamura, T., Ito, Y., Yanagiba, Y., Ramdhan, D. H., Kono, Y., Naito, H., Hayashi, Y., Li, Y., Aoyama, T., Gonzalez, F. J., & Nakajima, T.
- Affiliations
- Nagoya University (JP)
- Shinshu University (JP)
- National Institutes of Health (US)
- Corresponding author
- Nakajima, Tamie
- ORCID
- Venue
- Toxicology
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 265
- Issue
- 1-2
- Pages
- 27-33
- ISSN
- 0300-483X (ISSN-L)
- PMC
- PMC2848383
- OpenAlex
- W1976699926
- Cited by
- 57
- References
- 41
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 4 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 6
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Environmental Protection Agency
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Cancer Institute (ZIABC005708)
- 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 › Effects and risks of endocrine disrupting chemicals
- Keywords
- perfluorooctanoic acid, ammonium perfluorooctanoate, PPARα, species differences, PPARα target genes, Cyp4a10, hepatic lipid metabolism, VLCAD
- MeSH terms
- Alanine Transaminase, Animals, Biotransformation, Body Weight, Caprylates, Cell Nucleus, Cricetulus, Female, Fluorocarbons, Cricetinae, Humans, Lipids, Male, Organ Size, RNA, Messenger, Species Specificity, Blotting, Western, Gene Expression, CHO Cells, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, PPAR alpha, Lipid Metabolism, Mice
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