The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Activation of human nuclear receptors by perfluoroalkylated substances (PFAS)
Abstract
Perfluoralkylated substances (PFAS) such as perfluorooctanoic acid (PFOA) or perfluorooctanesulfonic acid (PFOS) are used to produce, e.g., surface coatings with water- and dirt-repellent properties. These substances have been shown to be hepatotoxic in rodents, and the mechanism of action is mostly attributed to the PFAS-mediated activation of the peroxisome proliferator-activated receptor alpha (PPARα). In the present study, we investigated by using luciferase-based reporter gene assays whether PFOA, PFOS and six alternative PFAS can activate, in addition to PPARα, eight other human nuclear receptors. All tested PFAS except for perfluorobutanesulfonic acid (PFBS) were able to activate human PPARα. Perfluoro-2-methyl-3-oxahexanoic acid (PMOH) and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were weak agonists of human PPARγ. The other human nuclear receptors (PPARδ, CAR, PXR, FXR, LXRα, RXRα and RARα) were not affected by any PFAS tested in this study. Although PMOH was more effective than PFOA in stimulating PPARα in the transactivation assay, it was less effective in stimulating PPARα-dependent target gene expression in human HepG2 hepatocarcinoma cells. Notably, any effect observed in this in vitro study only occurred at concentrations higher than 10 μM of the respective PFAS which is in all cases several magnitudes above the average blood concentration in the Western population. Thus, the results suggest that nuclear receptor activation may only play a minor role in potential PFAS-mediated adverse effects in humans.
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“The results showed that all of the PFAS tested, except PFBS, activated human PPARα. Perfluoro-2-methyl-3-oxahexanoic acid (PMOH) and 3H-perfluoro-3-[(3-methoxypropoxy)propanoic acid] (PMPP) were weak agonists of human PPARγ. The other human nuclear receptors tested (PPARδ, CAR, PXR, FXR, LXRα, RXRα, and RARα) were not activated by any of the tested PFAS.”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [38]
In the citing paper
“PPARs within the brain may serve as important molecular targets of PFAS that can impact metabolic homeostasis”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Behr et al., 2020
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Peroxisome Proliferator-Activated Receptor Alpha Target Genes
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Trends in Exposure to Polyfluoroalkyl Chemicals in the U.S. Population: 1999−2008
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The toxicology of perfluorooctanoate
Kennedy, G. L., Butenhoff, J. L., Olsen, G. W., O'Connor, J. C., Seacat, A. M., Perkins, R. G., Biegel, L. B., Murphy, S. R., & Farrar, D. G. (2004) · Critical Reviews in Toxicology · doi:10.1080/10408440490464705 · Cited by 742
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Fenton, S. E., Ducatman, A., Boobis, A., DeWitt, J. C., Lau, C., Ng, C., Smith, J. S., & Roberts, S. M. (2020) · Environmental Toxicology and Chemistry · doi:10.1002/etc.4890 · Cited by 2,445
Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests
Masoodi, M., Gastaldelli, A., Hyötyläinen, T., Arretxe, E., Alonso, C., Gaggini, M., Brosnan, J., Anstee, Q. M., Millet, O., Ortiz, P., et al. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00502-9 · Cited by 451
Costello, E., Rock, S., Stratakis, N., Eckel, S. P., Walker, D. I., Valvi, D., Cserbik, D., Jenkins, T., Xanthakos, S. A., Kohli, R., et al. (2022) · Environmental Health Perspectives · doi:10.1289/ehp10092 · Cited by 420
Consideration of pathways for immunotoxicity of per-and polyfluoroalkyl substances (PFAS)
Ehrlich, V., Bil, W., Vandebriel, R., Granum, B., Luijten, M., Lindeman, B., Grandjean, P., Kaiser, A.-M., Hauzenberger, I., Hartmann, C., et al. (2023) · Environmental Health · doi:10.1186/s12940-022-00958-5 · Cited by 318
Roth, K., Yang, Z., Agarwal, M., Liu, W. J., Peng, Z., Long, Z., Birbeck, J. A., Westrick, J. A., Liu, W., & Petriello, M. C. (2021) · Environment International · doi:10.1016/j.envint.2021.106843 · Cited by 322
Metadata
- Authors
- Behr, A.-C., Plinsch, C., Braeuning, A., & Buhrke, T.
- Affiliations
- German Federal Institute for Risk Assessment (BfR) (DE)
- Corresponding author
- Buhrke, Thorsten
- Venue
- Toxicology in Vitro
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 62
- Pages
- 104700
- ISSN
- 0887-2333 (ISSN-L)
- OpenAlex
- W2982329931
- Cited by
- 235
- References
- 53
- Citations by year
- 2026: 36 · 2025: 41 · 2024: 32 · 2023: 40 · 2022: 43 · 2021: 32 · 2020: 11
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology in Vitro (publishedVersion)
- PubMed (publishedVersion)
- OpenAgrar (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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 › Chemistry › Organic Chemistry › Fluorine in Organic Chemistry
- Keywords
- perfluorooctanoic acid, PFOS, PFBS, PPARα, PPARγ, nuclear receptor activation, hepatotoxicity, PPARα agonist, PFAS alternatives, HepG2 cells, endocrine disruption
- MeSH terms
- Caprylates, Fluorocarbons, Humans, Sulfonic Acids, Transcriptional Activation, Gene Expression, Alkanesulfonic Acids, Genes, Reporter, Receptors, Cytoplasmic and Nuclear, Cell Line, Tumor, PPAR alpha, Hep G2 Cells, HEK293 Cells
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