Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance-Associated Protein 2 at the Blood-Brain Barrier
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BACKGROUND: Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid (GenX) is a replacement for perfluorooctanoic acid in the production of fluoropolymers used in a variety of consumer products.GenX alters fetal development and antibody production and elicits toxic responses in the livers and kidneys of rodents.The GenX effect on the blood-brain barrier (BBB) is unknown.The BBB protects the brain from xenobiotic neurotoxicants and harmful endogenous metabolites.OBJECTIVES: We aimed to investigate the effects of GenX on the transport activity and expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) at the BBB.METHODS: Transporter activities were measured in isolated rat brain capillaries by a confocal microscopy-based method.ATPase (enzymatic hydrolysis of adenosine triphosphate to inorganic phosphate) levels were measured in vitro.Western blotting determined P-gp and BCRP protein levels.Cell survival after GenX exposure was determined for two human cell lines.RESULTS: Nanomolar levels of GenX inhibited P-gp and BCRP but not MRP2 transport activities in male and female rat brain capillaries.P-gp transport activity returned to control levels after GenX removal.GenX did not reduce P-gp-or BCRP-associated ATPase activity in an in vitro transport assay system.Reductions of P-gp but not BCRP transport activity were blocked by a peroxisome proliferator-activated receptor c (PPARc) antagonist.GenX reduced P-gp and BCRP transport activity in human cells.CONCLUSION: In rats, GenX at 0:1-100 nM rapidly (in 1-2 h) inhibited P-gp and BCRP transport activities at the BBB through different mechanisms.PPARc was required for the GenX effects on P-gp but not BCRP transport activity.
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Decreased breast cancer resistance protein transport activity following GenX exposure was not reversible, suggesting GenX may permanently alter blood-brain barrier xenobiotic efflux transport following short-term exposure in vitro.
“However, the decreased transport activity of BCRP following GenX exposure was not reversible, suggesting that GenX may permanently alter BBB xenobiotic efflux transport following short-term exposure in vitro (Cannon et al., 2020).”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Cannon et al., 2020
The Results (Reversibility Assays; page unavailable) report that BCRP transport in isolated rat brain capillaries did not return to control levels after GenX removal. The Methods (Measuring Transport Activity after GenX Removal; page unavailable) show that activity was measured for only three hours afterward, so the suggestion of a permanent alteration goes beyond what the experiment establishes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDiscontinuation of GenX exposure allowed P-glycoprotein transport activity to return to baseline.
“Discontinuation of exposure to GenX allowed P-gp transport activity to return to baseline.”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Cannon et al., 2020
GenX decreases the transport activity of P-glycoprotein and breast cancer resistance protein in isolated rat brain capillaries.
“This study found that GenX decreases the transport activity of P-gp and breast cancer resistance protein (BCRP), two ABC transporters which actively limit endogenous ligands, xenobiotics, and drugs from reaching sensitive target tissues, including the brain.”
From A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior (2022) · cites this paper as Cannon et al., 2020
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- Authors
- Cannon, R. E., Richards, A. C., Trexler, A. W., Juberg, C. T., Sinha, B., Knudsen, G. A., & Birnbaum, L. S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Cannon, Ronald E.
- Venue
- Environmental Health Perspectives
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-03
- Volume
- 128
- Issue
- 3
- Pages
- 37002-37002
- ISSN
- 0091-6765 (ISSN-L)
- 1552-9924
- PMC
- PMC7137913
- OpenAlex
- W3013542392
- Cited by
- 43
- References
- 33
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 4 · 2023: 10 · 2022: 9 · 2021: 4 · 2020: 1
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- Locations
- Environmental Health Perspectives (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (ZIABC011476)
- National Institute of Environmental Health Sciences
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Keywords
- GenX, perfluorinated compounds, blood-brain barrier, P-glycoprotein, ABCG2, MRP2, transporter inhibition, PPARc, brain capillaries, neurotoxicity, fluorinated polymers
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Blood-Brain Barrier, Female, Fluorocarbons, Male, Propionates, Rats, Sprague-Dawley, ATP-Binding Cassette Transporters, ATP Binding Cassette Transporter, Subfamily B, Member 1, Rats
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