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In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor
Per- and poly-fluoroalkyl substances (PFASs) are used extensively in a broad range of industrial applications and consumer products. While a few legacy PFASs have been voluntarily phased out, over 5000 PFASs have been produced as replacements for their predecessors. The potential endocrine disruptin...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9705075/ https://www.ncbi.nlm.nih.gov/pubmed/35093747 http://dx.doi.org/10.1016/j.jhazmat.2022.128243 |
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author | Tachachartvanich, Phum Singam, Ettayapuram Ramaprasad Azhagiya Durkin, Kathleen A. Furlow, J. David Smith, Martyn T. Merrill, Michele A. La |
author_facet | Tachachartvanich, Phum Singam, Ettayapuram Ramaprasad Azhagiya Durkin, Kathleen A. Furlow, J. David Smith, Martyn T. Merrill, Michele A. La |
author_sort | Tachachartvanich, Phum |
collection | PubMed |
description | Per- and poly-fluoroalkyl substances (PFASs) are used extensively in a broad range of industrial applications and consumer products. While a few legacy PFASs have been voluntarily phased out, over 5000 PFASs have been produced as replacements for their predecessors. The potential endocrine disrupting hazards of most emerging PFASs have not been comprehensively investigated. In silico molecular docking to the human androgen receptor (hAR) combined with machine learning techniques were previously applied to 5206 PFASs and predicted 23 PFASs bind the hAR. Herein, the in silico results were validated in vitro for the five candidate AR ligands that were commercially available. Three manufactured PFASs namely (9-(nonafluorobutyl)– 2,3,6,7-tetrahydro-1 H,5 H,11 H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one (NON), 2-(heptafluoropropyl)– 3-phenylquinoxaline (HEP), and 2,2,3,3,4,4,5,5,5-nonafluoro-N-(4-nitrophenyl)pentanamide (NNN) elicited significant antiandrogenic effects at relatively low concentrations. We further investigated the mechanism of AR inhibition and found that all three PFASs inhibited AR transactivation induced by testosterone through a competitive binding mechanism. We then examined the antiandrogenic effects of these PFASs on AR expression and its responsive genes. Consistently, these PFASs significantly decreased the expression of PSA and FKBP5 and increased the expression of AR, similar to the effects elicited by a known competitive AR inhibitor, hydroxyflutamide. This suggests they are competitive antagonists of AR activity and western blot analysis revealed these PFASs decreased intracellular AR protein in androgen sensitive human prostate cancer cells. Hence, the findings presented here corroborate our published in silico approach and indicate these emerging PFASs may adversely affect the human endocrine system. |
format | Online Article Text |
id | pubmed-9705075 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-97050752022-11-28 In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor Tachachartvanich, Phum Singam, Ettayapuram Ramaprasad Azhagiya Durkin, Kathleen A. Furlow, J. David Smith, Martyn T. Merrill, Michele A. La J Hazard Mater Article Per- and poly-fluoroalkyl substances (PFASs) are used extensively in a broad range of industrial applications and consumer products. While a few legacy PFASs have been voluntarily phased out, over 5000 PFASs have been produced as replacements for their predecessors. The potential endocrine disrupting hazards of most emerging PFASs have not been comprehensively investigated. In silico molecular docking to the human androgen receptor (hAR) combined with machine learning techniques were previously applied to 5206 PFASs and predicted 23 PFASs bind the hAR. Herein, the in silico results were validated in vitro for the five candidate AR ligands that were commercially available. Three manufactured PFASs namely (9-(nonafluorobutyl)– 2,3,6,7-tetrahydro-1 H,5 H,11 H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one (NON), 2-(heptafluoropropyl)– 3-phenylquinoxaline (HEP), and 2,2,3,3,4,4,5,5,5-nonafluoro-N-(4-nitrophenyl)pentanamide (NNN) elicited significant antiandrogenic effects at relatively low concentrations. We further investigated the mechanism of AR inhibition and found that all three PFASs inhibited AR transactivation induced by testosterone through a competitive binding mechanism. We then examined the antiandrogenic effects of these PFASs on AR expression and its responsive genes. Consistently, these PFASs significantly decreased the expression of PSA and FKBP5 and increased the expression of AR, similar to the effects elicited by a known competitive AR inhibitor, hydroxyflutamide. This suggests they are competitive antagonists of AR activity and western blot analysis revealed these PFASs decreased intracellular AR protein in androgen sensitive human prostate cancer cells. Hence, the findings presented here corroborate our published in silico approach and indicate these emerging PFASs may adversely affect the human endocrine system. 2022-05-05 2022-01-10 /pmc/articles/PMC9705075/ /pubmed/35093747 http://dx.doi.org/10.1016/j.jhazmat.2022.128243 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Tachachartvanich, Phum Singam, Ettayapuram Ramaprasad Azhagiya Durkin, Kathleen A. Furlow, J. David Smith, Martyn T. Merrill, Michele A. La In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor |
title | In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor |
title_full | In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor |
title_fullStr | In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor |
title_full_unstemmed | In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor |
title_short | In Vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (PFASs) on the human androgen receptor |
title_sort | in vitro characterization of the endocrine disrupting effects of per- and poly-fluoroalkyl substances (pfass) on the human androgen receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9705075/ https://www.ncbi.nlm.nih.gov/pubmed/35093747 http://dx.doi.org/10.1016/j.jhazmat.2022.128243 |
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