Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars)
Toxicity mediated by per- and polyfluoroalkyl substances (PFAS), and especially perfluoroalkyl acids (PFAAs), has been linked to activation of peroxisome proliferator-activated receptors (Ppar) in many vertebrates. Here, we present the primary structures, phylogeny, and tissue-specific distributions...
Published in: | Environment International |
---|---|
Main Authors: | , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Elsevier
2022
|
Subjects: | |
Online Access: | https://hdl.handle.net/11250/3011657 https://doi.org/10.1016/j.envint.2022.107203 |
id |
ftunivbergen:oai:bora.uib.no:11250/3011657 |
---|---|
record_format |
openpolar |
spelling |
ftunivbergen:oai:bora.uib.no:11250/3011657 2023-05-15T15:27:01+02:00 Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars) Söderström, Sofie Karin Lille-Langøy, Roger Yadetie, Fekadu Rauch, Mateusz Milinski, Ana Dejaegere, Annick Stote, Roland H. Goksøyr, Anders Karlsen, Odd André 2022 application/pdf https://hdl.handle.net/11250/3011657 https://doi.org/10.1016/j.envint.2022.107203 eng eng Elsevier Norges forskningsråd: 244564 Norges forskningsråd: 248840 Norges forskningsråd: 323092 urn:issn:0160-4120 https://hdl.handle.net/11250/3011657 https://doi.org/10.1016/j.envint.2022.107203 cristin:2019260 Environment International. 2022, 163, 107203. Navngivelse 4.0 Internasjonal http://creativecommons.org/licenses/by/4.0/deed.no Copyright 2022 The Author(s) 107203 Environment International 163 Journal article Peer reviewed 2022 ftunivbergen https://doi.org/10.1016/j.envint.2022.107203 2023-03-14T17:42:31Z Toxicity mediated by per- and polyfluoroalkyl substances (PFAS), and especially perfluoroalkyl acids (PFAAs), has been linked to activation of peroxisome proliferator-activated receptors (Ppar) in many vertebrates. Here, we present the primary structures, phylogeny, and tissue-specific distributions of the Atlantic cod (Gadus morhua) gmPpara1, gmPpara2, gmPparb, and gmPparg, and demonstrate that the carboxylic acids PFHxA, PFOA, PFNA, as well as the sulfonic acid PFHxS, activate gmPpara1 in vitro, which was also supported by in silico analyses. Intriguingly, a binary mixture of PFOA and the non-activating PFOS produced a higher activation of gmPpara1 compared to PFOA alone, suggesting that PFOS has a potentiating effect on receptor activation. Supporting the experimental data, docking and molecular dynamics simulations of single and double-ligand complexes led to the identification of a putative allosteric binding site, which upon binding of PFOS stabilizes an active conformation of gmPpara1. Notably, binary exposures of gmPpara1, gmPpara2, and gmPparb to model-agonists and PFAAs produced similar potentiating effects. This study provides novel mechanistic insights into how PFAAs may modulate the Ppar signaling pathway by either binding the canonical ligand-binding pocket or by interacting with an allosteric binding site. Thus, individual PFAAs, or mixtures, could potentially modulate the Ppar-signaling pathway in Atlantic cod by interfering with at least one gmPpar subtype. publishedVersion Article in Journal/Newspaper atlantic cod Gadus morhua University of Bergen: Bergen Open Research Archive (BORA-UiB) Environment International 163 107203 |
institution |
Open Polar |
collection |
University of Bergen: Bergen Open Research Archive (BORA-UiB) |
op_collection_id |
ftunivbergen |
language |
English |
description |
Toxicity mediated by per- and polyfluoroalkyl substances (PFAS), and especially perfluoroalkyl acids (PFAAs), has been linked to activation of peroxisome proliferator-activated receptors (Ppar) in many vertebrates. Here, we present the primary structures, phylogeny, and tissue-specific distributions of the Atlantic cod (Gadus morhua) gmPpara1, gmPpara2, gmPparb, and gmPparg, and demonstrate that the carboxylic acids PFHxA, PFOA, PFNA, as well as the sulfonic acid PFHxS, activate gmPpara1 in vitro, which was also supported by in silico analyses. Intriguingly, a binary mixture of PFOA and the non-activating PFOS produced a higher activation of gmPpara1 compared to PFOA alone, suggesting that PFOS has a potentiating effect on receptor activation. Supporting the experimental data, docking and molecular dynamics simulations of single and double-ligand complexes led to the identification of a putative allosteric binding site, which upon binding of PFOS stabilizes an active conformation of gmPpara1. Notably, binary exposures of gmPpara1, gmPpara2, and gmPparb to model-agonists and PFAAs produced similar potentiating effects. This study provides novel mechanistic insights into how PFAAs may modulate the Ppar signaling pathway by either binding the canonical ligand-binding pocket or by interacting with an allosteric binding site. Thus, individual PFAAs, or mixtures, could potentially modulate the Ppar-signaling pathway in Atlantic cod by interfering with at least one gmPpar subtype. publishedVersion |
format |
Article in Journal/Newspaper |
author |
Söderström, Sofie Karin Lille-Langøy, Roger Yadetie, Fekadu Rauch, Mateusz Milinski, Ana Dejaegere, Annick Stote, Roland H. Goksøyr, Anders Karlsen, Odd André |
spellingShingle |
Söderström, Sofie Karin Lille-Langøy, Roger Yadetie, Fekadu Rauch, Mateusz Milinski, Ana Dejaegere, Annick Stote, Roland H. Goksøyr, Anders Karlsen, Odd André Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars) |
author_facet |
Söderström, Sofie Karin Lille-Langøy, Roger Yadetie, Fekadu Rauch, Mateusz Milinski, Ana Dejaegere, Annick Stote, Roland H. Goksøyr, Anders Karlsen, Odd André |
author_sort |
Söderström, Sofie Karin |
title |
Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars) |
title_short |
Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars) |
title_full |
Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars) |
title_fullStr |
Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars) |
title_full_unstemmed |
Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars) |
title_sort |
agonistic and potentiating effects of perfluoroalkyl substances (pfas) on the atlantic cod (gadus morhua) peroxisome proliferator-activated receptors (ppars) |
publisher |
Elsevier |
publishDate |
2022 |
url |
https://hdl.handle.net/11250/3011657 https://doi.org/10.1016/j.envint.2022.107203 |
genre |
atlantic cod Gadus morhua |
genre_facet |
atlantic cod Gadus morhua |
op_source |
107203 Environment International 163 |
op_relation |
Norges forskningsråd: 244564 Norges forskningsråd: 248840 Norges forskningsråd: 323092 urn:issn:0160-4120 https://hdl.handle.net/11250/3011657 https://doi.org/10.1016/j.envint.2022.107203 cristin:2019260 Environment International. 2022, 163, 107203. |
op_rights |
Navngivelse 4.0 Internasjonal http://creativecommons.org/licenses/by/4.0/deed.no Copyright 2022 The Author(s) |
op_doi |
https://doi.org/10.1016/j.envint.2022.107203 |
container_title |
Environment International |
container_volume |
163 |
container_start_page |
107203 |
_version_ |
1766357488162045952 |