Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro
Vitamin D receptor (VDR) mediates the biological function of the steroid hormone calcitriol, which is the metabolically active version of vitamin D. Calcitriol is important for a wide array of physiological functions, including calcium and phosphate homeostasis. In contrast to mammals, which harbor...
Published in: | Aquatic Toxicology |
---|---|
Main Authors: | , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
2021
|
Subjects: | |
Online Access: | https://hdl.handle.net/11250/2838280 https://doi.org/10.1016/j.aquatox.2021.105914 |
id |
ftimr:oai:imr.brage.unit.no:11250/2838280 |
---|---|
record_format |
openpolar |
spelling |
ftimr:oai:imr.brage.unit.no:11250/2838280 2023-05-15T15:27:07+02:00 Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro Goksøyr, Siri Øfsthus Goldstone, Jed Lille-Langøy, Roger Lock, Erik Jan Robert Olsvik, Pål Asgeir Goksøyr, Anders Karlsen, Odd André 2021 application/pdf https://hdl.handle.net/11250/2838280 https://doi.org/10.1016/j.aquatox.2021.105914 eng eng Norges forskningsråd: 248840 Norges forskningsråd: 244564 Aquatic Toxicology. 2021, 238 1-11. urn:issn:0166-445X https://hdl.handle.net/11250/2838280 https://doi.org/10.1016/j.aquatox.2021.105914 cristin:1966214 1-11 238 Aquatic Toxicology Peer reviewed Journal article 2021 ftimr https://doi.org/10.1016/j.aquatox.2021.105914 2022-01-26T23:38:54Z Vitamin D receptor (VDR) mediates the biological function of the steroid hormone calcitriol, which is the metabolically active version of vitamin D. Calcitriol is important for a wide array of physiological functions, including calcium and phosphate homeostasis. In contrast to mammals, which harbor one VDR encoding gene, teleosts possess two orthologous vdr genes encoding Vdr alpha (Vdra) and Vdr beta (Vdrb). Genome mining identified the vdra and vdrb paralogs in the Atlantic cod (Gadus morhua) genome, which were further characterized regarding their phylogeny, tissue-specific expression, and transactivational properties induced by calcitriol. In addition, a selected set of polycyclic aromatic hydrocarbons (PAHs), including naphthalene, phenanthrene, fluorene, pyrene, chrysene, benzo[a]pyrene (BaP), and 7-methylbenzo[a]pyrene, were assessed for their ability to modulate the transcriptional activity of gmVdra and gmVdrb in vitro. Both gmVdra and gmVdrb were activated by calcitriol with similar potencies, but gmVdra produced significantly higher maximal fold activation. Notably, none of the tested PAHs showed agonistic properties towards the Atlantic cod Vdrs. However, binary exposures of calcitriol together with phenanthrene, fluorene, or pyrene, antagonized the activation of gmVdra, while chrysene and BaP significantly potentiated the calcitriol-mediated activity of both receptors. Homology modeling, solvent mapping, and docking analyses complemented the experimental data, and revealed a putative secondary binding site in addition to the canonical ligand-binding pocket (LBP). Calcitriol was predicted to interact with both binding sites, whereas PAHs docked primarily to the LBP. Importantly, our in vitro data suggest that PAHs can interact with the paralogous gmVdrs and interfere with their transcriptional activities, and thus potentially modulate the vitamin D signaling pathway and contribute to adverse effects of crude oil and PAH exposures on cardiac development and bone deformities in fish. publishedVersion Article in Journal/Newspaper atlantic cod Gadus morhua Institute for Marine Research: Brage IMR Aquatic Toxicology 238 105914 |
institution |
Open Polar |
collection |
Institute for Marine Research: Brage IMR |
op_collection_id |
ftimr |
language |
English |
description |
Vitamin D receptor (VDR) mediates the biological function of the steroid hormone calcitriol, which is the metabolically active version of vitamin D. Calcitriol is important for a wide array of physiological functions, including calcium and phosphate homeostasis. In contrast to mammals, which harbor one VDR encoding gene, teleosts possess two orthologous vdr genes encoding Vdr alpha (Vdra) and Vdr beta (Vdrb). Genome mining identified the vdra and vdrb paralogs in the Atlantic cod (Gadus morhua) genome, which were further characterized regarding their phylogeny, tissue-specific expression, and transactivational properties induced by calcitriol. In addition, a selected set of polycyclic aromatic hydrocarbons (PAHs), including naphthalene, phenanthrene, fluorene, pyrene, chrysene, benzo[a]pyrene (BaP), and 7-methylbenzo[a]pyrene, were assessed for their ability to modulate the transcriptional activity of gmVdra and gmVdrb in vitro. Both gmVdra and gmVdrb were activated by calcitriol with similar potencies, but gmVdra produced significantly higher maximal fold activation. Notably, none of the tested PAHs showed agonistic properties towards the Atlantic cod Vdrs. However, binary exposures of calcitriol together with phenanthrene, fluorene, or pyrene, antagonized the activation of gmVdra, while chrysene and BaP significantly potentiated the calcitriol-mediated activity of both receptors. Homology modeling, solvent mapping, and docking analyses complemented the experimental data, and revealed a putative secondary binding site in addition to the canonical ligand-binding pocket (LBP). Calcitriol was predicted to interact with both binding sites, whereas PAHs docked primarily to the LBP. Importantly, our in vitro data suggest that PAHs can interact with the paralogous gmVdrs and interfere with their transcriptional activities, and thus potentially modulate the vitamin D signaling pathway and contribute to adverse effects of crude oil and PAH exposures on cardiac development and bone deformities in fish. publishedVersion |
format |
Article in Journal/Newspaper |
author |
Goksøyr, Siri Øfsthus Goldstone, Jed Lille-Langøy, Roger Lock, Erik Jan Robert Olsvik, Pål Asgeir Goksøyr, Anders Karlsen, Odd André |
spellingShingle |
Goksøyr, Siri Øfsthus Goldstone, Jed Lille-Langøy, Roger Lock, Erik Jan Robert Olsvik, Pål Asgeir Goksøyr, Anders Karlsen, Odd André Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro |
author_facet |
Goksøyr, Siri Øfsthus Goldstone, Jed Lille-Langøy, Roger Lock, Erik Jan Robert Olsvik, Pål Asgeir Goksøyr, Anders Karlsen, Odd André |
author_sort |
Goksøyr, Siri Øfsthus |
title |
Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro |
title_short |
Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro |
title_full |
Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro |
title_fullStr |
Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro |
title_full_unstemmed |
Polycyclic aromatic hydrocarbons modulate the activity of Atlantic cod (Gadus morhua) vitamin D receptor paralogs in vitro |
title_sort |
polycyclic aromatic hydrocarbons modulate the activity of atlantic cod (gadus morhua) vitamin d receptor paralogs in vitro |
publishDate |
2021 |
url |
https://hdl.handle.net/11250/2838280 https://doi.org/10.1016/j.aquatox.2021.105914 |
genre |
atlantic cod Gadus morhua |
genre_facet |
atlantic cod Gadus morhua |
op_source |
1-11 238 Aquatic Toxicology |
op_relation |
Norges forskningsråd: 248840 Norges forskningsråd: 244564 Aquatic Toxicology. 2021, 238 1-11. urn:issn:0166-445X https://hdl.handle.net/11250/2838280 https://doi.org/10.1016/j.aquatox.2021.105914 cristin:1966214 |
op_doi |
https://doi.org/10.1016/j.aquatox.2021.105914 |
container_title |
Aquatic Toxicology |
container_volume |
238 |
container_start_page |
105914 |
_version_ |
1766357574954778624 |