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Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders

Benjamin Lemaire, Akira Kubota, Conor M. O'Meara, David Lamb Orcid Logo, Robert L. Tanguay, Jared V. Goldstone, John J. Stegeman

Toxicology and Applied Pharmacology, Volume: 296, Pages: 73 - 84

Swansea University Author: David Lamb Orcid Logo

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DOI (Published version): 10.1016/j.taap.2016.02.001

Abstract

Cytochrome P450 (CYP) enzymes for which there is no functional information are considered "orphan" CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, sugge...

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Published in: Toxicology and Applied Pharmacology
ISSN: 0041008X
Published: 2016
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URI: https://cronfa.swan.ac.uk/Record/cronfa29840
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spelling 2019-08-18T16:50:09.6111598 v2 29840 2016-09-08 Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false 2016-09-08 BMS Cytochrome P450 (CYP) enzymes for which there is no functional information are considered "orphan" CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, suggesting involvement in brain and in early development. Moreover, hyperactivity is reported in humans with chromosome 2 microdeletions including CYP20A1. We examined CYP20A1 in zebrafish, including impacts of chemical exposure on expression. Zebrafish CYP20A1 cDNA was cloned, sequenced, and aligned with cloned human CYP20A1 and predicted vertebrate orthologs. CYP20A1s share a highly conserved N-terminal region and unusual sequences in the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including the liver, heart, gonads, spleen and brain, as well as the eye and optic nerve. Putative binding sites in proximal promoter regions of CYP20A1s, and response of zebrafish CYP20A1 to selected nuclear and xenobiotic receptor agonists, point to up-regulation by agents involved in steroid hormone response, cholesterol and lipid metabolism. There also was a dose-dependent reduction of CYP20A1 expression in embryos exposed to environmentally relevant levels of methylmercury. Morpholino knockdown of CYP20A1 in developing zebrafish resulted in behavioral effects, including hyperactivity and a slowing of the optomotor response in larvae. The results suggest that altered expression of CYP20A1 might be part of a mechanism linking methylmercury exposure to neurobehavioral deficits. The expanded information on CYP20A1 brings us closer to "deorphanization" CYP20A1 functions and its roles in health and disease. Journal Article Toxicology and Applied Pharmacology 296 73 84 0041008X cytochrome P450; zebrafish; neurobiology 1 4 2016 2016-04-01 10.1016/j.taap.2016.02.001 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-08-18T16:50:09.6111598 2016-09-08T14:45:24.1767383 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Benjamin Lemaire 1 Akira Kubota 2 Conor M. O'Meara 3 David Lamb 0000-0001-5446-2997 4 Robert L. Tanguay 5 Jared V. Goldstone 6 John J. Stegeman 7 0029840-18122016172916.pdf LemaireTAAP2016.pdf 2016-12-18T17:29:16.7630000 Output 2043986 application/pdf Accepted Manuscript true 2016-12-18T00:00:00.0000000 true
title Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders
spellingShingle Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders
David Lamb
title_short Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders
title_full Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders
title_fullStr Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders
title_full_unstemmed Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders
title_sort Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders
author_id_str_mv 1dc64e55c2c28d107ef7c3db984cccd2
author_id_fullname_str_mv 1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
author David Lamb
author2 Benjamin Lemaire
Akira Kubota
Conor M. O'Meara
David Lamb
Robert L. Tanguay
Jared V. Goldstone
John J. Stegeman
format Journal article
container_title Toxicology and Applied Pharmacology
container_volume 296
container_start_page 73
publishDate 2016
institution Swansea University
issn 0041008X
doi_str_mv 10.1016/j.taap.2016.02.001
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description Cytochrome P450 (CYP) enzymes for which there is no functional information are considered "orphan" CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, suggesting involvement in brain and in early development. Moreover, hyperactivity is reported in humans with chromosome 2 microdeletions including CYP20A1. We examined CYP20A1 in zebrafish, including impacts of chemical exposure on expression. Zebrafish CYP20A1 cDNA was cloned, sequenced, and aligned with cloned human CYP20A1 and predicted vertebrate orthologs. CYP20A1s share a highly conserved N-terminal region and unusual sequences in the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including the liver, heart, gonads, spleen and brain, as well as the eye and optic nerve. Putative binding sites in proximal promoter regions of CYP20A1s, and response of zebrafish CYP20A1 to selected nuclear and xenobiotic receptor agonists, point to up-regulation by agents involved in steroid hormone response, cholesterol and lipid metabolism. There also was a dose-dependent reduction of CYP20A1 expression in embryos exposed to environmentally relevant levels of methylmercury. Morpholino knockdown of CYP20A1 in developing zebrafish resulted in behavioral effects, including hyperactivity and a slowing of the optomotor response in larvae. The results suggest that altered expression of CYP20A1 might be part of a mechanism linking methylmercury exposure to neurobehavioral deficits. The expanded information on CYP20A1 brings us closer to "deorphanization" CYP20A1 functions and its roles in health and disease.
published_date 2016-04-01T03:36:22Z
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