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Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse
Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intrates...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449127/ https://www.ncbi.nlm.nih.gov/pubmed/26023917 http://dx.doi.org/10.1371/journal.pone.0128694 |
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author | Musicki, Biljana Zhang, Yuxi Chen, Haolin Brown, Terry R. Zirkin, Barry R. Burnett, Arthur L. |
author_facet | Musicki, Biljana Zhang, Yuxi Chen, Haolin Brown, Terry R. Zirkin, Barry R. Burnett, Arthur L. |
author_sort | Musicki, Biljana |
collection | PubMed |
description | Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi) exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease. |
format | Online Article Text |
id | pubmed-4449127 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44491272015-06-09 Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse Musicki, Biljana Zhang, Yuxi Chen, Haolin Brown, Terry R. Zirkin, Barry R. Burnett, Arthur L. PLoS One Research Article Testosterone deficiency is associated with sickle cell disease (SCD), but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle) exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH) levels compared with wild type (WT) mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol)- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR), but not cholesterol side-chain cleavage enzyme (P450scc), in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi) exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease. Public Library of Science 2015-05-29 /pmc/articles/PMC4449127/ /pubmed/26023917 http://dx.doi.org/10.1371/journal.pone.0128694 Text en © 2015 Musicki et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Musicki, Biljana Zhang, Yuxi Chen, Haolin Brown, Terry R. Zirkin, Barry R. Burnett, Arthur L. Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse |
title | Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse |
title_full | Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse |
title_fullStr | Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse |
title_full_unstemmed | Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse |
title_short | Mechanism of Testosterone Deficiency in the Transgenic Sickle Cell Mouse |
title_sort | mechanism of testosterone deficiency in the transgenic sickle cell mouse |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449127/ https://www.ncbi.nlm.nih.gov/pubmed/26023917 http://dx.doi.org/10.1371/journal.pone.0128694 |
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