Dexamethasone suppresses the differentiation of stem Leydig cells in rats in vitro

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Abstract

Background

It is an established fact that excess of glucocorticoids could cause the harmful effects, such as suppression on the male reproduction. Although glucocorticoids pharmacologically inhibit the Leydig cell function, their roles in Leydig cell development are unclear. Therefore, the present study was designed to investigate effects of synthetic glucocorticoid dexamethasone (DEX) on rat stem Leydig cell proliferation and differentiation.

Methods

Male Sprague-Dawley rats received a single intraperitoneal injection of 75 mg/kg EDS to eliminate Leydig cells and an in vitro culture system of the seminiferous tubules was established from Leydig cell-depleted testis. Using basal medium and Leydig cell differentiation-inducing medium (LIM) in the culture system, we examined the effects of DEX (0–100 nM) on the proliferation and differentiation of the stem Leydig cells in vitro , respectively.

Results

Results showed that LIM is a good agent to induce stem Leydig cell differentiation into Leydig cells that produce testosterone in vitro . DEX inhibited the differentiation of stem Leydig cells by reducing the expression levels of Cyp17a1 and Scarb1 and that NR3C1 antagonist RU38486 reversed the DEX-mediated effects. However, DEX are not involved with the proliferation of stem Leydig cells.

Conclusions

DEX suppressed the differentiation of rat Leydig cells in vitro and glucocorticoid-induced effects acted through NR3C1. This suppression partially targets on Cyp17a1 and Scarb1 gene expression.

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Most cited references 35

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The human glucocorticoid receptor: molecular basis of biologic function.

Nicolas C Nicolaides, Zoi Galata, Tomoshige Kino … (2010)

The characterization of the subfamily of steroid hormone receptors has enhanced our understanding of how a set of hormonally derived lipophilic ligands controls cellular and molecular functions to influence development and help achieve homeostasis. The glucocorticoid receptor (GR), the first member of this subfamily, is a ubiquitously expressed intracellular protein, which functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes. The effector domains of the GR mediate transcriptional activation by recruiting coregulatory multi-subunit complexes that remodel chromatin, target initiation sites, and stabilize the RNA-polymerase II machinery for repeated rounds of transcription of target genes. This review summarizes the basic aspects of the structure and actions of the human (h) GR, and the molecular basis of its biologic functions.

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In search of rat stem Leydig cells: identification, isolation, and lineage-specific development.

Barry Zirkin, Qiang Dong, Chantal Sottas … (2006)

Leydig cells (LCs) are thought to differentiate from spindle-shaped precursor cells that exhibit some aspects of differentiated function, including 3beta-hydroxysteroid dehydrogenase (3betaHSD) activity. The precursor cells ultimately derive from undifferentiated stem LCs (SLCs), which are postulated to be present in testes before the onset of precursor cell differentiation. We searched for cells in the neonatal rat testis with the abilities to: (i) proliferate and expand indefinitely in vitro (self renew); (ii) differentiate (i.e., 3betaHSD and ultimately synthesize testosterone); and (iii) when transplanted into host rat testes, colonize the interstitium and subsequently differentiate in vivo. At 1 week postpartum, spindle-shaped cells were seen in the testicular interstitium that differed from the precursor cells in that they were 3betaHSD-negative, luteinizing hormone (LH) receptor (LHR)-negative, and platelet-derived growth factor receptor alpha (PDGFR alpha)-positive. These cells were purified from the testes of 1-week-old rats. The cells contained proteins known to be involved in LC development, including GATA4, c-kit receptor, and leukemia inhibitory factor receptor. The putative SLCs expanded over the course of 6 months while remaining undifferentiated. When treated in media that contained thyroid hormone, insulin-like growth factor I, and LH, 40% of the putative SLCs came to express 3betaHSD and to synthesize testosterone. When transplanted into host rat testes from which LCs had been eliminated, the putative SLCs colonized the interstitium and subsequently expressed 3betaHSD, demonstrating their ability to differentiate in vivo. We conclude that these cells are likely to be the sought-after SLCs.

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Insights into the Development of the Adult Leydig Cell Lineage from Stem Leydig Cells

Leping Ye, Xiaoheng Li, Linxi Li … (2017)

Adult Leydig cells (ALCs) are the steroidogenic cells in the testes that produce testosterone. ALCs develop postnatally from a pool of stem cells, referred to as stem Leydig cells (SLCs). SLCs are spindle-shaped cells that lack steroidogenic cell markers, including luteinizing hormone (LH) receptor and 3β-hydroxysteroid dehydrogenase. The commitment of SLCs into the progenitor Leydig cells (PLCs), the first stage in the lineage, requires growth factors, including Dessert Hedgehog (DHH) and platelet-derived growth factor-AA. PLCs are still spindle-shaped, but become steroidogenic and produce mainly androsterone. The next transition in the lineage is from PLC to the immature Leydig cell (ILC). This transition requires LH, DHH, and androgen. ILCs are ovoid cells that are competent for producing a different form of androgen, androstanediol. The final stage in the developmental lineage is ALC. The transition to ALC involves the reduced expression of 5α-reductase 1, a step that is necessary to make the cells to produce testosterone as the final product. The transitions along the Leydig cell lineage are associated with the progressive down-regulation of the proliferative activity, and the up-regulation of steroidogenic capacity, with each step requiring unique regulatory signaling.

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Author and article information

Contributors

Jingwei Zhang: 15zhangjingwei@tongji.edu.cn

Guanghui Hu: 12guanghui@tongji.edu.cn

Bisheng Huang: 103294@tongji.edu.cn

Dong Zhuo: whzhuo2008@sina.com

Yujie Xu: xyj_1213@126.com

Huitao Li: lihuitao1991@163.com

Xiangcheng Zhan: ybfqnl3@126.com

Ren-Shan Ge: r_ge@yahoo.com

Yunfei Xu: xuyunfeibb@sina.com

Journal

Journal ID (nlm-ta): BMC Pharmacol Toxicol

Journal ID (iso-abbrev): BMC Pharmacol Toxicol

Title: BMC Pharmacology & Toxicology

Publisher: BioMed Central (London )

ISSN (Electronic): 2050-6511

Publication date (Electronic): 27 May 2019

Publication date PMC-release: 27 May 2019

Publication date Collection: 2019

Volume: 20

Electronic Location Identifier: 32

Affiliations

[1 ]ISNI 0000000123704535, GRID grid.24516.34, Department of Urology, Shanghai Tenth People’s Hospital, , Tongji University, ; Shanghai, China

[2 ]GRID grid.443626.1, Department of Urology, Yijishan Hospital, , Wannan Medical College, ; Wuhu, Anhui China

[3 ]ISNI 0000 0004 1764 2632, GRID grid.417384.d, Center of Scientific Research, , the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, ; Wenzhou, Zhejiang China

[4 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of Urology, Shanghai Tenth People’s Hospital, , Nanjing Medical University, ; Nanjing, Jiangsu China

Article

Publisher ID: 312

DOI: 10.1186/s40360-019-0312-z

PMC ID: 6537393

PubMed ID: 31133074

SO-VID: d6c76247-27a1-4990-a917-fb4667e5fb02

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 October 2018

Date accepted : 9 May 2019

Funding

Funded by: National Natural Science Foundation of China

Award ID: 81370699

Award Recipient : Yunfei Xu

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81671446

Award Recipient : Yunfei Xu

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ScienceOpen disciplines: Toxicology

Keywords: glucocorticoid,dexamethasone,stem leydig cells,proliferation,differentiation,testosterone

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ScienceOpen disciplines: Toxicology

Keywords: glucocorticoid, dexamethasone, stem leydig cells, proliferation, differentiation, testosterone

Dexamethasone suppresses the differentiation of stem Leydig cells in rats in vitro

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 35

The human glucocorticoid receptor: molecular basis of biologic function.

In search of rat stem Leydig cells: identification, isolation, and lineage-specific development.

Insights into the Development of the Adult Leydig Cell Lineage from Stem Leydig Cells

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