Dataset Information

Aldosterone Blocks Rat Stem Leydig Cell Development In Vitro.

ABSTRACT: Aldosterone (ALDO) is a primary endogenous mineralocorticoid, appearing as the main hormone controlling sodium and water homeostasis. Its emerging role in the development of many organs has gained interest over the past few years. In the testis, Leydig cells contain mineralocorticoid receptors and ALDO stimulates androgen synthesis via the mineralocorticoid receptors in rat adult Leydig cells. Although ALDO pharmacologically promoted the Leydig cell function, its role in Leydig cell development was unclear. In the present study, we investigated effects of ALDO on rat stem Leydig cell (SLC) proliferation and differentiation. Using an in vitro culture system of the seminiferous tubules from Leydig cell-depleted testis and EdU (a modified thymidine analog) incorporation into the SLC for flurorescent labeling to judge its DNA synthesis and measurement of medium testosterone production, steroidogenesis-related gene and protein expression, we found that: (1) ALDO suppressed EdU incorporation into SLCs at 100 nM via mineralocorticoid receptor-mediated mechanism and (2) ALDO reduced Leydig cell number. In conclusion, ALDO pharmacologically blocked rat SLC development.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5787991 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Aldosterone Blocks Rat Stem Leydig Cell Development <i>In Vitro</i>.

Zhang Jingwei J Huang Bisheng B Hu Guanghui G Zhan Xiangcheng X Xie Tiancheng T Li Saiyang S Zhang Xiaolu X Li Huitao H Ge Ren-Shan RS Xu Yunfei Y

Frontiers in endocrinology 20180124

Aldosterone (ALDO) is a primary endogenous mineralocorticoid, appearing as the main hormone controlling sodium and water homeostasis. Its emerging role in the development of many organs has gained interest over the past few years. In the testis, Leydig cells contain mineralocorticoid receptors and ALDO stimulates androgen synthesis <i>via</i> the mineralocorticoid receptors in rat adult Leydig cells. Although ALDO pharmacologically promoted the Leydig cell function, its role in Leydig cell devel ...[more]

PMID: 29416526

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Project description:Background: Tributyltin (TBT) is widely used as an antifouling agent that may cause reproductive toxicity. The mechanism of TBT on Leydig cell development is still unknown. The objective of the present study was to investigate whether a brief exposure to low doses of TBT permanently affects Leydig cell development and to clarify the underlying mechanism. Methods: Adult male Sprague Dawley rats were randomly assigned into four groups and gavaged normal saline (control), 0.1, 1.0, or 10.0 mg/kg/day TBT for a consecutive 10 days, respectively. At the end of TBT treatment, all rats received a single intraperitoneal injection of 75 mg/kg ethane dimethane sulfonate (EDS) to eliminate all of adult Leydig cells. Leydig cells began a developmental regeneration process on post-EDS day 35. The Leydig cell regeneration was evaluated by measuring serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels on post-EDS day 7, 35, and 56, the expression levels of Leydig cell genes, Leydig cell morphology and number and proliferation on post-EDS day 56. Results: TBT significantly reduced serum testosterone levels on post-EDS day 35 and 56 and increased serum luteinizing hormone and follicle-stimulating hormone levels on post-EDS day 56 at ≥1 mg/kg/day. Immunohistochemical staining showed that there were fewer regenerated Leydig cells in the TBT-treated testis on post-EDS day 56. Further study demonstrated that the mRNA or protein levels of Leydig (Lhcgr, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3) and Sertoli cells (Fshr, Dhh, and Sox9) were significantly down-regulated in the TBT-treated testes when compared to the control. Immunofluorescent staining showed that TBT inhibited Leydig cell proliferation as judged by the reduced number of proliferating cyclin nuclear antigen-positive Leydig cells on post-EDS day 35. Conclusion: The present study demonstrated that a short-term TBT exposure blocked Leydig cell developmental regeneration process via down-regulating steroidogenesis-related proteins and inhibiting the proliferation of Leydig cells.

Project description:Bone morphogenetic protein 4 (BMP4) is an important member of the transforming growth factor-β superfamily. BMP4 is expressed in the Leydig cell lineage. We hypothesized that BMP4 might regulate the development of stem/progenitor Leydig cells. The BMP4 receptors, BMPR1A, BMPR1B, and BMPR2 were found to be expressed in progenitor Leydig cells of prepubertal testis and isolated cells. BMP4 at 1 and 10 ng/mL significantly reduced androgen production and down-regulated steroidogenesis-related gene and protein expression possibly by activating the SMAD signaling pathway (increasing SMAD1/5 phosphorylation and SMAD4) at 24 h treatment. BMP4 at 0.1 ng/mL and higher concentrations markedly reduced the EdU labeling index of CD90+ stem Leydig cells after 24 h treatment and significantly reduced the number of EdU+ stem Leydig cells on the surface of seminiferous tubules after 7 days of culture. BMP4 at 0.01 ng/mL and higher concentrations significantly blocked the differentiation of stem Leydig cells into adult cells, as shown by the reduction of testosterone secretion and the downregulation of Lhcgr, Scarb1, Cyp11a1, Hsd11b1, and Insl3 and their function after 3D seminiferous tubule culture for 3 weeks, and this effect was reversed by co-treatment with the BMP4 antagonists noggin and doxomorphine. In addition, BMP4 also blocked stem Leydig cell differentiation through SMAD-independent signaling pathways (ERK1/2 and AMPK). Ethanedimethane sulfonate (EDS) single injection can result in reduction of testosterone, restoration can happen post treatment. In an in vivo model of Leydig cell regeneration following EDS treatment, intratesticular injection of BMP4 from day 14 to day 28 post-elimination significantly reduced serum testosterone levels and down-regulated the expression of Scarb1, Star, Hsd11b1, and Insl3 and its proteins, possibly through SMAD-dependent and SMAD-independent (ERK1/2 and AMPK) signaling pathways. In conclusion, BMP4 is expressed in cells of the Leydig cell lineage and blocks entry of stem/progenitor Leydig cells into adult Leydig cells through SMAD-dependent and SMAD-independent signaling pathways.

Dataset Information

Aldosterone Blocks Rat Stem Leydig Cell Development In Vitro.

Publications

Aldosterone Blocks Rat Stem Leydig Cell Development <i>In Vitro</i>.

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