Dexamethasone downregulates expression of several genes encoding orphan nuclear receptors that are important to steroidogenesis in stallion testes.
Abstract: Glucocorticoids impair testosterone synthesis by an unknown mechanism. Stallions treated with the synthetic glucocorticoid dexamethasone had testes collected at 6 or 12 hours postinjection. The testicular expression of selected genes encoding nuclear receptors and steroidogenic enzymes was measured. At 6 hours, dexamethasone treatment decreased levels of NR0B2, NR4A1, NR5A1, and NR5A2 messenger RNAs (mRNAs) and NR5A2 mRNA levels remained depressed at 12 hours. In contrast, dexamethasone increased levels of NFKBIA mRNA at both time points. At 6 hours, dexamethasone did not alter levels of NR0B1, NR2F1, NR2F2, NR3C1, CYP11A1, CYP17A1, CYP19A1, DHCR24, GSTA3, HSD3B2, HSD17B3, LHCGR, or STAR mRNAs. In primary cultures of Leydig cells, 10 and 10 M dexamethasone decreased levels of NR4A1 and NR5A1 mRNAs and increased those of NFKBIA mRNA. Our discovery that dexamethasone downregulates NR4A1, NR5A1, and NR5A2 genes, known to be important for testicular functions, may be part of the mechanism by which glucocorticoids acutely decreases testosterone.
© 2019 Wiley Periodicals, Inc.
Publication Date: 2019-02-24 PubMed ID: 30801912DOI: 10.1002/jbt.22309Google Scholar: Lookup
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- Journal Article
Summary
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This research study investigates how the synthetic glucocorticoid dexamethasone impacts testosterone synthesis in stallions by affecting the expression of various genes in the testes. Results reveal that dexamethasone suppresses certain genes crucial for testicular functions, which may contribute to its ability to decrease testosterone levels.
Research Context
- The study was inspired by the observation that glucocorticoids, a class of steroids, impair the synthesis of testosterone through an undefined mechanism. The research aimed to understand this process better by investigating the impact of dexamethasone, a synthetic glucocorticoid, on the expression of genes in stallion testes.
Methodology
- Stallions were treated with dexamethasone, and their testes were collected at two stages for analysis – 6 hours and 12 hours post-injection.
- The researchers monitored the testicular expression of selected genes that encode nuclear receptors and steroidogenic enzymes, vital for the production of steroids like testosterone.
Key Findings
- After 6 hours of dexamethasone treatment, levels of NR0B2, NR4A1, NR5A1, and NR5A2 messenger RNAs (mRNAs) decreased. This reduction in NR5A2 mRNA levels also persisted at the 12 hours point.
- Converse to the previous finding, dexamethasone treatment increased levels of NFKBIA mRNA at both 6- and 12-hour time points.
- Dexamethasone did not impact the levels of several other mRNAs – including NR0B1, NR2F1, NR2F2, NR3C1, CYP11A1, CYP17A1, CYP19A1, DHCR24, GSTA3, HSD3B2, HSD17B3, LHCGR, and STAR – at the 6-hour mark.
- In primary cultures of Leydig cells, dexamethasone treatment decreased levels of NR4A1 and NR5A1 mRNAs and increased NFKBIA mRNA levels.
Implications
- The research uncovered that dexamethasone downregulates the NR4A1, NR5A1, and NR5A2 genes, which are known to be crucial for testicular functions. This downregulation might be a part of the mechanism through which glucocorticoids acutely decrease testosterone.
- This finding helps in expanding the knowledge about the modulation of testosterone synthesis by glucocorticoids and can open up new research avenues for targeted intervention strategies.
Cite This Article
APA
Valdez R, Cavinder CA, Varner DD, Welsh TH, Vogelsang MM, Ing NH.
(2019).
Dexamethasone downregulates expression of several genes encoding orphan nuclear receptors that are important to steroidogenesis in stallion testes.
J Biochem Mol Toxicol, 33(6), e22309.
https://doi.org/10.1002/jbt.22309 Publication
Researcher Affiliations
- Department of Animal Science, Texas A&M University, College Station, Texas.
- Department of Animal and Dairy Science, Mississippi State University, Starkville, Mississippi.
- Department of Large Animal Clinical Sciences, Texas A&M University, College Station, Texas.
- Department of Animal Science, Texas A&M University, College Station, Texas.
- Department of Animal Science, Texas A&M University, College Station, Texas.
- Department of Animal Science, Texas A&M University, College Station, Texas.
MeSH Terms
- Animals
- Cytochrome P-450 Enzyme System / biosynthesis
- Dexamethasone / adverse effects
- Dexamethasone / pharmacology
- Down-Regulation / drug effects
- Horses
- Leydig Cells / metabolism
- Male
- Orphan Nuclear Receptors / biosynthesis
- Testosterone / biosynthesis
Grant Funding
- Glucocorticoid modulation of steroidogenic genes / American Quarter Horse Foundation
Citations
This article has been cited 2 times.- Pan Z, Wang Y, Wang M, Wang Y, Zhu X, Gu S, Zhong C, An L, Shan M, Damas J, Halstead MM, Guan D, Trakooljul N, Wimmers K, Bi Y, Wu S, Delany ME, Bai X, Cheng HH, Sun C, Yang N, Hu X, Lewin HA, Fang L, Zhou H. An atlas of regulatory elements in chicken: A resource for chicken genetics and genomics.. Sci Adv 2023 May 3;9(18):eade1204.
- Deng JW, Yang Q, Cai XP, Zhou JM, E WG, An YD, Zheng QX, Hong M, Ren YL, Guan J, Wang G, Lai SJ, Chen Z. Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner.. J Zhejiang Univ Sci B 2020 Sept.;21(9):727-739.
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