Dexamethasone acutely down-regulates genes involved in steroidogenesis in stallion testes.
Abstract: In rodents, livestock and primate species, a single dose of the synthetic glucocorticoid dexamethasone acutely lowers testosterone biosynthesis. To determine the mechanism of decreased testosterone biosynthesis, stallions were treated with 0.1mg/kg dexamethasone 12h prior to castration. Dexamethasone decreased serum concentrations of testosterone by 60% compared to saline-treated control stallions. Transcriptome analyses (microarrays, northern blots and quantitative PCR) of testes discovered that dexamethasone treatment decreased concentrations of glucocorticoid receptor alpha (NR3C1), alpha actinin 4 (ACTN4), luteinizing hormone receptor (LHCGR), squalene epoxidase (SQLE), 24-dehydrocholesterol reductase (DHCR24), glutathione S-transferase A3 (GSTA3) and aromatase (CYP19A1) mRNAs. Dexamethasone increased concentrations of NFkB inhibitor A (NFKBIA) mRNA in testes. SQLE, DHCR24 and GSTA3 mRNAs were predominantly expressed by Leydig cells. In man and livestock, the GSTA3 protein provides a major 3-ketosteroid isomerase activity: conversion of Δ(5)-androstenedione to Δ(4)-androstenedione, the immediate precursor of testosterone. Consistent with the decrease in GSTA3 mRNA, dexamethasone decreased the 3-ketosteroid isomerase activity in testicular extracts. In conclusion, dexamethasone acutely decreased the expression of genes involved in hormone signaling (NR3C1, ACTN4 and LHCGR), cholesterol synthesis (SQLE and DHCR24) and steroidogenesis (GSTA3 and CYP19A1) along with testosterone production. This is the first report of dexamethasone down-regulating expression of the GSTA3 gene and a very late step in testosterone biosynthesis. Elucidation of the molecular mechanisms involved may lead to new approaches to modulate androgen regulation of the physiology of humans and livestock in health and disease.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication Date: 2014-07-07 PubMed ID: 25010478DOI: 10.1016/j.jsbmb.2014.07.003Google Scholar: Lookup
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- Journal Article
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Summary
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The research discovered that dexamethasone, a synthetic steroid, acutely decreases testosterone production in stallion testes by lowering the expression of genes involved in hormone signaling, cholesterol synthesis, and steroidogenesis.
Understanding Dexamethasone’s Effect on Testosterone Biosynthesis
- Testosterone is a crucial hormone related to sexual and reproductive development, primarily in male species. This research explores the effect of dexamethasone, a synthetic glucocorticoid steroid, on testosterone production in stallions. This understanding provides insights into androgen regulation and its applications to human and livestock health.
- Researchers treated stallions with a 0.1mg/kg dose of dexamethasone 12 hours before castration and noted a significant decrease, up to 60%, in serum testosterone concentrations compared to control subjects treated with saline.
Gene Expression Alteration due to Dexamethasone
- The scientific team utilized microarrays, northern blots, and quantitative PCR to analyze the testes and discovered that dexamethasone treatment resulted in decreased concentrations of several mRNAs, responsible for various functions in the body. These included genes involved in hormone signaling (NR3C1, ACTN4, and LHCGR), cholesterol synthesis (SQLE and DHCR24), and steroidogenesis (GSTA3 and CYP19A1).
- In contrast, a significant increase was documented in the mRNA concentrations of the NFkB inhibitor A (NFKBIA) gene present in the testes.
- The gene expressions of SQLE, DHCR24, and GSTA3, which are predominantly expressed in Leydig cells, known for the production of testosterone in males, were notably affected.
- Specifically, GSTA3, which assists in converting Δ(5)-androstenedione to Δ(4)-androstenedione (a direct precursor of testosterone in species including humans and livestock), showed a decrease in expression leading to reduced 3-ketosteroid isomerase activity.
Implications and Conclusions
- The impact of dexamethasone on testosterone production centers around the decrease in gene expression and consequently reduced activity in processes involved in hormone signaling, cholesterol synthesis, and steroidogenesis.
- This study offers the first report on how dexamethasone down-regulates the GSTA3 gene expression and indirectly affects a later stage in testosterone biosynthesis.
- Understanding these molecular mechanics could pave the way for novel approaches to manipulate androgen regulation, carrying significant implications not only for medical applications in human health and disease but also for livestock management and health.
Cite This Article
APA
Ing NH, Forrest DW, Riggs PK, Loux S, Love CC, Brinsko SP, Varner DD, Welsh TH.
(2014).
Dexamethasone acutely down-regulates genes involved in steroidogenesis in stallion testes.
J Steroid Biochem Mol Biol, 143, 451-459.
https://doi.org/10.1016/j.jsbmb.2014.07.003 Publication
Researcher Affiliations
- Department of Animal Science, Texas A&M AgriLife Research, College Station, TX 77843, United States. Electronic address: ning@cvm.tamu.edu.
- Department of Animal Science, Texas A&M AgriLife Research, College Station, TX 77843, United States.
- Department of Animal Science, Texas A&M AgriLife Research, College Station, TX 77843, United States.
- Department of Animal Science, Texas A&M AgriLife Research, College Station, TX 77843, United States.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biosciences, Texas A&M University, College Station, TX 77843, United States.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biosciences, Texas A&M University, College Station, TX 77843, United States.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biosciences, Texas A&M University, College Station, TX 77843, United States.
- Department of Animal Science, Texas A&M AgriLife Research, College Station, TX 77843, United States.
MeSH Terms
- Animals
- Biomarkers / metabolism
- Blotting, Northern
- Dexamethasone / pharmacology
- Down-Regulation
- Gene Expression Profiling
- Glutathione Transferase / metabolism
- Horses
- Hydrocortisone / blood
- Male
- Oligonucleotide Array Sequence Analysis
- RNA, Messenger / genetics
- Radioimmunoassay
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Testis / cytology
- Testis / metabolism
- Testosterone / metabolism
Citations
This article has been cited 10 times.- Vanhorebeek I, Coppens G, Güiza F, Derese I, Wouters PJ, Joosten KF, Verbruggen SC, Van den Berghe G. Abnormal DNA methylation within genes of the steroidogenesis pathway two years after paediatric critical illness and association with stunted growth in height further in time. Clin Epigenetics 2023 Jul 19;15(1):116.
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- Bai X, Wu J, Zhang M, Xu Y, Duan L, Yao K, Zhang J, Bo J, Zhao Y, Xu G, Zu H. DHCR24 Knock-Down Induced Tau Hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396 Epitopes and Inhibition of Autophagy by Overactivation of GSK3β/mTOR Signaling. Front Aging Neurosci 2021;13:513605.
- Curley M, Milne L, Smith S, Jørgensen A, Frederiksen H, Hadoke P, Potter P, Smith LB. A young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging. FASEB J 2019 Jan;33(1):978-995.
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- Lieberman R, Kranzler HR, Levine ES, Covault J. Examining FKBP5 mRNA expression in human iPSC-derived neural cells. Psychiatry Res 2017 Jan;247:172-181.
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