Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells
Animals
Cell Differentiation
/ drug effects
Leydig Cells
/ drug effects
Male
Midazolam
/ pharmacology
Progesterone
/ metabolism
Rats
Rats, Sprague-Dawley
Scavenger Receptors, Class B
/ metabolism
Stem Cells
/ drug effects
Steroid 17-alpha-Hydroxylase
/ metabolism
Testis
/ drug effects
Testosterone
/ metabolism
Up-Regulation
/ drug effects
AKT-CREB signaling
midazolam
progesterone
stem Leydig cell
steroidogenesis
testosterone
Journal
Frontiers in endocrinology
ISSN: 1664-2392
Titre abrégé: Front Endocrinol (Lausanne)
Pays: Switzerland
ID NLM: 101555782
Informations de publication
Date de publication:
2021
2021
Historique:
received:
26
08
2021
accepted:
04
10
2021
entrez:
6
12
2021
pubmed:
7
12
2021
medline:
19
2
2022
Statut:
epublish
Résumé
Midazolam is a neurological drug with diverse functions, including sedation, hypnosis, decreased anxiety, anterograde amnesia, brain-mediated muscle relaxation, and anticonvulsant activity. Since it is frequently used in children and adolescents for extended periods of time, there is a risk that it may affect their pubertal development. Here, we report a potential effect of the drug on the development of Leydig cells (LCs), the testosterone (T)-producing cells in the testis. Stem LCs (SLCs), isolated from adult rat testes by a magnetic-activated cell sorting technique, were induced to differentiate into LCs Midazolam has dose-dependent effects on SLC differentiation. At low concentrations (0.1-5 μM), the drug can mildly increase SLC differentiation (increased T production), while at higher concentrations (15-30 μM), it inhibits LC development (decreased T production). T increases at lower levels may be due to upregulations of scavenger receptor class b Member 1 (SCARB1) and cytochrome P450 17A1 (CYP17A1), while T reductions at higher levels of midazolam could be due to changes in multiple steroidogenic proteins. The uneven changes in steroidogenic pathway proteins, especially reductions in CYP17A1 at high midazolam levels, also result in an accumulation of progesterone. In addition to changes in T, increases in progesterone could have additional impacts on male reproduction. The loss in steroidogenic proteins at high midazolam levels may be mediated in part by the inactivation of protein kinase B/cAMP response element-binding protein (AKT/CREB) signaling pathway. Midazolam has the potential to affect adult Leydig cell (ALC) development at concentrations comparable with the blood serum levels in human patients. Further studies are needed to test the effects on human cells.
Sections du résumé
Background
Midazolam is a neurological drug with diverse functions, including sedation, hypnosis, decreased anxiety, anterograde amnesia, brain-mediated muscle relaxation, and anticonvulsant activity. Since it is frequently used in children and adolescents for extended periods of time, there is a risk that it may affect their pubertal development. Here, we report a potential effect of the drug on the development of Leydig cells (LCs), the testosterone (T)-producing cells in the testis.
Methods
Stem LCs (SLCs), isolated from adult rat testes by a magnetic-activated cell sorting technique, were induced to differentiate into LCs
Results
Midazolam has dose-dependent effects on SLC differentiation. At low concentrations (0.1-5 μM), the drug can mildly increase SLC differentiation (increased T production), while at higher concentrations (15-30 μM), it inhibits LC development (decreased T production). T increases at lower levels may be due to upregulations of scavenger receptor class b Member 1 (SCARB1) and cytochrome P450 17A1 (CYP17A1), while T reductions at higher levels of midazolam could be due to changes in multiple steroidogenic proteins. The uneven changes in steroidogenic pathway proteins, especially reductions in CYP17A1 at high midazolam levels, also result in an accumulation of progesterone. In addition to changes in T, increases in progesterone could have additional impacts on male reproduction. The loss in steroidogenic proteins at high midazolam levels may be mediated in part by the inactivation of protein kinase B/cAMP response element-binding protein (AKT/CREB) signaling pathway.
Conclusion
Midazolam has the potential to affect adult Leydig cell (ALC) development at concentrations comparable with the blood serum levels in human patients. Further studies are needed to test the effects on human cells.
Identifiants
pubmed: 34867807
doi: 10.3389/fendo.2021.765251
pmc: PMC8632869
doi:
Substances chimiques
Scavenger Receptors, Class B
0
Testosterone
3XMK78S47O
Progesterone
4G7DS2Q64Y
Steroid 17-alpha-Hydroxylase
EC 1.14.14.19
Midazolam
R60L0SM5BC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
765251Informations de copyright
Copyright © 2021 Zhao, Ji, Wen, Chen, Huang, Guan, Tian, Xie, Shao, Wang, Huang, Lin, Ye and Chen.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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