TY - JOUR
T1 - Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro
AU - Zhao, Xingyi
AU - Ji, Minpeng
AU - Wen, Xin
AU - Chen, Dan
AU - Huang, Fu
AU - Guan, Xiaoju
AU - Tian, Jing
AU - Xie, Jiajia
AU - Shao, Jingjing
AU - Wang, Jiexia
AU - Huang, Luoqi
AU - Lin, Han
AU - Ye, Leping
AU - Chen, Haolin
N1 - Funding Information:
This work was financially sponsored by National Natural Science Foundation of China (Grant Nos. 91949123, 81771635) and Wenzhou Major Scientific and Technological Innovation Project (Grant No. ZY2019002).
Publisher Copyright:
Copyright © 2021 Zhao, Ji, Wen, Chen, Huang, Guan, Tian, Xie, Shao, Wang, Huang, Lin, Ye and Chen.
PY - 2021/11/12
Y1 - 2021/11/12
N2 - 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 in vitro for 3 weeks. Midazolam (0.1–30 μM) was added to the culture medium, and the effects on LC development were assayed. 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.
AB - 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 in vitro for 3 weeks. Midazolam (0.1–30 μM) was added to the culture medium, and the effects on LC development were assayed. 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.
KW - AKT-CREB signaling
KW - midazolam
KW - progesterone
KW - stem Leydig cell
KW - steroidogenesis
KW - testosterone
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U2 - 10.3389/fendo.2021.765251
DO - 10.3389/fendo.2021.765251
M3 - Article
C2 - 34867807
AN - SCOPUS:85120438340
SN - 1664-2392
VL - 12
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 765251
ER -