Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro
BackgroundMidazolam 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 ris...
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2021
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oai:doaj.org-article:371714273671415a924eb9072d8ee3052021-11-12T05:15:37ZEffects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro1664-239210.3389/fendo.2021.765251https://doaj.org/article/371714273671415a924eb9072d8ee3052021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fendo.2021.765251/fullhttps://doaj.org/toc/1664-2392BackgroundMidazolam 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.MethodsStem 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.ResultsMidazolam 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.ConclusionMidazolam 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.Xingyi ZhaoMinpeng JiXin WenDan ChenFu HuangXiaoju GuanXiaoju GuanJing TianJing TianJiajia XieJingjing ShaoJiexia WangLuoqi HuangHan LinLeping YeHaolin ChenHaolin ChenHaolin ChenFrontiers Media S.A.articlemidazolamstem Leydig celltestosteroneprogesteronesteroidogenesisAKT-CREB signalingDiseases of the endocrine glands. Clinical endocrinologyRC648-665ENFrontiers in Endocrinology, Vol 12 (2021) |
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midazolam stem Leydig cell testosterone progesterone steroidogenesis AKT-CREB signaling Diseases of the endocrine glands. Clinical endocrinology RC648-665 |
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midazolam stem Leydig cell testosterone progesterone steroidogenesis AKT-CREB signaling Diseases of the endocrine glands. Clinical endocrinology RC648-665 Xingyi Zhao Minpeng Ji Xin Wen Dan Chen Fu Huang Xiaoju Guan Xiaoju Guan Jing Tian Jing Tian Jiajia Xie Jingjing Shao Jiexia Wang Luoqi Huang Han Lin Leping Ye Haolin Chen Haolin Chen Haolin Chen Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro |
| description |
BackgroundMidazolam 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.MethodsStem 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.ResultsMidazolam 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.ConclusionMidazolam 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. |
| format |
article |
| author |
Xingyi Zhao Minpeng Ji Xin Wen Dan Chen Fu Huang Xiaoju Guan Xiaoju Guan Jing Tian Jing Tian Jiajia Xie Jingjing Shao Jiexia Wang Luoqi Huang Han Lin Leping Ye Haolin Chen Haolin Chen Haolin Chen |
| author_facet |
Xingyi Zhao Minpeng Ji Xin Wen Dan Chen Fu Huang Xiaoju Guan Xiaoju Guan Jing Tian Jing Tian Jiajia Xie Jingjing Shao Jiexia Wang Luoqi Huang Han Lin Leping Ye Haolin Chen Haolin Chen Haolin Chen |
| author_sort |
Xingyi Zhao |
| title |
Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro |
| title_short |
Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro |
| title_full |
Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro |
| title_fullStr |
Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro |
| title_full_unstemmed |
Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro |
| title_sort |
effects of midazolam on the development of adult leydig cells from stem cells in vitro |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/371714273671415a924eb9072d8ee305 |
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