ERO1α promotes testosterone secretion in hCG‐stimulated mouse Leydig cells via activation of the PI3K/AKT/mTOR signaling pathway

Chen, Fenglei; Wang, Yujing; Liu, Qinguang; Hu, Jiahui; Jin, Jianxun; Ma, Zhiyu; Zhang, Jinlong

doi:10.1002/jcp.29498

Cited by 17 publications

(15 citation statements)

References 46 publications

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“…After one week of adaptation to laboratory conditions, the adult mice were used to isolate PLCs following the procedure of our recent study [ 50 ]. Specifically, the testes were excised, collected, and trypsinized with collagenase I (1 mg/mL) at 37 °C for 10 min.…”

Section: Methodsmentioning

confidence: 99%

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Activation of Autophagy by Low-Dose Silica Nanoparticles Enhances Testosterone Secretion in Leydig Cells

Zhang

Grunberger

et al. 2022

IJMS

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Silica nanoparticles (SNPs) can cause abnormal spermatogenesis in male reproductive toxicity. However, the toxicity and toxicological mechanisms of SNPs in testosterone synthesis and secretion in Leydig cells are not well known. Therefore, this study aimed to determine the effect and molecular mechanism of low doses of SNPs in testosterone production in Leydig cells. For this, mouse primary Leydig cells (PLCs) were exposed to 100 nm Stöber nonporous spherical SNPs. We observed significant accumulation of SNPs in the cytoplasm of PLCs via transmission electron microscopy (TEM). CCK-8 and flow cytometry assays confirmed that low doses (50 and 100 μg/mL) of SNPs had no significant effect on cell viability and apoptosis, whereas high doses (more than 200 μg/mL) decreased cell viability and increased cell apoptosis in PLCs. Monodansylcadaverine (MDC) staining showed that SNPs caused the significant accumulation of autophagosomes in the cytoplasm of PLCs. SNPs activated autophagy by upregulating microtubule-associated protein light chain 3 (LC3-II) and BCL-2-interacting protein (BECLIN-1) levels, in addition to downregulating sequestosome 1 (SQSTM1/P62) level at low doses. In addition, low doses of SNPs enhanced testosterone secretion and increased steroidogenic acute regulatory protein (StAR) expression. SNPs combined with rapamycin (RAP), an autophagy activator, enhanced testosterone production and increased StAR expression, whereas SNPs combined with 3-methyladenine (3-MA) and chloroquine (CQ), autophagy inhibitors, had an opposite effect. Furthermore, BECLIN-1 depletion inhibited testosterone production and StAR expression. Altogether, our results demonstrate that low doses of SNPs enhanced testosterone secretion via the activation of autophagy in PLCs.

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Section: Methodsmentioning

confidence: 99%

“…The sequences of the shRNAs are listed in Table 1 . The process of lentivirus packaging was reported in our previous study [ 50 ]. Briefly, recombinant lentivirus vectors and packaging vectors (pGag/Pol, pRev, and pVSV-G) were co-transfected into HEK 293T cells.…”

Section: Methodsmentioning

confidence: 99%

Activation of Autophagy by Low-Dose Silica Nanoparticles Enhances Testosterone Secretion in Leydig Cells

Zhang

Grunberger

et al. 2022

IJMS

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“…Studies have revealed that the PI3K/AKT/mTOR pathway participates in the biological processes of apoptosis and steroidogenesis in granulosa and Leydig cells (110)(111)(112)(113)(114).…”

Section: Effect Of Bmal1 Deficiency On Signaling Pathways Associated ...mentioning

confidence: 99%

“…The PI3K/NF-kB pathway is also involved in steroidogenesis. NF-kB was demonstrated to participate in circadian rhythm generation and was also associated with the PI3K/AKT/ mTORC1 pathway, which functions in steroid hormone production (110)(111)(112)(113)(114). Female BMAL1-KO mice exhibited impaired steroidogenesis and activated phosphorylation of the PI3K/NF-kB pathway.…”

Section: Effect Of Bmal1 Deficiency On Signaling Pathways Associated ...mentioning

confidence: 99%

Critical Roles of the Circadian Transcription Factor BMAL1 in Reproductive Endocrinology and Fertility

Jiang

et al. 2022

Front. Endocrinol.

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Brain and muscle aryl-hydrocarbon receptor nuclear translocator like protein1 (BMAL1), a core component of circadian oscillation, is involved in many physiological activities. Increasing evidence has demonstrated the essential role of BMAL1 in reproductive physiology. For instance, BMAL1-knockout (KO) mice were infertile, with impaired reproductive organs and gametes. Additionally, in BMAL1-KO mice, hormone secretion and signaling of hypothalamus-pituitary-gonadal (H-P-G) hormones were also disrupted, indicating that H-P-G axis was impaired in BMAL1-KO mice. Moreover, both BMAL1-KO mice and BMAL1-knockdown by small interfering RNA (siRNA) in vitro cultured steroidogenic cells showed that BMAL1 was associated with gonadal steroidogenesis and expression of related genes. Importantly, BMAL1 also participates in pathogenesis of human reproductive diseases. In this review, we elaborate on the impaired reproduction of BMAL1-KO mice including the reproductive organs, reproductive endocrine hormones, and reproductive processes, highlighting the vital role of BMAL1 in fertility and reproductive endocrinology.

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“…The PI3K/AKT signaling pathway has been shown to play an important role in steroidogenic cell development, function, and apoptosis (51)(52)(53). To examine whether this signaling pathway is affected by midazolam treatment, the protein expression levels and phosphorylation of the two key components in the pathway, AKT and CREB, were analyzed by Western blotting (Figure 8).…”

Section: Effect Of Midazolam On Akt-creb Signaling Pathwaymentioning

confidence: 99%

Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro

Zhao

Wen

et al. 2021

Front. Endocrinol.

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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.

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ERO1α promotes testosterone secretion in hCG‐stimulated mouse Leydig cells via activation of the PI3K/AKT/mTOR signaling pathway

Cited by 17 publications

References 46 publications

Activation of Autophagy by Low-Dose Silica Nanoparticles Enhances Testosterone Secretion in Leydig Cells

Activation of Autophagy by Low-Dose Silica Nanoparticles Enhances Testosterone Secretion in Leydig Cells

Critical Roles of the Circadian Transcription Factor BMAL1 in Reproductive Endocrinology and Fertility

Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro

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