Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells

Weisser, J.; Landreh, Luise; Söder, Olle; Svechnikov, Konstantin

doi:10.1016/j.mce.2011.03.008

Cited by 20 publications

(14 citation statements)

References 36 publications

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“…Curiously, the fetal Leydig cells had the potential to synthesize not only androstenedione but also testosterone under cAMP stimulation. Consistent with this finding, steroidogenic genes including Hsd17b3 were expressed in the rat fetal Leydig cells [Weisser et al, 2011]. Although the reasons for the contradictory conclusions obtained in the 2 studies are unknown, future studies using Leydig and Sertoli cells purified from fetal testes should provide us with a definite conclusion concerning the steroid-synthetic activity of fetal Leydig cells.…”

Section: Do Fetal Leydig Cells Synthesize Testosterone?supporting

confidence: 60%

Steroid Hormones and the Development of Reproductive Organs

Morohashi¹,

Baba²,

Tanaka

2012

Sex Dev

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It has been more than 150 years since the physiological function of androgen was reported for the first time in fowl. This finding has served as a basis for many studies focusing on steroid hormones from various aspects. These studies have significantly enhanced our knowledge about the structures of steroid hormones, their synthetic pathways, enzymes involved in the synthetic pathways, steroid hormone-specific receptors, actions of steroid hormones through receptor binding, and the differentiation of steroidogenic cells. However, there are still many attractive and important issues in these areas, some of which are currently being addressed. In this review, we trace the history and findings of the previous studies on steroid hormones, summarize our present understanding in this area, and discuss issues that remain to be elucidated.

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Section: Do Fetal Leydig Cells Synthesize Testosterone?supporting

confidence: 60%

Steroid Hormones and the Development of Reproductive Organs

Morohashi¹,

Baba²,

Tanaka

2012

Sex Dev

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“…Moreover, CYP17A1 is one the main proteins studied in Leydig cells during toxicology experiments investigating the effects of drugs or compounds on steroidogenesis. It has been demonstrated that a change in the expression of CYP17A1 mRNA and protein may directly affect the level of testosterone [11,12]. Our results led us to believe that we have determined the pathway through which CLA affects steroidogenesis.…”

Section: Discussionmentioning

confidence: 64%

“…Second, CLA may alter steroidogenesis by up-regulating specific genes encoding enzymes and transport proteins involved in the synthesis of testosterone, such as 17α-hydroxylase/17,20-lyase (CYP17A1), which converts progesterone into androstenedione. It has been demonstrated that a change in CYP17A1 expression may directly affect the level of testosterone [11,12]. …”

Section: Introductionmentioning

confidence: 99%

Endurance Exercise and Conjugated Linoleic Acid (CLA) Supplementation Up-Regulate CYP17A1 and Stimulate Testosterone Biosynthesis

et al. 2013

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A new role for fat supplements, in particular conjugated linoleic acid (CLA), has been delineated in steroidogenesis, although the underlying molecular mechanisms have not yet been elucidated. The aims of the present study were to identify the pathway stimulated by CLA supplementation using a cell culture model and to determine whether this same pathway is also stimulated in vivo by CLA supplementation associated with exercise. In vitro, Leydig tumour rat cells (R2C) supplemented with different concentrations of CLA exhibited increasing testosterone biosynthesis accompanied by increasing levels of CYP17A1 mRNA and protein. In vivo, trained mice showed an increase in free plasma testosterone and an up-regulation of CYP17A1 mRNA and protein. The effect of training on CYP17A1 expression and testosterone biosynthesis was significantly higher in the trained mice supplemented with CLA compared to the placebo. The results of the present study demonstrated that CLA stimulates testosterone biosynthesis via CYP17A1, and endurance training led to the synthesis of testosterone in vivo by inducing the overexpression of CYP17A1 mRNA and protein in the Leydig cells of the testis. This effect was enhanced by CLA supplementation. Therefore, CLA-associated physical activity may be used for its steroidogenic property in different fields, such as alimentary industry, human reproductive medicine, sport science, and anti-muscle wasting.

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“…Unfortunately, this ex vivo approach resulted in cell death after infection with LV-COUP-TFII (data not shown). There are also inherent problems with applying similar approaches to the ex vivo culture of fetal LC, which rapidly (∼48 h) lose their steroidogenic function after isolation [24]. Therefore, to provide more definitive evidence that nuclear COUP-TFII expression in fetal LC was associated causally with reduced ITT, DBP treatment was delayed until a time-point (e19.5–e20.5; = late treatment window) when ∼80% of LC have normally switched off nuclear expression of COUP-TFII (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous studies have shown that the mechanism underlying such effects involves competition between COUP-TFII and SF-1 for binding to an overlapping response element in the promoter region of genes encoding steroidogenic enzymes [18], [19], [20], [21], [23], [30], [31], [32], [33], [34], [35], [36], [37], [38], as proposed for the present studies in fetal rat LC. Unfortunately, our studies using viral transfection of ex vivo cultured rat fetal LC with COUP-TFII resulted in cell death (unpublished data), and there are also inherent problems with the culture of fetal LC, which rapidly lose their steroidogenic function [24]. Therefore, this direct approach was not an option for us.…”

Section: Discussionmentioning

confidence: 99%

Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents

et al. 2012

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Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal ‘masculinization programming window’. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ∼3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.

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Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells

Cited by 20 publications

References 36 publications

Steroid Hormones and the Development of Reproductive Organs

Steroid Hormones and the Development of Reproductive Organs

Endurance Exercise and Conjugated Linoleic Acid (CLA) Supplementation Up-Regulate CYP17A1 and Stimulate Testosterone Biosynthesis

Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents

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