scholarly journals Permethrin May Disrupt Testosterone Biosynthesis via Mitochondrial Membrane Damage of Leydig Cells in Adult Male Mouse

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3941-3949 ◽  
Author(s):  
Shu-Yun Zhang ◽  
Yuki Ito ◽  
Osamu Yamanoshita ◽  
Yukie Yanagiba ◽  
Miya Kobayashi ◽  
...  
Keyword(s):  
Adult Male ◽  
Mitochondrial Membrane ◽  
Leydig Cells ◽  
Membrane Damage ◽  
Electron Microscopic Level ◽  
Plasma Testosterone ◽  
Dependent Manner ◽  
Expression Levels ◽  
Testosterone Production ◽  
Testosterone Biosynthesis

Permethrin, a popular synthetic pyrethroid insecticide used to control noxious insects in agriculture, forestry, households, horticulture, and public health throughout the world, poses risks of environmental exposure. Here we evaluate the reproductive toxicity of cis-permethrin in adult male ICR mice that were orally administered cis-permethrin (0, 35, or 70 mg/kg·d) for 6 wk. Caudal epididymal sperm count and sperm motility in the treated groups were statistically reduced in a dose-dependent manner. Testicular testosterone production and plasma testosterone concentration were significantly and dose-dependently decreased with an increase in LH, and a significant regression was observed between testosterone levels and cis-permethrin residues in individual mice testes after exposure. However, no significant changes were observed in body weight, reproductive organ absolute and relative weights, sperm morphology, and plasma FSH concentration after cis-permethrin treatment. Moreover, cis-permethrin exposure significantly diminished the testicular mitochondrial mRNA expression levels of peripheral benzodiazepine receptor (PBR), steroidogenic acute regulatory protein (StAR), and cytochrome P450 side-chain cleavage (P450scc) and enzyme and protein expression levels of StAR and P450scc. At the electron microscopic level, mitochondrial membrane damage was found in Leydig cells of the exposed mouse testis. Our results suggest that the insecticide permethrin may cause mitochondrial membrane impairment in Leydig cells and disrupt testosterone biosynthesis by diminishing the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone in the cells, thus reducing subsequent testosterone production.

scholarly journals Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

2008 ◽  
Vol 41 (3) ◽  
pp. 165-175 ◽  
Author(s):  
Luc J Martin ◽  
Jacques J Tremblay
Keyword(s):  
Leydig Cells ◽  
Dependent Manner ◽  
Orphan Nuclear Receptor ◽  
Western Blots ◽  
Testosterone Production ◽  
Repressive Effect ◽  
Testosterone Biosynthesis ◽  
Underlying Mechanisms ◽  
Steroidogenic Acute Regulatory ◽  
Steroidogenic Genes

It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain the mechanism of action of Gc on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory (STAR) protein, have been shown to be repressed by Gc in a GR-dependent manner but the underlying mechanisms remain to be fully elucidated. Here, we found that dexamethasone (Dex), a potent synthetic Gc, partly antagonizes the cAMP-dependent stimulation of the mouse Star promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at −95 bp previously implicated in the activation of the Star promoter by the nuclear receptors, NR4A1 and NR5A1. Dex was found to inhibit NR4A1-dependent transactivation of the Star promoter in Leydig cells by decreasing NR4A1, but not NR5A1, recruitment to the proximal Star promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that Dex did not affect NR4A1 or NR5A1 expression in response to cAMP. These data suggest that NR4A1 would be associated with the GR in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.

scholarly journals The effects of gold nanoparticles on Leydig cells and male reproductive function in mice

2020 ◽  
Author(s):  
Ying Liu ◽  
Xiaojie Li ◽  
Shuwen Xiao ◽  
Xinyi Liu ◽  
Xuanming Chen ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Leydig Cells ◽  
Reproductive Function ◽  
Great Promise ◽  
Plasma Testosterone ◽  
Control Group ◽  
Dependent Manner ◽  
Epididymal Sperm ◽  
Testosterone Production ◽  
Male Reproductive Function

Abstract Background: Gold nanoparticles (AuNPs) have shown great promise in various biomedical applications, but their effects on male reproductive function remain to be ascertained. The aim of this study was to investigate the uptake, cytotoxicity and testosterone production inhibition of AuNPs in mouse Leydig cells, as well as their accumulation in the testes of male mice and their effects on male reproductive function.Results: AuNPs (5 nm) were able to be internalized into the endosomes/lysosomes of TM3 Leydig cells, induce the formation of autophagosomes, increase the production of reactive oxygen species (ROS), and arrest the cell cycle in S phase, resulting in concentration-dependent cytotoxicity and DNA damage. Interestingly, AuNPs significantly reduced testosterone production in TM3 cells by inhibiting the expression of 17α-hydroxylase, an important enzyme in androgen synthesis. After repeated intravenous injection, AuNPs gradually accumulated and retained in the testes of male BALB/c mice in a dose-dependent manner. One week after withdrawal, the level of plasma testosterone in the 0.5 mg/kg AuNPs group was significantly reduced compared to that in the PBS control group, accompanied by the decreased expression of 17α-hydroxylase in the testes. In addition, AuNPs treatment significantly increased the rate of epididymal sperm malformation, but without affecting fertility.Conclusion: Our results suggest that AuNPs can accumulate in the testes and reduce testosterone production in Leydig cells by down-regulating the expression of 17α-hydroxylase, thus affecting the quality of epididymal sperm.

A comparative study of the action of several lutropin derivatives on rat Leydig cells

1980 ◽  
Vol 93 (2) ◽  
pp. 250-256 ◽  
Author(s):  
M. P. de la Llosa-Hermier ◽  
C. Tertrin-Clary ◽  
M. Evrard-Herouard ◽  
Y. Colleaux ◽  
C. Hermier ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Binding Activity ◽  
Camp Accumulation ◽  
Lh Receptor ◽  
Testosterone Production ◽  
Receptor Assay ◽  
Testosterone Biosynthesis ◽  
Radioligand Receptor Assay ◽  
Relative Potencies ◽  
Good Agreement

Abstract. Rat intestinal cells prepared from testes were incubated in the presence of different lutropin derivatives obtained by chemical modification of the amino groups. The cAMP accumulation and the testosterone biosynthesis were determined in the cell homogenates. Binding determinations were carried out by a radioligand receptor assay using tritiated methylated lutropin. The binding activities — relative to native LH — of three different derivatives obtained by reductive alkylation (methylated, ethylated and isopropylated LH) were in good agreement with the relative potencies assessed by their capacity to stimulate cAMP and testosterone production. Guanidinated LH (11 — NH2 groups modified) exhibited a binding activity and a relative potency relatively high with regard to cAMP accumulation (as compared with that of native LH). Its steroidogenic potency, however, was very low. When Leydig cells were incubated in the presence of native and guanidinated LH, the testosterone production was similar to that induced by the derivative alone, indicating that the derivative exerted a competitive inhibitory action preventing the stimulation of steroidogenesis by native LH. These results suggest that a guanidinated derivative is able to bind to the LH receptor and the complex so formed is able to be coupled with an adenylate cyclase pool (or cAMP compartment) which is not connected with the steroidogenic pathway.

scholarly journals Inhibin is an important factor in the regulation of FSH secretion in the adult male hamster

2000 ◽  
Vol 278 (4) ◽  
pp. E744-E751 ◽  
Author(s):  
Hisashi Kishi ◽  
Mariko Itoh ◽  
Sachiko Wada ◽  
Yoko Yukinari ◽  
Yumiko Tanaka ◽  
...  
Keyword(s):  
Adult Male ◽  
Leydig Cells ◽  
Initial Level ◽  
Plasma Concentrations ◽  
Plasma Testosterone ◽  
Gonadotropin Secretion ◽  
Α Subunit ◽  
Male Golden Hamsters ◽  
Lh Secretion

We investigated the importance of inhibin and testosterone in the regulation of gonadotropin secretion in adult male golden hamsters ( Mesocricetus auratus). After castration, plasma concentrations of inhibin and testosterone were reduced to undetectable, whereas plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were increased. After hemicastration, plasma FSH and LH increased moderately and plasma inhibin decreased to one-half its initial level. Plasma testosterone levels in hemicastrated animals decreased 3 h after hemicastration but returned to those in sham-operated animals at 6 h. Plasma LH in the castrated hamster declined comparably to intact animals with testosterone treatment; plasma FSH also decreased but still remained at levels higher than those in intact animals. After treatment with inhibin in long-term-castrated animals, plasma FSH decreased, whereas plasma LH was not altered. Intact males treated with flutamide, an anti-androgen, showed a significant increase in plasma LH but not in FSH. On the other hand, treatment with anti-inhibin serum induced a significant elevation in plasma FSH, but not in LH. Using immunohistochemistry, we showed that the inhibin α-subunit was localized to both Sertoli and Leydig cells. The present study in adult male hamsters indicates that FSH secretion is regulated mainly by inhibin, presumably from Sertoli and Leydig cells, and that LH secretion is controlled primarily by androgens produced from the Leydig cells. This situation is more similar to that of primates than of rats.

Effects of hypoxia on testosterone release in rat Leydig cells

2009 ◽  
Vol 297 (5) ◽  
pp. E1039-E1045 ◽  
Author(s):  
Guey-Shyang Hwang ◽  
Szu-Tah Chen ◽  
Te-Jung Chen ◽  
Shyi-Wu Wang
Keyword(s):  
Calcium Channel ◽  
Adenylyl Cyclase ◽  
Intermittent Hypoxia ◽  
Leydig Cells ◽  
Channel Blocker ◽  
Male Rats ◽  
Plasma Testosterone ◽  
Testosterone Production

The aim of this study was to explore the effect and action mechanisms of intermittent hypoxia on the production of testosterone both in vivo and in vitro. Male rats were housed in a hypoxic chamber (12% O2 + 88% N2, 1.5 l/ml) 8 h/day for 4 days. Normoxic rats were used as control. In an in vivo experiment, hypoxic and normoxic rats were euthanized and the blood samples collected. In the in vitro experiment, the enzymatically dispersed rat Leydig cells were prepared and challenged with forskolin (an adenylyl cyclase activator, 10−4 M), 8-Br-cAMP (a membrane-permeable analog of cAMP, 10−4 M), hCG (0.05 IU), the precursors of the biosynthesis testosterone, including 25-OH-C (10−5 M), pregnenolone (10−7 M), progesterone (10−7 M), 17-OH-progesterone (10−7 M), and androstendione (10−7-10−5 M), nifedipine (L-type Ca2+ channel blocker, 10−6-10−4 M), nimodipine (L-type Ca2+ channel blocker, 10−5 M), tetrandrine (L-type Ca2+ channel blocker, 10−5 M), and NAADP (calcium-signaling messenger causing release of calcium from intracellular stores, 10−6-10−4 M). The concentrations of testosterone in plasma and medium were measured by radioimmunoassay. The level of plasma testosterone in hypoxic rats was higher than that in normoxic rats. Enhanced testosterone production was observed in rat Leydig cells treated with hCG, 8-Br-cAMP, or forskolin in both normoxic and hypoxic conditions. Intermittent hypoxia resulted in a further increase of testosterone production in response to the testosterone precursors. The activity of 17β-hydroxysteroid dehydrogenase was stimulated by the treatment of intermittent hypoxia in vitro. The intermittent hypoxia-induced higher production of testosterone was accompanied with the influx of calcium via L-type calcium channel and the increase of intracellular calcium via the mechanism of calcium mobilization. These results suggested that the intermittent hypoxia stimulated the secretion of testosterone at least in part via stimulatory actions on the activities of adenylyl cyclase, cAMP, L-type calcium channel, and steroidogenic enzymes.

scholarly journals The role of calcium in luteinizing hormone-releasing hormone agonist (ICI 118630)-stimulated steroidogenesis in rat Leydig cells

1984 ◽  
Vol 218 (2) ◽  
pp. 621-624 ◽  
Author(s):  
M H F Sullivan ◽  
B A Cooke
Keyword(s):  
Luteinizing Hormone ◽  
Cyclic Amp ◽  
Leydig Cells ◽  
Calcium Ionophore ◽  
Dependent Manner ◽  
Lhrh Agonist ◽  
Luteinizing Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Rat Testis ◽  
Testosterone Production

The luteinizing hormone-releasing hormone (LHRH) agonist ICI 118630 was found to increase testosterone production in purified rat testis Leydig cells in a concentration- and time-dependent manner, but no consistent changes in cyclic AMP levels were detectable. The stimulation of steroidogenesis by LHRH agonist was found to be dependent on the concentration of Ca2+ in the incubation medium; at least 1 mM was required. The calcium ionophore A23187 mimicked the effects of the LHRH agonist on steroidogenesis, and addition of both compounds together did not further increase testosterone production. The calcium ionophore caused a small increase in cyclic AMP which was independent of the concentration of the ionophore and of the calcium concentrations. The evidence obtained in this study indicates that LHRH agonist-stimulated steroidogenesis in rat testis Leydig cells is primarily mediated by calcium and not cyclic AMP.

PLASMA LEVELS OF TESTOSTERONE IN BULLS

1978 ◽  
Vol 88 (4) ◽  
pp. 787-792 ◽  
Author(s):  
Anne Sundby ◽  
P. A. Torjesen
Keyword(s):  
Testosterone Level ◽  
Plasma Levels ◽  
Leydig Cells ◽  
Sharp Decrease ◽  
Plasma Testosterone ◽  
Plasma Samples ◽  
Elevated Plasma ◽  
Plasma Testosterone Level ◽  
Testosterone Levels ◽  
Testosterone Production

ABSTRACT Administration of 6000 IU HCG to 4 bulls was followed by an elevation of plasma testosterone lasting for 9–13 days. When HCG administration was repeated, the testosterone response was shortened to 4–6 days in 3 bulls due to the formation of antibodies against HCG. The appearance of HCG antibodies coincided with a sharp decrease in the plasma testosterone level, indicating that Leydig cells have to be under continuous HCG stimulation to maintain increased testosterone production. No antibody against bovine LH was detected in the plasma samples containing antibodies against HCG. In one bull the response following the second HCG injection was similar to the plasma testosterone pattern following the first. No antibodies against HCG were found in this bull. Five bulls received 750 IU HCG twice. Following the period with elevated plasma testosterone levels, subnormal levels were observed after both injections. One injection led to decreased levels without development of antibodies against HCG while the second HCG injection led to subnormal testosterone levels concomitant with measurable antibodies against HCG.

Bisphenol A reduces testosterone production in TM3 Leydig cells independently of its effects on cell death and mitochondrial membrane potential

2018 ◽  
Vol 76 ◽  
pp. 26-34 ◽  
Author(s):  
Gessica Dutra Gonçalves ◽  
Simone Cristine Semprebon ◽  
Bruna Isabela Biazi ◽  
Mario Sergio Mantovani ◽  
Glaura Scantamburlo Alves Fernandes
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Bisphenol A ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Leydig Cells ◽  
Testosterone Production

scholarly journals Dehydroepiandrosterone-Regulated Testosterone Biosynthesis via Activation of the ERK1/2 Signaling Pathway in Primary Rat Leydig Cells

2015 ◽  
Vol 36 (5) ◽  
pp. 1778-1792 ◽  
Author(s):  
Lin Liu ◽  
Jian Kang ◽  
Xiao Ding ◽  
Di Chen ◽  
Yingqiao Zhou ◽  
...  
Keyword(s):  
Protein Expression ◽  
Signaling Pathway ◽  
Leydig Cells ◽  
Expression Level ◽  
Target Cells ◽  
Protein Expression Level ◽  
Expression Levels ◽  
Creb Protein ◽  
Protein Levels ◽  
Testosterone Biosynthesis

Background: Dehydroepiandrosterone decreases with age and this reduction has been shown to be associated with physical health in human. Some studies have suggested that the effects of DHEA are exerted after it is biotransformed into more biologically-active hormones in peripheral target cells. This study investigated the effects of DHEA on the testosterone biosynthesis and possible signaling pathway mechanism underlying these DHEA effects were also explored in primary rat Leydig cells. Methods: Primary Leydig cells were treated with DHEA and then detected testosterone content by RIA and steroidogenic enzymes, ERK1/2 signal pathway factors protein expression level by Western blot. Results: Incubation of primary Leydig cells with DHEA significantly increased testosterone content and 3β-HSD and 17β-HSD protein expression levels, while aromatase protein expression levels were decreased. Compared with the control group, p-ERK1/2 and p-CREB protein levels were significantly increased in DHEA-treated groups. Testosterone content was significantly decreased in the DHEA-treated group pre-incubated with U0126 (p-ERK1/2 inhibitor). Additionally, the rise in p-ERK1/2, 3β-HSD and 17β-HSD protein levels induced by DHEA was reversed when cells were pre-incubated with U0126. Interestingly, no significant difference was found in aromatase protein expression level in cells pretreated with U0126. Conclusion: These findings demonstrate that (a) exogenous DHEA might preferentially convert to testosterone rather than estradiol due to the up-regulation of 3β-HSD and 17β-HSD protein levels and the down-regulation of aromatase protein level in primary Leydig cells, and (b) the action of DHEA is at least partly associated with the elevation of p-ERK1/2 and p-CREB protein levels.

Immunization of male rabbits with sheep luteal receptor to LH results in production of antibodies exhibiting hormone-agonistic and -antagonistic activities

1996 ◽  
Vol 150 (3) ◽  
pp. 431-443 ◽  
Author(s):  
M Jeyakumar ◽  
N R Moudgal
Keyword(s):  
Leydig Cells ◽  
Serum Testosterone ◽  
Fold Increase ◽  
Dependent Manner ◽  
Primary Immunization ◽  
Testosterone Production ◽  
Dose Dependent ◽  
Receptor Antibodies

Abstract Antibodies to LH/chorionic gonadotrophin receptor (LH/CG-R; molecular weight 67 000), isolated in a homogenous state (established by SDS-PAGE and ligand blotting) from sheep luteal membrane using human CG (hCG)–Sepharose affinity chromatography, were raised in three adult male rabbits (R-I, R-II and R-III). Each of the rabbits received 20–30 μg of the purified receptor in Freund's complete adjuvant at a time. Primary immunization was followed by booster injection at intervals. Production of receptor antibodies was monitored by (1) determining the dilution of the serum (IgG fraction) that could specifically bind 50% of 125I-LH/CG-R added and (2) analysing sera for any change in testosterone levels. Following primary immunization and the first booster, all three rabbits exhibited a 2·5- to 6·0-fold increase in serum testosterone over basal levels and this effect was spread over a period of time (∼40 days) coinciding with the rise and fall of receptor antibodies. The maximal antibody titre (ED50) produced at this time ranged from 1:350 to 1:100 to below detectable limits for R-I, R-II and R-III respectively. Subsequent immunizations followed by the second booster resulted in a substantial increase in anti-body titre (ED50 of 1:5000) in R-I, but this was not accompanied by any change in serum testosterone over preimmune levels, suggesting that with the progress of immunization the character of the antibody produced had also changed. Two pools of antisera from R-I collected 10 days following the booster (at day 70 (bleed I) and day 290 (bleed II)) were used in further experiments. IgG isolated from bleed I but not from bleed II antiserum showed a dose-dependent stimulation of testosterone production by mouse Leydig cells in vitro, thus confirming the in vivo hormone-mimicking activity of antibodies generated during the early immunization phase. The IgG fractions from both bleeds were, however, capable of inhibiting (1) 125I-hCG binding to crude sheep luteal membrane (EC50 of 1:70 and 1:350 for bleed I and II antisera respectively) and (2) ovine LH-stimulated testosterone production by mouse Leydig cells in vitro, indicating the presence of antagonistic antibodies irrespective of the period of time during which the rabbits were immunized. The fact that bleed I-stimulated testosterone production could be inhibited in a dose-dependent manner by the addition of IgG from bleed II to the mouse Leydig cell in vitro assay system showed that the agonistic activity is intrinsic to the bleed I antibody. The receptor antibody (bleed II) was also capable of blocking LH action in vivo, as rabbits passively (for 24 h with LH/CG-R antiserum) as well as actively (for 430 days) immunized against LH/CG-R failed to respond to a bolus injection of LH (50 μg). At no time, however, was the serum testosterone reduced below the basal level. This study clearly shows that, unlike with LH antibody, attempts to achieve an LH deficiency effect in vivo by resorting to immunization with holo LH receptor is difficult, as receptor antibodies exhibit both hormone-mimicking (agonistic) as well as hormone-blocking (antagonistic) activities. Journal of Endocrinology (1996) 150, 431–443

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