scholarly journals Antagonistic Effects of Testosterone and the Endocrine Disruptor Mono-(2-Ethylhexyl) Phthalate on INSL3 Transcription in Leydig Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4688-4694 ◽  
Author(s):  
Éric Laguë ◽  
Jacques J. Tremblay
Keyword(s):  
Androgen Receptor ◽  
Leydig Cells ◽  
Endocrine Disruptor ◽  
Testicular Descent ◽  
Postnatal Life ◽  
Fetal Life ◽  
Mrna Levels ◽  
Androgen Response Element ◽  
Ethylhexyl Phthalate

Insulin-like 3 (INSL3) is a small peptide produced by testicular Leydig cells throughout embryonic and postnatal life and by theca and luteal cells of the adult ovary. During fetal life, INSL3 regulates testicular descent in males, whereas in adults, it acts as an antiapoptotic factor for germ cells in males and as a follicle selection and survival factor in females. Despite its considerable roles in the reproductive system, the mechanisms that regulate Insl3 expression remain poorly understood. There is accumulating evidence suggesting that androgens might regulate Insl3 expression in Leydig cells, but transcriptional data are still lacking. We now report that testosterone does increase Insl3 mRNA levels in a Leydig cell line and primary Leydig cells. We also show that testosterone activates the activity of the Insl3 promoter from different species. In addition, the testosterone-stimulating effects on Insl3 mRNA levels and promoter activity require the androgen receptor. We have mapped the testosterone-responsive element to the proximal Insl3 promoter region. This region, however, lacks a consensus androgen response element, suggesting an indirect mechanism of action. Finally we show that mono-(2-ethylhexyl) phthalate, a widely distributed endocrine disruptor with antiandrogenic activity previously shown to inhibit Insl3 expression in vivo, represses Insl3 transcription, at least in part, by antagonizing testosterone/androgen receptor action. All together our data provide important new insights into the regulation of Insl3 transcription in Leydig cells and the mode of action of phthalates.

In vivo acute testicular testosterone response to injection of luteinizing hormone in the rat fetus

1993 ◽  
Vol 128 (3) ◽  
pp. 268-273 ◽  
Author(s):  
René Habert
Keyword(s):  
Plasma Concentration ◽  
Luteinizing Hormone ◽  
Leydig Cells ◽  
Time Dependent ◽  
Fetal Life ◽  
Dependent Manner ◽  
Adult Rats ◽  
Rat Fetus ◽  
Age Related

The acute in vivo testosterone response to LH stimulation and its change during late fetal life were determined in the rat. In 18.5-day-old fetuses, testicular testosterone content was increased in a dose-and time-dependent manner after fetal subcutaneous LH injection. The maximum response was small: the testicular content and plasma concentration were increased by 200% and 2 50% over basal values respectively, while they were increased 1100% and 1200% in adult rats. Similarly, comparable low responses were obtained after subcutaneously injecting the fetuses with human chorionic gonadotropin (hCG) and after injecting LH into the vitelline vein. Between days 18.5 and 21.5 of fetal life, the testosterone levels in the testis and plasma of uninjected or PBS-injected fetuses decreased and were comparable in both groups. In maximally LH-stimulated fetuses, the testicular content did not change with age, and plasma concentration was lower on day 21.5 than on day 18.5. Since the number of Leydig cells increases 1.5 to 2-fold between days 18.5 and 21.5, these results show an age-related decrease in basal and maximally LH-stimulated in vivo testosterone secretions per Leydig cell during late fetal life.

Cellular distribution of insulin-like growth factor binding protein mRNAs and peptides during rat lung development

1997 ◽  
Vol 155 (2) ◽  
pp. 313-327 ◽  
Author(s):  
LD Wallen ◽  
W Myint ◽  
K Nygard ◽  
S Shimasaki ◽  
DR Clemmons ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Lung Development ◽  
Fetal Lung ◽  
Northern Analysis ◽  
Postnatal Life ◽  
Mrna Levels ◽  
Igf Binding Proteins ◽  
Paracrine Factors ◽  
Igfbp 3

A role for IGF binding proteins (IGFBPs) in lung development is suggested by the identification of IGFBPs in lung tissue and production of IGFBPs by fetal lung cells in culture. To characterize the expression of IGFBPs during lung development in the rat in vivo (16 days gestation through adulthood), the expression of IGFBP mRNAs (IGFBP-1 to IGFBP-6) was examined by Northern analysis and in situ hybridization, and IGFBP peptides (IGFBP-2, IGFBP-3, and IGFBP-5) were localized by immunohistochemistry. IGFBP-1 mRNA was not detectable. IGFBP-2 mRNA (1.8 kb) was expressed in both fetal and postnatal life with peak expression during the fetal pseudoglandular stage. IGFBP-2 mRNA was localized mainly to airway epithelium. IGFBP-3 mRNA (2.4 kb) was maximally expressed postnatally in the saccular stage of lung development; it was identified in airway epithelium and interstitium in the fetal lung, but predominantly in airway epithelium after birth. IGFBP-4 (2.6 kb) and IGFBP-5 (6.0 kb) mRNA levels were maximal after birth, from 3 to 21 days postnatal (saccular and alveolar stage). IGFBP-4 mRNA was localized primarily to the interstitium and blood vessels early in development, but was abundant in airway epithelium in the adult. IGFBP-5 mRNA was most abundant in the airway epithelium. IGFBP-3, IGFBP-4, IGFBP-5, and to a lesser extent IGFBP-6 were localized to the large cartilaginous airways in the adult. IGFBP-2, IGFBP-3, and IGFBP-5 peptides were distributed more widely than their respective mRNAs, with a temporal pattern of immunoreactivity following that of their mRNAs. Maximal staining was noted in airway epithelium for IGFBP-2 in the newborn, for IGFBP-3 in the saccular stage (newborn to 3 days postnatal), and for IGFBP-5 in the alveolar stage (5 to 21 days postnatal). Our studies demonstrate that IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 are synthesized and distributed in spatially and temporally different patterns in the developing lung. The widespread distribution of IGFBP immunoreactivity compared with their respective mRNAs suggests that IGFBPs are important paracrine factors in the regulation of IGF action in the developing lung.

scholarly journals Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhengfang Liu ◽  
Cheng Liu ◽  
Keqiang Yan ◽  
Jikai Liu ◽  
Zhiqing Fang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Mrna Levels ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Protease ◽  
Hormone Sensitive

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

scholarly journals Differential regulation of Igf1 and Igf2 mRNA levels in tilapia hepatocytes: effects of insulin and cortisol on GH sensitivity

2011 ◽  
Vol 211 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Andrew L Pierce ◽  
Jason P Breves ◽  
Shunsuke Moriyama ◽  
Tetsuya Hirano ◽  
E Gordon Grau
Keyword(s):  
Growth And Development ◽  
Mrna Level ◽  
Differential Regulation ◽  
Postnatal Life ◽  
Mrna Levels ◽  
Primary Cultured Hepatocytes ◽  
Mammalian Liver ◽  
Growth Promoting ◽  
Stimulation Of

Igf1 and Igf2 stimulate growth and development of vertebrates. In mammals, liver-derived endocrine Igf1 mediates the growth promoting effects of GH during postnatal life, whereas Igf2 stimulates placental and fetal growth and is not regulated by GH. Insulin enhances Igf1 production by the mammalian liver directly, and by increasing hepatocyte sensitivity to GH. We examined the regulation ofigf1andigf2mRNA levels by GH, insulin, and cortisol, and the effects of insulin and cortisol on GH sensitivity in primary cultured hepatocytes of tilapia, a cichlid teleost. GH increased mRNA levels of bothigf1andigf2in a concentration-related and biphasic manner over the physiological range, with a greater effect onigf2mRNA level. Insulin increased basaligf2mRNA level, and strongly increased GH-stimulatedigf2mRNA level, but slightly reduced basaligf1mRNA level and did not affect GH-stimulatedigf1mRNA level. Cortisol inhibited GH stimulation ofigf1, but increased GH stimulation ofigf2mRNA level. The synergistic effect of insulin and GH onigf2mRNA level was confirmedin vivo. These results indicate that insulin and cortisol differentially modulate the response ofigf1andigf2mRNA to GH in tilapia hepatocytes, and suggest that the regulation of liver Igf2 production differs between fish and mammals. Regulation of liver Igf2 production in fish appears to be similar to regulation of liver Igf1 production in mammals.

Molecular adaptations of testosterone-producing Leydig cells during systemic in vivo blockade of the androgen receptor

2014 ◽  
Vol 396 (1-2) ◽  
pp. 10-25 ◽  
Author(s):  
Maja M. Bjelic ◽  
Natasa J. Stojkov ◽  
Aleksandar Z. Baburski ◽  
Srdjan J. Sokanovic ◽  
Aleksandar I. Mihajlovic ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Leydig Cells

scholarly journals The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

2014 ◽  
Vol 53 (1) ◽  
pp. 43-55 ◽  
Author(s):  
Raifish E Mendoza-Villarroel ◽  
Mickaël Di-Luoffo ◽  
Etienne Camiré ◽  
Xavier C Giner ◽  
Catherine Brousseau ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Protein Interactions ◽  
Leydig Cells ◽  
Molecular Mechanisms ◽  
Direct Repeat ◽  
Testicular Descent ◽  
Mrna Levels ◽  
Orphan Nuclear Receptor ◽  
Protein Protein Interactions ◽  
Dna Precipitation

Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues. Although COUP-TFII-deficient mice had Leydig cell dysfunction and impaired fertility, it remained unknown whether Insl3 expression was directly regulated by COUP-TFII. In this study, we observed a significant decrease in Insl3 mRNA levels in MA-10 Leydig cells depleted of COUP-TFII. Furthermore, a −1087 bp mouse Insl3 promoter was activated fourfold by COUP-TFII in MA-10 Leydig cells. Using 5′ progressive deletions, the COUP-TFII-responsive element was located between −186 and −79 bp, a region containing previously uncharacterised direct repeat 0-like (DR0-like) and DR3 elements. The recruitment and direct binding of COUP-TFII to the DR0-like element were confirmed by chromatin immunoprecipitation and DNA precipitation assay respectively. Mutation of the DR0-like element, which prevented COUP-TFII binding, significantly decreased COUP-TFII-mediated activation of the −1087 bp Insl3 reporter in CV-1 fibroblast cells but not in MA-10 Leydig cells. Finally, we found that COUP-TFII cooperates with the nuclear receptor steroidogenic factor 1 (SF1) to further enhance Insl3 promoter activity. Our results identify Insl3 as a target for COUP-TFII in Leydig cells and revealed that COUP-TFII acts through protein–protein interactions with other DNA-bound transcription factors, including SF1, to activate Insl3 transcription in these cells.

Effect of decapitation and chronic in-vivo treatment with a gonadotrophin-releasing hormone agonist on testicular steroidogenesis in the rat fetus

1992 ◽  
Vol 133 (2) ◽  
pp. 245-251 ◽  
Author(s):  
R. Habert
Keyword(s):  
Gnrh Agonist ◽  
Leydig Cells ◽  
Maternal Plasma ◽  
Plasma Testosterone ◽  
Fetal Life ◽  
Rat Fetus ◽  
Control Female ◽  
Releasing Hormone ◽  
Gonadotrophin Releasing Hormone

ABSTRACT To study the effect of in-vivo gonadotrophin-releasing hormone (GnRH) treatment on testicular testosterone production during late fetal life in the rat, 18·5-, or 20·5-day-old fetuses were decapitated and injected with either long-acting microcapsules containing the GnRH agonist d-Trp-6-GnRH or vehicle only. Two days later, fetal and maternal plasma was collected and fetal testes were removed and incubated for 6 h in medium with either 100 ng LH/ml or without LH. The GnRH agonist concentrations in the plasma of GnRH-treated decapitated male fetuses were comparable in the two age-related groups (5 nmol/l). After treatment of the fetus with d-Trp-6-GnRH, the agonist was recovered in maternal plasma, showing that this peptide can cross the fetal–maternal barrier. In 22·5-day-old decapitated vehicle-treated male fetuses, the plasma testosterone level dropped to that observed in control female fetuses, and treatment of decapitated male fetuses with the GnRH agonist did not further reduce it. At both days 20·5 and 22·5, basal in-vitro testosterone secretion by testes from decapitated vehicle-treated fetuses was lower than secretion by testes from intact control fetuses from the same litter, but LH-stimulated secretion was similar in both groups. Both basal and LH-stimulated secretion by testes from GnRH-treated decapitated fetuses was lower than secretion by testes from vehicle-treated decapitated fetuses and larger reductions were measured on day 22·5 than on day 20·5 (−48 vs −18% for basal secretion, and −76 vs −40% for LH-stimulated secretion). These results suggest that, in contrast to immature Leydig cells, fetal Leydig cells are not desensitized to gonadotrophic stimulation after hypophysial deprivation, and that, in the rat, a negative testicular response to a putative intratesticular GnRH or to some other factor using the same intracellular pathway is established during late fetal life. Journal of Endocrinology (1992) 133, 245–251

scholarly journals Ghrelin Inhibits the Proliferative Activity of Immature Leydig Cells in Vivo and Regulates Stem Cell Factor Messenger Ribonucleic Acid Expression in Rat Testis

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4825-4834 ◽  
Author(s):  
M. L. Barreiro ◽  
F. Gaytan ◽  
J. M. Castellano ◽  
J. S. Suominen ◽  
J. Roa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Leydig Cell ◽  
Stem Cell Factor ◽  
Proliferative Activity ◽  
Leydig Cells ◽  
Human Testis ◽  
Seminiferous Tubules ◽  
Mrna Levels ◽  
Messenger Ribonucleic Acid

Abstract Ghrelin has emerged as putative regulator of an array of endocrine and nonendocrine functions, including cell proliferation. Recently, we provided evidence for the expression of ghrelin in mature, but not in undifferentiated, Leydig cells of rat and human testis. Yet testicular actions of ghrelin, other than modulation of testosterone secretion, remain unexplored. In the present study we evaluated the effects of ghrelin on proliferation of Leydig cell precursors during puberty and after selective elimination of mature Leydig cells by treatment with ethylene dimethane sulfonate. In these settings, intratesticular injection of ghrelin significantly decreased the proliferative activity of differentiating immature Leydig cells, estimated by 5-bromodeoxyuridine labeling. This response was selective and associated, in ethylene dimethane sulfonate-treated animals, with a decrease in the mRNA levels of stem cell factor (SCF), i.e. a key signal in spermatogenesis and a putative regulator of Leydig cell development. Thus, the effects of ghrelin on SCF gene expression were evaluated. In adult rats, ghrelin induced a significant decrease in SCF mRNA levels in vivo. Such an inhibitory action was also detected in vitro using cultures of staged seminiferous tubules. The inhibitory effect of ghrelin in vivo was dependent on proper FSH input, because it was detected in hypophysectomized rats only after FSH replacement. Overall, it is proposed that acquisition of ghrelin expression by Leydig cell precursors during differentiation may operate as a self-regulatory signal for the inhibition of the proliferative activity of this cell type through direct or indirect (i.e. SCF-mediated) mechanisms. In addition, we present novel evidence for the ability of ghrelin to modulate the expression of the SCF gene, which may have implications for the mode of action of this molecule in the testis as well as in other physiological systems.

Long-term changes of somatotrophic function induced by deprivation of growth hormone-releasing hormone during the fetal life of the rat

1994 ◽  
Vol 140 (1) ◽  
pp. 111-117 ◽  
Author(s):  
S G Cella ◽  
V Locatelli ◽  
M L Broccia ◽  
E Menegola ◽  
E Giavini ◽  
...  
Keyword(s):  
Body Weight ◽  
Somatic Growth ◽  
Rabbit Serum ◽  
Normal Rabbit Serum ◽  
Fetal Life ◽  
Mrna Levels ◽  
Neuronal System ◽  
Releasing Hormone ◽  
Gh Secretion

Abstract We have studied the effects of intra-amniotic administration of an anti-GH-releasing hormone serum (GHRH-Ab) on day 16 of fetal life in the rat, when the ontogenetic development of the GHRH neuronal system occurs. Control animals received normal rabbit serum. Following delivery, body weight was monitored for the next 30 days as an index of somatic growth, and the following indices of somatotrophic function were determined: plasma and pituitary GH, pituitary GH mRNA, hypothalamic GHRH and somatostatin mRNA, and the in vivo GH responsiveness to GHRH. At birth, GHRH-Ab-treated rats had a body weight that was equivalent to that of control rats but, starting from postnatal day 6 up to day 30, they had a significantly reduced body weight. Pituitary weight, the absolute pituitary GH content and GH mRNA levels were lower in experimental compared with control rats, while pituitary GH concentrations were similar in the two groups, thus implying that there was a defect, not only in GH synthesis, but also in GH release. In agreement with this theory, basal GH levels and GHRH-stimulated GH secretion were reduced in GHRH-Ab-treated rats but, in contrast, hypothalamic regulation of GH secretion appeared to be working in these rats as they were still able to respond to the low plasma GH by increasing GHRH and decreasing somatostatin mRNA levels. These findings indicate that deprivation of GHRH during fetal life induces long-lasting changes of growth rate and somatotrophic function. In addition, when comparing these changes with those in rats given GHRH-Ab postnatally, it would appear that deprivation of GHRH affects different regulatory levels of the hypothalamo-pituitary-somatotroph axis depending on when the deprivation occurs. Journal of Endocrinology (1994) 140, 111–117

scholarly journals Biomarkers of male hypogonadism in childhood and adolescence

2020 ◽  
Vol 1 (2) ◽  
Author(s):  
Rodolfo A. Rey
Keyword(s):  
Leydig Cells ◽  
Serum Levels ◽  
Diagnostic Value ◽  
Inhibin B ◽  
Postnatal Life ◽  
Childhood And Adolescence ◽  
Male Hypogonadism ◽  
Fetal Life ◽  
Hpg Axis ◽  
Developmental Physiology

AbstractObjectivesThe objective of this review was to characterize the use of biomarkers of male hypogonadism in childhood and adolescence.ContentsThe hypothalamic-pituitary-gonadal (HPG) axis is active during fetal life and over the first months of postnatal life. The pituitary gland secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH), whereas the testes induce Leydig cells to produce testosterone and insulin-like factor 3 (INSL), and drive Sertoli cells to secrete anti-Müllerian hormone (AMH) and inhibin B. During childhood, serum levels of gonadotropins, testosterone and insulin-like 3 (INSL3) decline to undetectable levels, whereas levels of AMH and inhibin B remain high. During puberty, the production of gonadotropins, testosterone, and INSL3 is reactivated, inhibin B increases, and AMH decreases as a sign of Sertoli cell maturation.Summary and outlookBased on our knowledge of the developmental physiology of the HPG axis, these biomarkers can be used in clinical practice to interpret the physiopathology of hypogonadism. Additionally, these markers can have diagnostic value in different forms of hypogonadism that may appear during childhood and adolescence.

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