scholarly journals Role of Nodal signalling in testis development and initiation of testicular cancer

Reproduction ◽  
2019 ◽  
Vol 158 (2) ◽  
pp. R67-R77 ◽  
Author(s):  
Katrine Harpelunde Poulsen ◽  
Anne Jørgensen
Keyword(s):  
Testicular Cancer ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Cell Function ◽  
Testicular Development ◽  
Fetal Life ◽  
Cell Specification ◽  
Testis Development ◽  
Fetal Testis ◽  
Cancer Pathogenesis

Testicular development from the initially bipotential gonad is a tightly regulated process involving a complex signalling cascade to ensure proper sequential expression of signalling factors and secretion of steroid hormones. Initially, Sertoli cell specification facilitates differentiation of the steroidogenic fetal Leydig cells and establishment of the somatic niche, which is critical in supporting the germ cell population. Impairment of the somatic niche during fetal life may lead to development of male reproductive disorders, including arrest of gonocyte differentiation, which is considered the first step in the testicular cancer pathogenesis. In this review, we will outline the signalling pathways involved in fetal testis development focusing on the Nodal pathway, which has recently been implicated in several aspects of testicular differentiation in both mouse and human studies. Nodal signalling plays important roles in germ cell development, including regulation of pluripotency factor expression, proliferation and survival. Moreover, the Nodal pathway is involved in establishment of the somatic niche, including formation of seminiferous cords, steroidogenesis and Sertoli cell function. In our outline of fetal testis development, important differences between human and mouse models will be highlighted to emphasise that information obtained from mouse studies cannot always be directly translated to humans. Finally, the implications of dysregulated Nodal signalling in development of the testicular cancer precursor, germ cell neoplasia in situ, and testicular dysgenesis will be discussed – none of which arise in rodents, emphasising the importance of human models in the effort to increase our understanding of origin and early development of these disorders.

scholarly journals Environmental exposures, fetal testis development and function: phthalates and beyond

Reproduction ◽  
2021 ◽  
Author(s):  
Hui Li ◽  
Daniel J. Spade
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Current Knowledge ◽  
Environmental Chemicals ◽  
Environmental Toxicants ◽  
Cell Contacts ◽  
Testis Development ◽  
Fetal Testis

Fetal development of the mammalian testis relies on a series of interrelated cellular processes: commitment of somatic progenitor cells to Sertoli and Leydig cell fate, migration of endothelial cells and Sertoli cells, differentiation of germ cells, deposition of basement membrane, and establishment of cell-cell contacts, including Sertoli-Sertoli and Sertoli-germ cell contacts. These processes are orchestrated by intracellular, endocrine, and paracrine signaling processes. Because of this complexity, testis development can be disrupted by a variety of environmental toxicants. Toxicity of phthalic acid esters (phthalates) to the fetal testis has been the subject of extensive research for two decades, and phthalates have become an archetypal fetal testis toxicant. Phthalates disrupt the seminiferous cord formation and maturation, Sertoli cell function, biosynthesis of testosterone in Leydig cells, and impair germ cell survival and development, producing characteristic multinucleated germ cells. However, the mechanisms responsible for these effects are not fully understood. This review describes current knowledge of the adverse effects of phthalates on the fetal testis and their associated windows of sensitivity, and compares and contrasts the mechanisms by which toxicants of current interest, bisphenol A and its replacements, analgesics, and perfluorinated alkyl substances, alter testicular developmental processes. Working towards a better understanding of the molecular mechanisms responsible for phthalate toxicity will be critical for understanding the long-term impacts of environmental chemicals and pharmaceuticals on human reproductive health.

Impaired Testicular Function in Patients With Carcinoma-In-Situ of the Testis

1999 ◽  
Vol 17 (1) ◽  
pp. 173-173 ◽  
Author(s):  
Peter Meidahl Petersen ◽  
Aleksander Giwercman ◽  
Steen W. Hansen ◽  
Jørgen G. Berthelsen ◽  
Gedske Daugaard ◽  
...  
Keyword(s):  
Testicular Cancer ◽  
Germ Cell ◽  
Leydig Cell ◽  
Carcinoma In Situ ◽  
Cell Function ◽  
Semen Quality ◽  
Sperm Concentration ◽  
Testicular Dysfunction ◽  
Leydig Cell Function

PURPOSE: To elucidate the biologic association between germ cell neoplasia and testicular dysfunction, through investigation of Leydig cell function and semen quality in men with carcinoma-in-situ (CIS) of the testis. PATIENTS AND METHODS: We examined two groups of men, unilaterally orchidectomized for testicular cancer. Biopsy of the contralateral testis had showed CIS in a group of 24 patients and no evidence of CIS in the other group of 30 patients. Semen quality and serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were compared in these two groups of men after orchidectomy but before further treatment for testicular cancer. RESULTS: Significantly higher LH levels (median, 8.1 IU/L v 4.8 IU/L; P < .001) and generally lower testosterone levels (median, 12.5 nmol/L v 15.5 nmol/L; P = .13) were found in the CIS group. The proportion of patients with Leydig cell dysfunction was higher in the group of patients with CIS (11 of 24) than in the group of patients without (two of 30) (P = .01). Sperm concentration and total sperm count were significantly lower (P < .001) in patients with CIS (median, 0.03 × 106/mL and 0.10 × 106, respectively) than in patients without (median, 9.1 × 106/mL and 32 × 106, respectively), whereas the levels of FSH were significantly higher (P < .001) in the former group of men (median, 19.6 IU/L v 9.0 IU/L). CONCLUSION: Not only spermatogenesis but also Leydig cell function is impaired in testes with CIS. This impairment could be due to common factors in the pathogenesis of germ cell neoplasm and testicular dysfunction. Alternatively, CIS cells may have a negative impact on Leydig cell function.

scholarly journals Smad3 Dosage Determines Androgen Responsiveness and Sets the Pace of Postnatal Testis Development

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 2076-2089 ◽  
Author(s):  
Catherine Itman ◽  
Chin Wong ◽  
Briony Hunyadi ◽  
Matthias Ernst ◽  
David A. Jans ◽  
...  
Keyword(s):  
Germ Cell ◽  
Sertoli Cell ◽  
Pubertal Development ◽  
Cell Development ◽  
Cell Maturation ◽  
Developmentally Regulated ◽  
Testis Development ◽  
Essentially Normal ◽  
Endocrine Factors ◽  
Immature Cells

The establishment and maturation of the testicular Sertoli cell population underpins adult male fertility. These events are influenced by hormones and endocrine factors, including FSH, testosterone and activin. Activin A has developmentally regulated effects on Sertoli cells, enhancing proliferation of immature cells and later promoting postmitotic maturation. These differential responses correlate with altered mothers against decapentaplegic (SMAD)-2/3 signaling: immature cells signal via SMAD3, whereas postmitotic cells use both SMAD2 and SMAD3. This study examined the contribution of SMAD3 to postnatal mouse testis development. We show that SMAD3 production and subcellular localization are highly regulated and, through histological and molecular analyses, identify effects of altered Smad3 dosage on Sertoli and germ cell development. Smad3+/− and Smad3−/− mice had smaller testes at 7 d postpartum, but this was not sustained into adulthood. Juvenile and adult serum FSH levels were unaffected by genotype. Smad3-null mice displayed delayed Sertoli cell maturation and had reduced expression of androgen receptor (AR), androgen-regulated transcripts, and Smad2, whereas germ cell and Leydig cell development were essentially normal. This contrasted remarkably with advanced Sertoli and germ cell maturation and increased expression of AR and androgen-regulated transcripts in Smad3+/− mice. In addition, SMAD3 was down-regulated during testis development and testosterone up-regulated Smad2, but not Smad3, in the TM4 Sertoli cell line. Collectively these data reveal that appropriate SMAD3-mediated signaling drives normal Sertoli cell proliferation, androgen responsiveness, and maturation and influences the pace of the first wave of spermatogenesis, providing new clues to causes of altered pubertal development in boys.

scholarly journals Distinct Roles for Rac1 in Sertoli Cell Function during Testicular Development and Spermatogenesis

Cell Reports ◽  
2020 ◽  
Vol 31 (2) ◽  
pp. 107513 ◽  
Author(s):  
Anna Heinrich ◽  
Sarah J. Potter ◽  
Li Guo ◽  
Nancy Ratner ◽  
Tony DeFalco
Keyword(s):  
Sertoli Cell ◽  
Cell Function ◽  
Testicular Development

scholarly journals Estrogen Receptor β-Mediated Inhibition of Male Germ Cell Line Development in Mice by Endogenous Estrogens during Perinatal Life

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3395-3403 ◽  
Author(s):  
Géraldine Delbès ◽  
Christine Levacher ◽  
Catherine Pairault ◽  
Chrystèle Racine ◽  
Clotilde Duquenne ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Germ Cell ◽  
Experimental Studies ◽  
Cell Lineage ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Testicular Development ◽  
Fetal Life ◽  
Germ Cell Line ◽  
Highly Sensitive ◽  
Labeling Method

Abstract Epidemiological, clinical, and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders and sperm abnormalities in adulthood. However, it is unknown whether endogenous concentrations of estrogens affect the establishment of the male fetal germ cell lineage. We addressed this question by studying the testicular development of mice in which the estrogen receptor (ER) β or the ERα gene was inactivated. The homozygous inactivation of ERβ (ERβ−/−) increased the number of gonocytes by 50% in 2- and 6-d-old neonates. The numbers of Sertoli and Leydig cells and the level of testicular testosterone production were unaffected, suggesting that estrogens act directly on the gonocytes. The increase in the number of gonocytes did not occur during fetal life but instead occurred just after birth, when gonocytes resumed mitosis and apoptosis. It seems to result from a decrease in the apoptosis rate evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and cleaved caspase-3 immunohistochemical detection. Last, mice heterozygous for the ERβ gene inactivation behaved similarly to their ERβ−/− littermates in terms of the number of gonocytes, apoptosis, and mitosis, suggesting that these cells are highly sensitive to the binding of estrogens to ERβ. ERα inactivation had no effect on the number of neonatal gonocytes and Sertoli cells. In conclusion, this study provides the first demonstration that endogenous estrogens can physiologically inhibit germ cell growth in the male. This finding may have important implications concerning the potential action of environmental estrogens.

scholarly journals Overexpression of Bcl-w in the Testis Disrupts Spermatogenesis: Revelation of a Role of BCL-W in Male Germ Cell Cycle Control

2003 ◽  
Vol 17 (9) ◽  
pp. 1868-1879 ◽  
Author(s):  
Wei Yan ◽  
Jun-Xing Huang ◽  
Anna-Stina Lax ◽  
Lauri Pelliniemi ◽  
Eeva Salminen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Testicular Development ◽  
Dna Ladder

Abstract To explore physiological roles of BCL-W, a prosurvival member of the BCL-2 protein family, we generated transgenic (TG) mice overexpressing Bcl-w driven by a chicken β-actin promoter. Male Bcl-w TG mice developed normally but were infertile. The adult TG testes displayed disrupted spermatogenesis with various severities ranging from thin seminiferous epithelium containing less germ cells to Sertoli cell-only appearance. No overpopulation of any type of germ cells was observed during testicular development. In contrast, the developing TG testes displayed decreased number of spermatogonia, degeneration, and detachment of spermatocytes and Sertoli cell vacuolization. The proliferative activity of germ cells was significantly reduced during testicular development and spermatogenesis, as determined by in vivo and in vitro 5′-bromo-2′deoxyuridine incorporation assays. Sertoli cells were structurally and functionally normal. The degenerating germ cells were TUNEL-negative and no typical apoptotic DNA ladder was detected. Our data suggest that regulated spatial and temporal expression of BCL-W is required for normal testicular development and spermatogenesis, and overexpression of BCL-W inhibits germ cell cycle entry and/or cell cycle progression leading to disrupted spermatogenesis.

scholarly journals Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis

PLoS ONE ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. e0191934 ◽  
Author(s):  
Soria Eladak ◽  
Delphine Moison ◽  
Marie-Justine Guerquin ◽  
Gabriele Matilionyte ◽  
Karen Kilcoyne ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Germ Cell ◽  
Leydig Cell ◽  
Cell Function ◽  
Cell Development ◽  
Germ Cell Development ◽  
Fetal Testis ◽  
Leydig Cell Function

scholarly journals New perspectives in the diagnosis of pediatric male hypogonadism: the importance of AMH as a Sertoli cell marker

2011 ◽  
Vol 55 (8) ◽  
pp. 512-519 ◽  
Author(s):  
Romina P. Grinspon ◽  
Rodolfo A. Rey
Keyword(s):  
Sertoli Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Tanner Stage ◽  
Inhibitory Effect ◽  
Male Hypogonadism ◽  
Fetal Life ◽  
Infancy And Childhood ◽  
Stimulation Tests ◽  
Enzyme Defects

Sertoli cells are the most active cell population in the testis during infancy and childhood. In these periods of life, hypogonadism can only be evidenced without stimulation tests, if Sertoli cell function is assessed. AMH is a useful marker of prepubertal Sertoli cell activity and number. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Serum AMH is undetectable in anorchidic patients. In primary or central hypogonadism affecting the whole gonad and established in fetal life or childhood, serum AMH is low. Conversely, when hypogonadism affects only Leydig cells (e.g. LHβ mutations, LH/CG receptor or steroidogenic enzyme defects), serum AMH is normal or high. In pubertal males with central hypogonadism, AMH is low for Tanner stage (reflecting lack of FSH stimulus), but high for the age (indicating lack of testosterone inhibitory effect). Treatment with FSH provokes an increase in serum AMH, whereas hCG administration increases testosterone levels, which downregulate AMH. In conclusion, assessment of serum AMH is helpful to evaluate gonadal function, without the need for stimulation tests, and guides etiological diagnosis of pediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action on the testis.

scholarly journals Rictor Regulates Spermatogenesis by Controlling Sertoli Cell Cytoskeletal Organization and Cell Polarity in the Mouse Testis

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4244-4256 ◽  
Author(s):  
Heling Dong ◽  
Zhenguo Chen ◽  
Caixia Wang ◽  
Zhi Xiong ◽  
Wanlu Zhao ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Cell Function ◽  
Regulatory Protein ◽  
Small Gtpase ◽  
Mutant Mice ◽  
Actin Dynamics ◽  
Testicular Development ◽  
Developmental Defects

Maintenance of cell polarity is essential for Sertoli cell and blood-testis barrier (BTB) function and spermatogenesis; however, the signaling mechanisms that regulate the integrity of the cytoskeleton and polarity of Sertoli cells are not fully understood. Here, we demonstrate that rapamycin-insensitive component of target of rapamycin (TOR) (Rictor), a core component of mechanistic TOR complex 2 (mTORC2), was expressed in the seminiferous epithelium during testicular development, and was down-regulated in a cadmium chloride-induced BTB damage model. We then conditionally deleted the Rictor gene in Sertoli cells and mutant mice exhibited azoospermia and were sterile as early as 3 months old. Further study revealed that Rictor may regulate actin organization via both mTORC2-dependent and mTORC2-independent mechanisms, in which the small GTPase, ras-related C3 botulinum toxin substrate 1, and phosphorylation of the actin filament regulatory protein, Paxillin, are involved, respectively. Loss of Rictor in Sertoli cells perturbed actin dynamics and caused microtubule disarrangement, both of which accumulatively disrupted Sertoli cell polarity and BTB integrity, accompanied by testicular developmental defects, spermiogenic arrest and excessive germ cell loss in mutant mice. Together, these findings establish the importance of Rictor/mTORC2 signaling in Sertoli cell function and spermatogenesis through the maintenance of Sertoli cell cytoskeletal dynamics, BTB integrity, and cell polarity.

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