[Transversal ectopia of the testis associated with pseudohermaphroditism].
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Adult↗
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Testis lesions and cellular and humoral immune responses induced in rats by immunization with laminin.
Sixty-six percent of rats immunized with laminin isolated from a mouse Engelbreth-Holm-Swarm (EHS) sarcoma developed moderate lesions in the testis characterized by multiple foci of seminiferous tubules with different degrees of sloughing of the germinal epithelium or atrophy intermingled with normal histological areas. Interstitial mononuclear cell infiltrates were seen in the epididymis. By electron microscopy, pathological changes in the basement membranes of the seminiferous tubules, such as splitting and focal thickenings of knob-like projections toward the epithelium, were observed. Moreover, Sertoli cell cytoplasm showed dilated smooth endoplasmic reticulum and large vacuoles. By electron microscopy with the immunoperoxidase technique, staining for in vivo-bound rat IgG was detected along the walls of the seminiferous tubules as a bright linear immunofluorescence and as a dense reaction product on the basal lamina. High titers of circulating antilaminin antibodies were detected by ELISA in all the rats immunized with laminin. As revealed by the skin test, a delayed type hypersensitivity reaction to laminin was observed in these rats.
Animals↗
NYD-SP15: a novel gene potentially involved in regulating testicular development and spermatogenesis.
By hybridizing human adult testis cDNA microarrays with human adult and embryo testis cDNA probes, we identified a novel human testis gene, NYD-SP15. NYD-SP15 expression was 3.26-fold higher in adult than in fetal testis; however, there was almost no NYD-SP15 expression in the sperm. NYD-SP15 comprises 3364 base pairs, including a 1545 bp open reading frame encoding a 514 amino acid protein possessing 89% sequence identity with the mouse testis homologous protein. NYD-SP15 is located on human chromosome 13q14.2. The deduced structure of the protein contains two dCMP_cyt_deam domains, indicating a potential functional role for zinc ion binding. The gene is expressed variably in a wide range of tissues, with high expression levels in the testis. Sequence analysis revealed that NYD-SP15 is not a highly conserved protein, with its distribution in high-level species such as vertebrates including Homo, Mus, Rattus, and Canis. The results of semiquantitative polymerase chain reaction in mouse testis representing different developmental stages indicate that NYD-SP15 expression was developmentally regulated. These results suggest the putative NYD-SP15 protein may play an important role in testicular development and spermatogenesis and may be an important factor governing male infertility.
Amino Acid Sequence↗
Concentration of androgens in whole testis, seminiferous tubules and interstitial tissue of rats at different stages of development.
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Androgens↗
Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules.
Testes from adult and prepubertal mice lacking the Desert hedgehog (DHH:) gene were examined in order to describe further the role of Dhh in spermatogenesis because, in a previous report, DHH:-null male mice were shown to be sterile. Dhh is a signaling molecule expressed by Sertoli cells. Its receptor, patched (Ptc), has been previously localized to Leydig cells and is herein described as being localized also to peritubular cells. Two phenotypes of the mice were observed: masculinized (7.5% of DHH:-null males) and feminized (92.5%), both of which displayed abnormal peritubular tissue and severely restricted spermatogenesis. Testes from adult feminized animals lacked adult-type Leydig cells and displayed numerous undifferentiated fibroblastic cells in the interstitium that produced abundant collagen. The basal lamina, normally present between the myoid cells and Sertoli cells, was focally absent. We speculate that the abnormal basal lamina contributed to other characteristics, such as extracordal gonocytes, apolar Sertoli cells, and anastomotic seminiferous tubules. The two DHH:-null phenotypes described have common peritubular cell defects that may be indicative of the essential role of peritubular cells in development of tubular morphology, the differentiation of Leydig cells, and the ultimate support of spermatogenesis.
Androgen-Insensitivity Syndrome↗
Expression of mixed lineage kinase 2 in germ cells of the testis.
Mixed Lineage Kinase 2 is a mammalian protein kinase that activates stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNKs) through direct phosphorylation of their upstream activator, SEK1/JNKK. We have examined expression of both MLK2 and SEK1/JNKK RNAs in the rat testis at various times during postnatal development and in isolated testicular cell populations. We also have used immunohistochemistry to examine MLK2 protein expression and localization in adult rat and mouse testis. In these analyses, we found rat MLK2 mRNA expression was first evident at a very low level on day 25 after birth and present from day 35 at much higher levels that continue into adulthood. In RNA from isolated cell types, a MLK2 transcript was detected in primary spermatocytes and round spermatids, but not in Leydig or Sertoli cells. MLK2 RNA was also absent from the testis of rats after induced cryptorchidism. SEK1/JNKK transcripts, on the other hand, were present at all stages of testicular development and in all cell types tested. In tissue sections from both adult rat and mouse testis, MLK2 immunoreactivity was present in the nucleus of primary and secondary spermatocytes and round spermatids within seminiferous tubules, but was absent from spermatogonia. These findings indicate the JNK pathway is most likely ubiquitous in rodent testicular cells, while the cell-specific pattern of MLK2 expression suggests that it may be involved in the regulation of processes specific to post-mitotic germ cells. Furthermore, the finding of MLK2 protein in the nucleus of spermatocytes and round spermatids indicates a role for MLK2 in regulation of nuclear events specific to germ cell development.
Animals↗
Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development.
To probe the relationship between the size of the Sertoli cell population, established during perinatal development, and production of germ cells in the adult testis, a Sertoli cell-depleted rat model was developed. This was accomplished by delivering an antimitotic drug, cytosine arabinoside (araC), directly to the testis of newborn pups. Initial studies of these araC-treated neonates indicated that 1) the drug is cleared rapidly from the testis; 2) it substantially reduces the level of Sertoli cell proliferation; 3) Sertoli cell division ceases at a normal time in spite of the previous drug treatment; and 4) araC itself has no residual effect on germ cell proliferation, which begins several days after the injection. Pups given araC were allowed to reach maturity, and their testes were perfuse-fixed for light microscopic morphometry. When the numbers of Sertoli cells in adult rats given araC as were compared with those in normal littermates, a 54% decrease in the size of the Sertoli cell population was detected in treated rats, now referred to as Sertoli cell-depleted. Moreover, when round spermatids were quantified and compared in normal and Sertoli cell-depleted adults, testes of the latter were found to contain 55% fewer round spermatids. Since, in the araC-treated group, the decrease in Sertoli cell population size was paralleled by a reduction in spermatid production of equal magnitude, the number of round spermatids per Sertoli cell was essentially identical in normal and Sertoli cell-depleted animals. Measurements of serum androgen-binding protein (ABP) and FSH in both groups indicated that the circulating level of ABP in Sertoli cell-depleted rats was approximately half, and the concentration of FSH approximately twice, that in normal animals. Thus, even though FSH is elevated in Sertoli cell-depleted rats, the production of ABP per Sertoli cell is unchanged. In addition, collective volume of Leydig cells and ventral prostate weights were normal in the Sertoli cell-depleted group, suggesting that Leydig cell function in these rats is normal. In summary, a Sertoli cell-depleted rat model has been produced by interfering specifically with Sertoli cell proliferation early in postnatal life, before onset of germ cell division. Moreover, our findings with this model indicate that production of normal numbers of germ cells in adults depends, at least in part, on the size of the Sertoli cell population. Thus, our observations identify the perinatal period, when the Sertoli cell population is established, as critical for development of quantitatively normal spermatogenesis in the adult.
Androgen-Binding Protein↗
Painful gynecomastia following cytotoxic therapy for testis cancer: a potentially favorable prognostic sign?
Ninety-six patients who received cytotoxic chemotherapy for germ cell neoplasms of the testis were studied. Painful gynecomastia developed in eight patients (8%) between 6 and 24 weeks after the initiation of cytotoxic therapy (mean 18 wk). Serum content of the beta subunit of human chorionic gonadotropin was normal in each patient when gynecomastia developed. Gynecomastia occurred following cytotoxic therapy for advanced disease in seven patients, and one patient was receiving adjunctive drug therapy for stage I disease. Six of the seven patients with advanced disease were in complete remission when gynecomastia developed; survival was superior in patients who developed treatment-related gynecomastia compared to those patients who did not (p less than 0.05). Gynecomastia may occur in adult males after cytotoxic therapy for testis cancer; such gynecomastia does not necessarily indicate recurrent malignancy and may be a favorable prognostic sign.
Adolescent↗
Somatic cell-germ cell relationships in mammalian testes during development and spermatogenesis.
In the mammalian testis, somatic cells under hormonal regulation greatly influence the different stages of spermatogenesis, both in intermittent breeders and in animals which produce sperm continuously. In turn, specific populations of germinal cells modulate the function of Sertoli cells, the chief somatic cells within mammalian seminiferous tubules. Tubule formation can take place in the absence of germinal cells. Unlike homologous granulosa cells in the ovary, Sertoli cells retain many of their usual functions in germ cell-free animals. Some of the properties of Sertoli cells and their responses to stimulation by androgens or follicle-stimulating hormone are dependent upon information transmitted from neighbouring germinal cells at specific stages of the cycle of the seminiferous epithelium. We review the roles of some of the growth factors and paracrine agents synthesized and secreted by different classes of testicular cells. The potential roles of some of the known factors secreted by Sertoli cells (e.g. activin, inhibin, anti-Müllerian hormones, TGF-beta and somatomedin C) are considered in relation to the control of tubule formation, spermatogonial proliferation and cytodifferentiation, meiosis and the subsequent stages of spermatogenesis. We stress the importance of the unique tubule cytoarchitecture within which cell interactions take place and the changing nature of this cytoarchitecture at different stages of gonadal maturation.
Animals↗
Surgery in testis cancer: laparoscopic and open techniques.
PURPOSE OF REVIEW: The review focuses on the current developments of the management of patients with testis cancer regarding surgery. For clinical stage I and stage II disease, the pros and cons of surgery as a diagnostic and therapeutic tool are updated. Additionally, the emerging role of laparoscopic techniques in the staging of the disease is critically discussed. The review presents the currently changing indications for surgery in addition to chemotherapy in metastatic disease. RECENT FINDINGS: The complication rates of primary retroperitoneal lymph node dissection have recently been assessed by the German Testicular Cancer Study Group. These data confirm the excellent results of the Indiana series published some years ago. Laparoscopic surgery has been performed in a larger cohort of patients in specialized centers, and, concomitantly, operative times and complication rates have dropped. Indications for surgery in the post-chemotherapy setting have been more clearly defined recently. Seminoma patients usually do not need surgical removal of the residual tumor after chemotherapy, whereas patients with non-seminoma disease probably need surgery even in cases of complete radiological remission after chemotherapy. In view of the recent data on late relapse, complete surgical removal of residual disease for non-seminoma seems of the utmost importance. SUMMARY: Larger series of surgical procedures, laparoscopic as well as open, have helped to define the role of this approach in the management of testis cancer. Long-term data on patients with complete response to initial treatment and late relapse have shown the danger of limiting the treatment of metastatic disease to chemotherapy alone. These data have also shown the importance of proper surgical techniques for all stages of testis cancer.
Germinoma↗
[Seminoma on ectopic testis associated with renal agenesis].
Tumors developing on ectopic testes, usually seminomas, are a rare occurrence, but when they do arise they are frequently associated with renal agenesis. Clinical manifestations vary, the presenting sign being generally an abdominal mass. Among the numerous exploratory techniques available the current examination of choice is computed tomography. The precise site of the lesion can be determined employing lower irradiation doses than those delivered during invasive methods.
Adult↗
Role of the gonads in sex differentiation of growth hormone-releasing hormone and somatostatin neurons in the mouse hypothalamus during postnatal development.
We clarify the mechanism of sexual dimorphism of growth hormone releasing hormone (GHRH) neurons in the arcuate nucleus (ARC) and somatostatin (SS) neurons in periventricular nucleus (PeN), by studying the role of the gonads during the neonatal period and after puberty using immunohistochemical and morphometric methods. As in our previous works the numbers of ARC GHRH-ir and PeN SS-ir neurons were significantly greater in adult normal male (NM) mice than in adult normal female (NF) mice. Adult female mice that were ovariectomized neonatally (NOF) increased the expression of GHRH-ir neurons to the male pattern, but adult female mice ovariectomized after puberty (APO) did not change. Adult male mice castrated neonatally and after puberty (NCM and APC, respectively) were not significantly different from NM mice. However, NCT male mice, which were castrated neonatally and transplanted with ovary just before puberty, showed a significantly reduced number of GHRH-ir neurons compared with NCM mice, but no significant difference from NM and NF mice. On the other hand, the PeN SS-ir neuron expression in NCM mice and APC mice showed a significant reduction compared with NM mice, but no significant difference from NF mice. The number of PeN SS-ir neurons in NOF increased to match that of NM mice. Our results suggest that the presence of the ovary during postnatal life inhibits the development of ARC GHRH-ir neurons. The presence of the testis during postnatal life may stimulate the development of PeN SS-ir neurons, while the presence of the ovary during neonatal period may inhibit the development of PeN SS-ir neurons; the presence of ovary after puberty does not inhibit.
Animals↗
Separation and quantification of histone H1 subtypes and high-mobility-group proteins by reversed-phase liquid chromatography: protein levels in rat tissues during postnatal development.
The rapid separation and quantification of histone H1 subtypes and high-mobility-group (HMG) chromatin proteins by reversed-phase liquid chromatography on a butylsilica-based column is described. The proteins were fractionated by means of a multi-step acetonitrile gradient containing 0.1% trifluoroacetic acid. This system is capable of resolving the four main HMG proteins (1, 2, 14 and 17), HMG I, protein P1 with HMG 18 and HMG 19 (in one peak) and five histone H1 subtypes in a single 33-min analysis. This method was used to study levels of these chromosomal proteins in nuclei of rat liver, spleen, testis and thymus during postnatal development from 1 to 20 weeks of age. Although no clear tissue specificity of the HMG proteins was apparent, there were significant differences in the relative amounts of these proteins in different tissues. The relative amount of HMG 1 increased from 1 to 12 weeks of age and decreased thereafter, whereas those of HMG 14 and HMG 17 remained almost unchanged. Marked quantitative differences were observed in the five histone H1 subtypes in different tissues. The largest changes in their levels during development were found in the liver and the smallest changes in the thymus. The changes in the spleen and testis were intermediate. These results suggest that the changes in the relative amounts of histone H1 subtypes and HMG proteins observed during postnatal development of the rat may result from differences in the structure of chromatin in these tissues and thus reflect the activity of molecular mechanisms involved in replication and differentiation of the cells.
Aging↗
Human sex determination.
Human sex determination is a fascinating topic, particularly at the level of molecular genetics, as it represents an excellent paradigm for mammalian organ development. Recent progress has seen the addition of several new pieces to this developmental jigsaw puzzle. In mammals, the Y chromosome is male determining, and encodes a gene referred to as TDF (testis-determining factor), which induces the indifferent embryonic gonad to develop as a testis. Subsequent male sexual differentiation is largely a consequence of hormonal secretion from the testis. In the absence of the Y chromosome, the testis-determining pathway fails to be initiated, and the embryonic gonad develops as an ovary, resulting in female development. (Ford et al. [1959] Lancet i:711; Jacobs and Strong [1959] Nature, 183:302-303; Jost et al. [1973] Rec. Prog. Horm. Res., 29:1-41).
Animals↗
Different developmental pattern of N-ras and unr gene expression in mouse gametogenic and somatic tissues.
Accumulation of transcripts from N-ras and unr genes was comparatively analyzed during the development of germline and somatic tissues. Northern blots on fetal and postnatal samples from somatic tissues, including brain, skeletal muscle, liver, kidney, small intestine and heart were studied together with ovaries and testis. While the expression of N-ras was rather stable all along the development of the different tissues analyzed, the expression of unr exhibited a specific pattern in some tissues. Specifically, in testis, there is a developmental regulation of the relative accumulation of the three alternative transcripts. Unr has a relative high expression in testes and heart but the accumulation seems to be different for the different size transcripts in each case. However, the expression in small intestine is practically absent in adults. From the comparative analysis of the expression of both genes, N-ras and unr, we propose that the regulation of N-ras is not directly coordinated with unr expression during the development. However, the expression of unr and its alternative transcripts is developmentally and differentially regulated in small intestine, heart and testis. The change in the pattern of accumulation during testis development from long to small alternative transcripts, could be interpreted in terms of possible alleviation of transcription interference of N-ras.
Aging↗
Analysis of testis-specific transcripts in the chicken.
Sequences of candidate chicken testis-specific genes were analysed in order to develop a resource for functional genomic studies of the testis and male germ cells. Tentative consensus sequences (TC) containing expressed sequence tags expressed in testis libraries were selected from the TIGR Gallus gallus Gene Index, resulting in 292 TC. The transcriptional expression of these genes were evaluated in several chicken tissues, including testis and ovary. One hundred ten of the 292 TC were expressed in a testis-specific manner. Annotation of the TC using the Gene Ontology database terms showed that the proportion of testis-specific TC that were classified as having catalytic activity (within the molecular function branch) was higher than the proportion of total chicken TC classified in the same way. Our results may facilitate the investigation of testis-specific genes and their functional analysis in the chicken, as well as in other avian species.
Animals↗
Conditions in utero and cancer risk.
There is increasing recognition that conditions in utero are of importance for later cancer risk in several organs, particularly the testis and breast. A review of the most recent literature on this topic is therefore warranted. The PubMed database was searched for relevant recent literature on intrauterine conditions associated with cancer risk later in life, with particular emphasis on the testis, breast, but also studies pertaining to other organs were included. Epidemiological and experimental data support the hypothesis that factors acting in utero play a role in the development of cancer in the testis and breast. For other organs, such as the prostate, urinary system and colorectum, the results are inconclusive. While conditions during foetal life are associated with later cancer risk in the testis and breast, the biological mechanisms are for the most part elusive. They are, however, likely to involve hormonal disturbances, number of cells at risk, and genetic or epigenetic events.
Adult↗
Immune privilege and inflammation of the testis.
Immune cells are found in considerable numbers within the normal, unaffected testes of mammals, including humans. Located in the interstitial compartment, they are implicated in the mechanisms that make the testis an immunologically privileged site where germ cells are protected from autoimmune attack and foreign tissue grafts may survive for extended periods of time. With regard to normal development and function of the testis, both pro- and antiinflammatory cytokines have been shown to play an important regulatory role. The testicular environment, however, does not preclude immune activation resulting in inflammatory reactions and potential damage. In experimental animals, active immunization with testicular tissue or adoptive transfer of specific T lymphocytes causes autoimmune orchitis. In men, infection and inflammation of the reproductive tract including the testes are widely accepted as important etiological factors of infertility. Whereas symptomatic orchitis due to bacterial or viral infections is considered to be rare, a high prevalence of asymptomatic testicular inflammatory reactions could be demonstrated among infertile males. Despite the patchy distribution of the lesions, inflammation is associated with disruption of testicular function, i.e. spermatogenesis. The pattern of lymphocyte infiltration and concomitant damage of seminiferous tubules supports the concept that activation of autoreactive T cells is involved.
Animals↗