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PubMed1988

The effect of mono-(2-ethylhexyl) phthalate and other phthalate esters on lactate production by Sertoli cells in vitro.

Sertoli cells produce lactate and pyruvate as energy substrates for the developing germ cells in the testis. Since the Sertoli cells are thought to be the initial target for phthalate esters causing testicular atrophy, the effect of some phthalates on lactate and pyruvate production by primary Sertoli cell-enriched cultures was studied. Mono-(2-ethylhexyl) phthalate (0.1-200 microM) produced a concentration-dependent stimulation of lactate, but not pyruvate production over a 24 h treatment period and an increase in the ratio of lactate/pyruvate concentration in the culture medium. Di-(2-ethylhexyl) phthalate and 2-ethylhexanol (200 microM) had no such effects. Other phthalate monoesters known to cause testicular atrophy also increased Sertoli cell lactate production and the lactate/pyruvate ratio, whereas monoesters not associated with testicular damage in vivo had no such effects. The results suggest that loss of germ cells in phthalate-induced testicular atrophy is not due to inhibition of energy substrate production by the Sertoli cells and that stimulation of lactate production may be a useful in vitro marker for phthalate esters and related compounds that cause testicular injury.

Animals↗
PubMed2006

Sex determination: time for meiosis? The gonad decides.

Germ cell sex determination is directed by the gonad and is characterized by a difference in the timing of entry into meiosis. Recent data show that retinoic acid signalling is responsible for the induction of germ cell meiosis in the developing ovary. In the fetal testis, this process is inhibited by a retinoic acid metabolizing enzyme.

Animals↗
PubMed2006

Distribution of the UV filter 3-benzylidene camphor in rat following topical application.

A straightforward analytical method for determination of 3-benzylidene camphor (3-BC) in rat adipose tissue, brain, liver, muscle, plasma and testis following topical application was developed and validated. Three exposure levels (60, 180 and 540 mg kg(-1) day(-1)) were tested for 65 days in male Sprague-Dawley rats (24 days postnatal). Sample preparation involving homogenization and n-heptane or methanol extraction of the tissue was applied before injection into the LC-ESI-MS-MS system. The response was linear from 2 to 100 microg l(-1) for the qualifier and the quantifier MRM transitions (R(2) (quantifier) > 0.994). Detection limit of the method corresponded to 0.005 microg g(-1) tissue and 12.5 microg l(-1) plasma, respectively. Recovery was determined for all tissues (adipose tissue: 40%; all other tissues: 80-100%) at three individual levels. 3-(4-Methyl benzylidene camphor) (4-MBC) was used throughout the study as internal standard. 3-Benzylidene camphor was detected in all tissues at all exposure levels at concentrations between 0.05 microg g(-1) (liver) and 36 microg g(-1) (adipose tissue) and in plasma at 16-89 microg l(-1). The method allowed for the quantification of 3-benzylidene camphor in all tested tissues following topical application. Furthermore, it was shown that 3-benzylidene camphor can be found in various tissues in the rat following topical application. These findings may suggest that following use of 3-benzylidene camphor containing sunscreen, similar disposition and distribution may occur in humans.

Administration, Topical↗
PubMed1995

Characteristics of mitotic cells in developing and adult testes with observations on cell lineages.

This report describes characteristics of dividing cells, primarily in developing (10-40 day) rat testis and relates the structure of the dividing cells to the structure of interphase cells. Mitotic cells were characterized in seven zones. Dividing Sertoli cells were seen prior to day 15 and possessed distinct characteristics as compared with dividing germ cells. Myoid cells showed morphological characteristics of precursor myoid cells; 'clear cells' self-replicated in the myoid cell layer; adult-type Leydig cells, some containing lipid, differentiated early (10th-15th postnatal days) from fibroblast-like cells of the multilayered tubule wall and later (15th-25th postnatal days) from dividing differentiated and semi-differentiated Leydig cells within the lymphatic space; fibroblastic cells arose from cells with similar morphological characteristics; semi-differentiated Leydig cells divided, and differentiated Leydig cells in the lymphatic space self-renewed; undifferentiated perivascular cells most likely gave rise to Leydig cells, pericytes; arteriolar smooth muscle cells and vascular endothelial cells arose from division of the pre-existing respective cell types. Fetal Leydig cells appeared to remain but, with time, they appeared to lose their lipid. The data suggest that (1) early recruitment of Leydig cells from undifferentiated peritubular fibroblast-like cells, (2) later mitosis of differentiated and semi-differentiated Leydig cells primarily in the interstitium but also in the perivascular region, and (3) the continued presence of pre-existing Leydig cells from the fetus constitute the adult population. Leydig cell division in the adult mouse was documented. This study provides the necessary information for the recognition of cell divisions to study of cell lineages among testis cells.

Animals↗
PubMed2002

XY female with a dysgerminoma and no mutation in the coding sequence of the SRY gene.

We report a 46,XY 11-year-old girl with pure gonadal dysgenesis who developed a dysgerminoma. The testis-determining gene SRY, a candidate for sex reversal, whose alterations seem to correlate with dysgerminoma, was analyzed and found to be normal; its coding sequence was negative for deletions and mutations. DMRT-1 gene mapping on 9p and DAX-1 on Xp21 were also normal. These results suggest the involvement of other genes in sex reversal and call into question the putative relationship between SRY alterations and dysgerminoma.

Child↗
PubMed1999

Sertoli cells decrease microglial response and increase engraftment of human hNT neurons in the hemiparkinsonian rat striatum.

Sertoli cells (SCs) provide immune protection and nutritive support to the developing germ cells in the testis. Sertoli cells have also been shown to provide immune protection to islets transplanted outside the testes. In this study, the ability of these cells to diminish the infiltration/activation of microglia into a neural graft implanted in the lesioned striatum of a hemiparkinsonian rat was investigated. Human neuron-like cells (hNT neurons) were implanted either alone or in combination with rat SCs. Three months later, the animals were sacrificed and immunohistochemistry was performed to determine the survival of the xenografted neurons as well as microglial infiltration/activation. Cotransplantation of the SCs with the hNT neurons increased graft survival and was associated with an increase in graft size. Furthermore, there were fewer microglia present in the grafted tissue of the cotransplantation groups. These results show that SCs retain their immunosuppressive ability even within the brain. As immune responses to grafted neural tissue within the central nervous system become better understood, this ability of the SCs to provide localized immunosuppression to the transplanted tissue may become more important. This is particularly true as the search for alternative sources of neural tissue to treat neurodegenerative diseases expands to encompass other species.

Animals↗
PubMed1997

Two independent nuclear localization signals are present in the DNA-binding high-mobility group domains of SRY and SOX9.

SRY and SOX9, members of the family of high-mobility group (HMG) domain transcription factors, are both essential for testis formation during human embryonic development. The HMG domain is a DNA-binding and DNA-bending motif comprising about 80 amino acid residues. It has been shown that SRY and SOX9 are nuclear proteins. Using normal or mutant SRY-beta-galactosidase and SOX9-beta-galactosidase fusion proteins in transfection studies involving COS-7 cells, we have identified two nuclear localization signals (NLSs) within the HMG domains of both proteins that can independently direct the fusion proteins into the nucleus. Only mutational inactivation of both NLS motifs resulted in complete exclusion of the fusion proteins from the nucleus. The NLS sequences are located at the N and C termini of the HMG domain and are a bipartite NLS motif and a basic cluster NLS motif, respectively. Both NLS motifs are conserved in the HMG domains of other transcription factors. The implications of the present results are discussed regarding (a) the apparent dual function of certain basic amino acid residues in the HMG domain of SRY in both DNA binding and in nuclear localization and (b) the possible control of SOX9 in early gonadal differentiation at the level of nuclear translocation.

Amino Acid Sequence↗
PubMed2004

The Id2 transcriptional repressor is induced by follicle-stimulating hormone and cAMP.

Id (inhibitor of DNA binding/differentiation) proteins repress differentiation and promote cell division by dimerizing with and inhibiting the action of basic helix-loop-helix transcription factors including those that bind to E-box motifs. Of the four characterized Id proteins, only Id2 is found in the nucleus of Sertoli cells that support the development of spermatozoa in the testis. Differential display analysis of rat primary Sertoli cell mRNA identified Id2 as being inducible by forskolin, a stimulator of cAMP production. Northern blot analysis confirmed that Id2 mRNA expression peaked in Sertoli cells 6-12 h after stimulation with forskolin or follicle-stimulating hormone (FSH), the major physiological stimulator of cAMP in Sertoli cells. Similarly, Id2 promoter activity in Sertoli cells was induced after forskolin or FSH stimulation as well as by overexpression of protein kinase A. Forskolin induction of the Id2 promoter required sequences located between positions -122 and -82. Protein(s) of 40-45 kDa were found to bind two activated transcription factor/cAMP-response element-like sites and a GATA motif within the regulatory region. The induction of the Id2 gene by FSH corresponded with a decrease in protein binding to an E-box consensus motif and decreased E-box-mediated transcription. Together, these findings raise the possibility that FSH-mediated induction of Id2 and resultant inhibition of basic helix-loop-helix transcription factor-regulated genes in Sertoli cells may contribute to the regulation of spermatogenesis.

Animals↗
PubMed2003

Malignant large cell calcifying Sertoli cell tumor of the testis.

A 45-year old man presented with a slow-growing, unilateral beige testicular mass, with a diameter of 4 cm. The testosterone, FSH, LH, estradiol and betahCG serum levels were within normal limits, and there were no associated hormonal syndromes. The patient was treated with inguinal orchidectomy. Microscopically, the tumor was composed of nests of cells with large eosinophilic, slightly granular cytoplasm. There was only a mild degree of atypia and no mitotic activity. The tumor extended into the rete testis. There were intratumoral calcifications, and in the vicinity of the tumor, there was intratubular growth. Although this case is histologically similar to the three previously reported cases of clinically benign large cell calcifying Sertoli cell tumor of the testis with rete testis involvement, the current patient developed right sided para-aortic lymph node metastases 18 months after the initial diagnosis.

Calcinosis↗
PubMed1998

Development of germ cell transplants in mice.

Development of spermatogonial transplants was studied by using 5- to 6-wk-old histocompatible mice as cell donors and sterile (W-locus) mice as recipients. Groups of animals transplanted with germ cell suspensions were killed at 10 min, 9 h, 24 h, 1 wk, 1 mo, 2 mo, and 3 mo along with age-matched "start" and "end" W-locus controls. Weight of testes increased significantly at 24 h through 3 mo after germ cell transplantation, suggesting that the infused cells quickly stimulated organ function. Small clones of young spermatocytes were evident at 1 mo and sperm at 2 mo. The percentage of tubular profiles containing active spermatogenesis originating from spermatogonia increased with time (0.8% at 1 mo, 8.9% at 2 mo, and 28.2% at 3 mo). Most transplanted germ cells were eliminated from the seminiferous epithelium through phagocytosis by Sertoli cells that occurred primarily before 1 wk, although some pachytene cells were able to proceed through meiosis by 1 wk. A variety of abnormal features are described that characterize developing spermatogenesis in the transplanted testis. Spermatogenesis improved quantitatively and qualitatively with time although released sperm were frequently engulfed by intratubular macrophages and Sertoli cells. A quantitative analysis of spermatogenesis from transplanted germ cells will serve as a basis for improving spermatogonial transplant efficiency.

Animals↗
PubMed1997

Two-stage Fowler-Stephens orchiopexy with laparoscopic clipping of the spermatic vessels.

PURPOSE: We report the outcome of a staged approach to the intra-abdominal testicle and provide baseline data on operative time, postoperative course and testicular survival. MATERIALS AND METHODS: We retrospectively reviewed the records of 441 boys (547 undescended testes). There were 105 boys (24%) with 124 nonpalpable testes (23%). All patients underwent laparoscopy. Ligation of spermatic vessels was performed as stage 1 on 20 abdominal testes (4%) in 18 boys (4%). Stage 2 orchiopexy was done using an open technique. RESULTS: Two-stage orchiopexy in 18 boys included a bilateral procedure in 2, of which 1 was asynchronous and 1 was synchronous. Average operative time was 55 minutes for stage 1 and 67 minutes for stage 2. Stage 1 and 2 procedures were performed on an outpatient basis in 18 and 17 (94%) boys, respectively. There were no complications after stage 1 and 1 wound infection developed after stage 2. One testis with no vas deferens was determined to be nonviable at stage 2. The remaining 19 testes (95%) were considered viable at a followup of 6 months or greater. Viability was based on testicular size and consistency similar to those of the contralateral testis. CONCLUSIONS: Laparoscopic ligation of spermatic vessels as a stage 1 procedure is a natural extension of laparoscopy. A staged approach provides adequate viability of the intra-abdominal testis.

Child↗
PubMedDate not supplied

Germinal epithelium changes in sexually immature rabbits treated with intratesticular testosterone implants.

The effect of testosterone (T) on germinal epithelium development and maturation was studied in prepubertal male rabbits. For this purpose, implants of free T (50 mg) or placebo (PL) were placed intratesticularly in 55-60-day-old animals. Each group was divided into sub-groups additionally treated with 0.9% NaCl, FSH/LH (3.0 IU) or cyproterone acetate (CA, 2.5 mg) over a 45-day period. Initial and final evaluations included measurements of testicular volume, testicular biopsy score count (TBSC) and plasma T, FSH and LH concentrations. At the end of the experiment, increment values (final-initial evaluation) of the parameters examined showed the following differences: (1) mean TBSC in T-implanted, irrespective of additional treatment, was higher than that of PL-implanted rabbits (P less than 0.01); (2) mean plasma T, FSH and LH values were significantly different in T- and PL-implanted rabbits, with higher T (P less than 0.05) but lower FSH and LH increments (P less than 0.01 for both) in the former group; (3) marked differences amongst types of additional treatment, irrespective of the implant used, were found for TBSC, T, FSH and LH (P less than 0.01 for all); animals treated with CA had markedly lower increments than other treatment groups. From these findings, it may be concluded, that in the prepubertal rabbit T plays an important role in development and maturation of the testis, but this effect probably requires the synergistic action of endogenous gonadotrophins.

Animals↗
PubMed1982

Partial inhibition of cell-mediated immunity (CMI) by niridazole: effect upon development of autoimmune aspermatogenic orchitis (AIAO) in guinea pigs.

The effects of Niridazole upon the development of autoimmune aspermatogenic orchitis (AIAO) was studied in guinea pigs. Niridazole administration before, during, or three days after alloimmunization with sperm cells emulsified in Freund's complete adjuvant (FCA) produced slight changes in some correlates of cell-mediated immunity. No significant changes in humoral immunity or testicular histopathology can be observed at these periods. When Niridazole was administered ten days after alloimmunization, a significant inhibition of all manifestations of cell-mediated immunity against spermatozoa was observed. Thirty days after alloimmunization, half of the animals studied failed to develop significant histopathological changes in testis or epididymis. However, the titer of cytotoxic antibodies to testicular cells increased from threefold to fourfold, when compared to those of alloimmunized animals not receiving Niridazole. The critical period for cell interactions concerned with the full expression of AIAO was found to be between ten and fifteen days after alloimmunization.

Animals↗
PubMed1987

Differential expression of the c-abl proto-oncogene and the homeo box-containing gene Hox 1.4 during mouse spermatogenesis.

Mammalian spermatogenesis is a complex developmental process. Spermatozoa, like ova, are uniquely capable of supporting embryonic development. Our approach to understanding this process is to identify genes whose developmental pattern of expression suggests that they may play a role in spermatogenesis. Experiments on the cellular oncogene c-abl and the homeo box-containing gene Hox-1.4 indicate that these genes may be important for male germ cell development. Both genes produce testis-specific transcripts that are present in particular cellular populations of the adult testis. Their developmental specificity, however, is different: c-abl is haploid-specific, whereas Hox-1.4 is expressed in the germ cells as soon as they have entered meiosis. Future studies will focus on examining the protein products of these genes and their function in testicular cells.

Amino Acid Sequence↗
PubMed1998

An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family.

It is now well established that the differentiation of the primitive gonad into the testis during early human embryonic development depends on the presence of the SRY gene. However, the existence of total or partial sex reversal in 46,XX males with genetic mutations not linked to the Y chromosome suggests that several autosomal genes acting in association with SRY may contribute to normal development of the male phenotype. We report a family in which four related 46,XX subjects with no evidence of Y chromosome DNA sequences underwent variable degrees of male sexual differentiation. One 46,XX male had apparently normal male external genitalia whereas his brother and two cousins had various degrees of sexual ambiguity and were found to be 46,XX true hermaphrodites. The presence of male sexual development in genetic females with transmission through normal male and female parents indicates that the critical genetic defect is most likely to be an autosomal dominant mutation, the different phenotypic effects arising from variable penetrance. Other autosomal loci have been implicated in male sexual development but the genetic mechanisms involved are unknown. In this family there may be an "activating" mutation which mimics the initiating role of the SRY gene in 46,XX subjects.

Adult↗
PubMed2002

Cloning and expression analysis of SALL4, the murine homologue of the gene mutated in Okihiro syndrome.

SALL4 is one out of four human homologues of the DROSOPHILA region-specific homeotic gene SPALT(SAL). Heterozygous mutations of SALL4 on chromosome 20q13.13--> q13.2 cause the autosomal dominant Okihiro syndrome which is characterized by radial limb defects, Duane anomaly and hearing loss. We have partially cloned the murine homologue of this gene, named SALL4, and completed the coding sequence by comparison to available EST and genomic sequences in the GenBank database. This comparison also revealed the chromosomal location of SALL4 on mouse chromosome 2H3 and suggested that a predicted testis expressed gene TEX20 at the very same locus is most likely not a gene on its own but part of the SALL4 3' UTR. We analyzed the expression of SALL4 during early embryogenesis by whole mount in situ hybridization and in the adult mouse by Northern blotting. In adult tissues, SALL4 expression is only found in testis and ovary. During embryonic development, SALL4 expression is widespread in early embryos and becomes gradually confined to the head region and the primitive streak. Prominent expression in the developing midbrain, branchial arches and the limbs suggests an important function of SALL4 during development of these structures as expected from the observation in Okihiro syndrome patients.

Age Factors↗
PubMed2005

Insulin-like factor 3: where are we now?

Insulin-like factor 3 (INSL3), previously known as the relaxin-like factor (RLF), is a major peptide hormone secreted from the testicular Leydig cells of adult men and circulating in the blood at a concentration of approximately 1 ng/mL. Women also produce INSL3 in the theca interna cells of ovarian follicles, but circulating levels remain below 100 pg/mL. INSL3 is structurally related to relaxin and insulin, but unlike the latter, signals through a novel G-protein-coupled receptor, LGR8. Ablation of the gene for INSL3 leads primarily to cryptorchidism because of a defect in the first, transabdominal phase of testicular descent. In the adult knockout mouse, a mild phenotype is evident in the testis and ovary. We have developed a panel of antibodies specific for INSL3 from various species, which are suitable for immunohistochemistry and, more recently, for immunoassays. INSL3 is an important marker for the mature Leydig cell phenotype, where it appears to be expressed constitutively, once the mature differentiation state is achieved. It is also an indicator of differentiation status not only for Leydig cells but also for the theca interna cells of the ovary.

Animals↗
PubMed1999

Function of stem cell factor as a survival factor of spermatogonia and localization of messenger ribonucleic acid in the rat seminiferous epithelium.

To address the possibility that stem cell factor (SCF) is a paracrine regulator of germ cell development in the adult rat testis, stage-specific distribution of SCF messenger RNA (mRNA) was investigated with Northern blot and in situ hybridization analyses. The highest levels of SCF mRNA were found in stages II-VI of the rat seminiferous epithelial cycle, whereas the lowest levels were in stages VII-VIII. Intermediate levels of SCF mRNA were detected in stages IX-XIV-I of the cycle. The expression of the SCF gene was found to be developmentally regulated, and the expression pattern followed the process of Sertoli cell proliferation and differentiation during postnatal life. The effect of mouse recombinant SCF on spermatogonial DNA synthesis was studied using an in vitro tissue culture system for stage-defined seminiferous tubules. A significant increase in DNA synthesis in spermatogonia could be detected when tubule segments from stage XII were cultured in the presence of 100 ng/ml SCF for 48 h (P < 0.05) and 72 h (P < 0.01). This observation was further confirmed with autoradiographic analyses; almost a 100-fold increase in thymidine incorporation in the SCF-treated (100 ng/ml) tubule segments was observed compared with that in untreated samples. The results of the present study suggest that SCF is a Sertoli cell-produced paracrine regulator and acts as a survival factor for spermatogonia in the adult rat seminiferous epithelium in a stage-specific manner.

Animals↗