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PubMed2001

Developing germ cells in mouse testis express pheromone receptors.

Pheromone receptors are expressed in the accessory olfactory system, which is vital for non-specific chemical communication and for sexual behavior. Under the hypothesis that some of the pheromone molecules released from female reproductive organs might regulate sperm chemotaxis or chemokinesis, we examined whether the V1R type pheromone receptor mRNAs are expressed in developing germ cells. By a reverse transcription-PCR method, we obtained nine kinds of cDNA fragments belonging to the receptor family. In situ hybridization analysis in testicular sections using probes of testicular pheromone receptors (TVRs) revealed that TVR mRNAs were expressed by spermatids. TVRs were also expressed in the accessory olfactory organ. In the testis, hybridization signals were localized in subsets of the seminiferous tubules, suggesting that TVRs were expressed by selective subsets of the spermatids. In situ hybridization study suggests also that each sperm expresses multiple pheromone receptors. The testicular pheromone receptors might have an important role in the maturation and/or migration of sperm.

Amino Acid Sequence↗
PubMed1993

Transcriptional control of MHC class I and beta 2-microglobulin genes in vivo.

The expression of class I and beta 2-microglobulin (beta 2-m) genes, which encode the H and L chains of the H-2 histocompatibility Ag, respectively, is complex both in the adult mouse and during development. Although they are ubiquitously expressed in the adult, the mRNA levels of these genes are variable from one organ to another, being high in liver, lung, and lymphoid organs and low in brain and testis. During development, both class I and beta 2-m mRNA are poorly expressed. To determine the molecular mechanism, either transcriptional or post-transcriptional, controlling class I and beta 2-m mRNA levels, we have compared their transcriptional activities by performing run-on experiments with nuclei extracted from several embryonic and adult organs. We show that most of the differences observed in H-2 and beta 2-m mRNA steady state levels are the reflection of their different transcriptional activities. These results demonstrate that MHC class I and beta 2-m gene expression in adult organs, as well as during development, is mainly controlled at the transcriptional level.

Animals↗
PubMed2003

Neuropeptides of the pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide/growth hormone-releasing hormone/secretin family in testis.

Mammalian testicular development and the maintenance of spermatogenesis are hormone-dependent processes that are controlled by the pituitary gonadotropins and testosterone. Recent studies have demonstrated the presence of many neuropeptides and their receptors in the testis, suggesting that these peptides operate as local regulators of testicular germ cell development and function. Among these testicular neuropeptides, the peptides that belong to the pituitary adenylate cyclase-activating polypeptide (PACAP) family, particularly growth hormone-releasing hormone and secretin, appear to show some unique common features in terms of intratesticular localization and the time of expression during the spermatogenic cycle. However, their precise physiologic roles and mechanisms of action remain unknown. This review analyzes the available information on the functional interactions among the testicular cells that appear to be mediated by locally produced neuropeptides, with a special emphasis on the peptides of the PACAP family.

Amino Acid Sequence↗
PubMed2000

Sexual development in marsupials: genetic characterization of bandicoot siblings with scrotal and testicular maldevelopment.

In marsupials testis determination requires the presence of a Y chromosome. The sex determining region on the Y gene (SRY) is necessary for testicular development in eutherians and it is assumed to play a similar role in marsupials. Relatively few studies have investigated the genetic basis of sexual development, and as yet there is no direct evidence that SRY is required for testis development in marsupials. Studies on intersexual marsupials have revealed a fundamental difference between marsupial and eutherian sex determination. The scrotum of marsupials is analogous, not homologous, to the eutherian scrotum and is under the control of X-linked genes not androgens. The current study describes two bandicoot (Isoodon macrourus) siblings. Both siblings had underdeveloped male reproductive tracts and testicular dysgenesis, one was ascrotal and the other had a diminutive scrotum. Their karyotypes were normal for this species which eliminates the Y chromosome from some somatic tissues. SRY was detected by Southern blotting. SRY, ubiquitin activating enzyme-1 on the Y (UBE1Y) and glucose 6-phosphate dehydrogenase (G6PD) gene expression were examined. UBE1Y was widely expressed in many tissues. SRY gene expression was much lower than normal in the abnormal siblings and may be responsible for their failure of testicular and epididymal development. The cause of their scrotal abnormalities is unknown. It is possible that the separate defects of scrotal and testis development in the two siblings, which had normal relatives, were due to a mutation in a gene common to both developmental pathways.

Animals↗
PubMed1998

Paracrine interaction in testicular somatic cells.

Initiation of spermatogenesis is regulated by signals derived from intratubular Sertoli cells as well as extratubular Leydig cells, both being systemic targets of hypophyseal gonadotropins. In addition to Leydig and Sertoli cells, a number of other cell types are present in the testis viz. peritubular cells, macrophages and vascular components. The specific paracrine functions of these cells are only partially understood. The peritubular and Sertoli cells form the structural scaffold of the germinal epithelium and are responsible for intratubular pressure, release and transport of spermatozoa and the formation of the blood-testis barrier. We have performed ex vivo and in vitro studies on the ultrastructure of peritubular and Sertoli cells and the distribution of steroid hormone receptors, cytoskeletal and extracellular matrix proteins using rat testes from different stages of postnatal development. Morphological observations were related to in vitro findings of gene expression on the respective hormones and structural proteins. In the developing rat testis, the peritubular cells showed a strong and consistent expression of fibronectin, entactin, laminin as well as the glucocorticoid, androgen, estrogen and partially also the progesterone receptor, while the Sertoli cells were devoid of glucocorticoid receptor and entactin. The glucocorticoid receptor was present in around 20% of the intratubular germ cells (in the 2nd postnatal week) and in 50% of the peritubular cells. In Leydig cells also, the expression reached its climax in the 3rd weak and declined thereafter. This is perhaps pointing to a differentiation-inhibiting role of glucocorticoids in gonocyte differentiation. In the 3rd developmental week, the androgen receptor was present in about 15% of all gonocytes and later in 50% of peritubular cells and about 40% of interstitial cells. The estrogen receptor was absent in peritubular cells of the adult testis. The progesterone receptor was present in about 30% of the peritubular and 25% of the Leydig cells. Taking into account the significant increase in seminiferous tubules following postnatal developmental day 18, the peritubular cells seem to exert an androgen dependent growth stimulus to the seminiferous cords perhaps via the Sertoli cells. In vitro studies of peritubular and Sertoli cells cultured either alone or in co-culture showed by RT-PCR the expression of the androgen and the glucocorticoid receptors in both cell types, as well as fibronectin. Secretion of fibronectin occurred in a clear-cut time-dependent increase in monocultures of peritubular cells (on day 3 of culture). In co-cultures of Sertoli and peritubular cells, fibronectin bio- synthesis was down-regulated. The paracrine interplay between extracellular matrix and hormonal signals joining peritubular and Sertoli cells is essential in the differentiation of the seminiferous tubules.

Animals↗
PubMed1986

Age-related effects of transection of the testicular blood vessels on subsequent testicular development in the pig.

Pigs of different ages were studied to assess the effect of age on the development of the testes after intra-abdominal transection of the testicular artery and vein. Transection of the testicular artery and vein at different stages of sexual development had a variable effect on the growth and differentiation of the testes. Transection performed at a young age (2 months) had no effect on the development of the testes (previous study). The animals used in this study were between 3 and 12 months (adult) at the time of surgical intervention. Their testes appeared to be more sensitive to disturbance of the main blood supply. The alternative vascular pedicle (vasal artery) was unable to adapt sufficiently to the increased physiological requirements of the testis during development in more than 50% of the animals. The results obtained from adult males indicate that intra-abdominal transection of the testicular vessels invariably has a deleterious effect on the testis.

Age Factors↗
PubMed2004

Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts late meiotic prophase and subsequent meiotic divisions of spermatogenesis.

Testicular orphan nuclear receptor 4 (TR4) is specifically and stage-dependently expressed in late-stage pachytene spermatocytes and round spermatids. In the developing mouse testis, the highest expression of TR4 can be detected at postnatal days 16 to 21 when the first wave of spermatogenesis progresses to late meiotic prophase. Using a knockout strategy to delete TR4 in mice, we found that sperm production in TR4(-/-) mice is reduced. The comparison of testes from developing TR4(+/+) and TR4(-/-) mice shows that spermatogenesis in TR4(-/-) mice is delayed. Analysis of the first wave of spermatogenesis shows that the delay can be due to delay and disruption of spermatogenesis at the end of late meiotic prophase and subsequent meiotic divisions. Seminiferous tubule staging shows that stages X to XII, where late meiotic prophase and meiotic divisions take place, are delayed and disrupted in TR4(-/-) mice. Histological examination of testis sections from TR4(-/-) mice shows degenerated primary spermatocytes and some necrotic tubules. Testis-specific gene analyses show that the expression of sperm 1 and cyclin A1, which are genes expressed at the end of meiotic prophase, was delayed and decreased in TR4(-/-) mouse testes. Taken together, results from TR4(+/+) and TR4(-/-) mice indicate that TR4 is essential for normal spermatogenesis in mice.

Animals↗
PubMed2003

Pre and postnatal exposure to endosulfan in Wistar rats.

The possible reproductive adverse effects of the pesticide endosulfan on male offspring rats exposed in utero and during lactation were investigated. Dams were treated orally with 0, 0.5 or 1.5 mg of endosulfan/kg 21 days prior to mating, during the mating, pregnancy and lactation. Maternal and reproductive outcome data and male sexual development landmarks (testis descent and preputial separation) were assessed. Reproductive endpoints of the male offspring were examined at adulthood: sex organ weights, daily sperm production, spermatid number, sperm transit, sperm morphology and testosterone level. No signs of maternal toxicity were detected at the dose levels tested. Sexual development landmarks were also unaffected. Moreover, with the exception of a significant increase in the relative epididymis weight seen in the group treated with the lowest dose, we have not found any statistically significant adverse effect in the reproductive endpoints investigated at adulthood. The results of the present study indicate that pre and postnatal exposure to low doses of endosulfan (0.5 and 1.5 mg/kg) do not induce significant adverse effects in the reproductive system of male offspring Wistar rats at adulthood.

Animals↗
PubMed1994

Ontogeny of the inhibitory guanine nucleotide-binding regulatory protein in the rat testis: mRNA expression and modulation of LH and FSH action.

The ontogeny of function and mRNA expression of the inhibitory guanine nucleotide-binding regulatory protein (Gi) was studied in the rat testis. Dispersed testis cells of animals aged 8, 15, 20 and 30 days were cultured with or without 100 micrograms/l pertussis toxin (PT) for 24 h. The cells were then cultured for another 24 h with medium only, cholera toxin (CT), PT, or their combination, and the amount of testosterone and cAMP production was measured. PT preincubation increased CT-stimulated cAMP production at all ages, thus indicating the presence of a functional Gi-protein in the postnatal testis. However, when testosterone production was measured, the enhancing effect of PT was absent at the age of 8 days only, indicating that Leydig cells at this age did not have functional Gi-protein. We then cultured 2-day-old and 8-11-day-old testis cells, after 24 h pretreatment with PT, in the presence of ovine follicle-stimulating hormone (FSH) (1 mg/l). The FSH-stimulated cAMP production was enhanced at both ages, thus indicating the presence of a functional Gi-protein in neonatal Sertoli cells. In Northern blot analyses, fetal and postnatal testis tissue had very similar levels of G alpha i2 and G alpha i3 mRNAs; the mRNA level of Gi1 in Northern blots remained low compared to those of Gi alpha 2 and Gi alpha 3. In conclusion, the Gi protein appears in the developing rat testis in utero but the activity first seems to be confined to non-Leydig cells including the Sertoli cell. In Leydig cells, the functional Gi-protein appears between days 8-15 post partum. This finding may be related to the fact that the fetal-neonatal population of Leydig cells possesses a high steroidogenic capacity and an apparent lack of the ability to respond to high gonadotropic stimulation with LH receptor down-regulation and steroidogenic enzyme desensitization.

Aging↗
PubMed1993

Production of estradiol by the fetal rat testis.

Testes from 17- to 20-d-old rat fetuses were cultured in vitro for various time intervals in Medium 199 alone or with added gonadotrophins. Estradiol released into the culture media was determined by radioimmunoassay. A basal estradiol secretion rate was inexistant or undetectable at all stages studied. In early stages (17 and 18 d) there was no difference in the stimulatory effect of FSH or LH at the same concentration. At 19 d, the prevalence of FSH became apparent. At 20 d, a significant action of FSH was noted after only 3 h culture time. 1-Methyl-1, 4-androstadiene-3,17-dione, an aromatase inhibitor, markedly depressed FSH-stimulated estradiol secretion. In the 20-d old testis, stimulation of estradiol production by FSH was more rapid and reached a higher level than by (Bu)2cAMP. It is suggested that the difference in the action of LH and FSH reflects the difference in the time of appearance of the corresponding receptors in the developing fetal testis.

Animals↗
PubMed2006

Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers.

The risk for the development of germ cell tumors is an important factor to deal with in the management of patients with disorders of sex development (DSD). However, this risk is often hard to predict. Recently, major progress has been made in identifying gene-products related to germ cell tumor development (testis-specific protein-Y encoded and octamer binding transcription factor 3/4) and in recognizing early changes of germ cells (maturation delay, preneoplastic lesions, and in situ neoplasia). The newly recognized "undifferentiated gonadal tissue" has been identified as a gonadal differentiation pattern bearing a high risk for the development of gonadoblastoma. It is expected that the combination of these findings will allow for estimation of the risk for tumor development in the individual patient (high risk/intermediate risk/low risk). This article reviews the recent literature regarding the prevalence of germ cell tumors in patients with DSD. Some major limitations regarding this topic, including a confusing terminology referring to the different forms of intersex disorders and unclear criteria for the diagnosis of malignant germ cells at an early age (maturation delay vs. early steps in malignant transformation) are discussed. Thereafter, an overview of the recent advances that have been made in our knowledge of germ cell tumor development and the correct diagnosis of early neoplastic lesions in this patient population is provided. A new classification system for patients with DSD is proposed as a tool to refine our insight in the prevalence of germ cell tumors in specific diagnostic groups.

Biomarkers↗
PubMed2003

The human fetal testis is a site of expression of neurotrophins and their receptors: regulation of the germ cell and peritubular cell population.

In the fetal testis, organization of the tissue into two compartments consisting of cords containing Sertoli and germ cells surrounded by peritubular cells and of other cells within the interstitium is essential for subsequent function. Neurotrophins (NTs) act as survival and differentiation factors in the nervous system and have been detected in the developing rodent testis. Expression of mRNA for nerve growth factor; NTs 3 and 4 and brain-derived neurotrophic factor; the high-affinity receptors TrkA, TrkB, and TrkC; and the low-affinity p75 receptor were detected in the human testis between 14 and 19 wk gestation. NT4 mRNA and protein were predominantly localized to the peritubular cells. These cells were also the site of expression of p75. By contrast, nerve growth factor and NT3 were mainly expressed in Sertoli and interstitial cells. Treatment of testis organ cultures with the Trk-specific kinase inhibitor K252a resulted in a marked decrease in both gonocyte and peritubular cell number and proliferation with little effect on Sertoli cells. These data demonstrate the expression of NTs and their receptors in the human fetal testis during the second trimester and indicate possible roles in the regulation of proliferation and survival of germ cells and peritubular cells.

Adult↗
PubMed2000

A dose-finding study of in utero and lactational exposure to diethylstilboestrol and flutamide in 129/Sv mice.

The purpose of the study was to test the experimental conditions and find the appropriate dose range for further investigations of the disruptive effects of oestrogens and antiandrogens on the development of testis. Groups of four 129/Sv mice were exposed from day 6 after mating until weaning to 1, 10 or 100 microg/kg/day of the non-steroidal oestrogen diethylstilboestrol and to 0.1, 1 or 10 mg/kg/day of the non-steroidal antiandrogen flutamide. The number of implantation sites, the litter size and reproductive parameters were examined and nipple development, anogenital distance and testicular morphology were investigated in the offspring. Dose-related post-implantation loss was seen in both diethylstilboestrol- and flutamide-treated dams and the mean litter size was smaller in the groups given the high dosages of diethylstilboestrol and flutamide. Disturbance of testicular development was seen in males exposed to diethylstilboestrol. Because of the small data material, no statistical analyses were performed. Our findings indicate that very high doses of both diethylstilboestrol and flutamide given at early stages of gestation result in a high post-implantation loss and should be avoided in further experiments using this strain which is known to have a poor reproductive performance. Exposure of the dams before mating may better reflect human exposure, but will presumably require even lower dose levels.

Androgen Antagonists↗
PubMed2026

Both L-Lactyl and D-Lactyl Enantiomers Modify Histones in Mouse Testis.

Dynamic histone posttranslational modifications are crucial to precisely orchestrate gene expression programs. The recently discovered histone lysine lactylation has already been explored in various pathological contexts, but less in normal tissues. This modification exists as two enantiomers, L- and D-lactylation; the former may more likely modify histones due to abundant L-lactate produced by glycolysis. Here, we report the identification by proteomics of L- and D-lactylation on lysines of histones H3 and H4 in mouse testis. We developed a targeted proteomic analysis of histone peptides using synthetic sequences modified by L- or D-lactyl, to acquire reliable identification and quantification data. Some histone peptides bearing either enantiomer are separated by reversed-phase chromatography. Interestingly, despite the fact that L-lactate is much more abundant than D-lactate in mouse testis, we estimated abundance ratios of L-over D-lactylation to lie between 0.4 and 1.6 on seven residues of histones H3 and H4. Next, targeted proteomic analyses were performed on histones extracted from meiotic and postmeiotic male germ cells (spermatocytes and round spermatids, respectively), which are known to use L-lactate as a main source of energy. Nonetheless, residues 18 and 23 of histone H3 (H3K18 and H3K23) were reliably quantified and shown to harbor balanced amounts of both enantiomers. The stoichiometry of lactylation is low over the whole sequence of H3 and H4, representing about 0.01 to 0.44%: this contrasts with acetylation which exists at up to 25 to 35% relative abundances on some N-terminal lysines. Yet, lactylation appears to be more abundant than acetylation on the C-terminal half of H3 and H4, where the latter modification is scarce. Collectively, our results suggest a mechanism producing a mixture of the two enantiomers of lactate, or of a more direct substrate for lactylation, that leads to the modification of histones by L- and D-lactylation.

Animals↗