Journal articles: 'Human fetal testis development'

1

Waters, Brenda, and Thomas Trainer. "Development of the Human Fetal Testis." Fetal and Pediatric Pathology 16, no. 1 (January 1, 1996): 9–23. http://dx.doi.org/10.3109/15513819609168658.

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Waters, Brenda L., and Thomas D. Trainer. "DEVELOPMENT OF THE HUMAN FETAL TESTIS." Pediatric Pathology & Laboratory Medicine 16, no. 1 (February 1, 1996): 9–23. http://dx.doi.org/10.1080/107710496175840.

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Waters, Brenda. "DEVELOPMENT OF THE HUMAN FETAL TESTIS." Fetal and Pediatric Pathology 16, no. 1 (February 1, 1996): 9–23. http://dx.doi.org/10.1080/713601130.

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O'Shaughnessy, Peter J., and Paul A. Fowler. "Development of the human fetal testis." Annales d'Endocrinologie 75, no. 2 (May 2014): 48–53. http://dx.doi.org/10.1016/j.ando.2014.03.009.

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Waters, Brenda L., and Thomas D. Trainer. "Development of the Human Fetal Testis." Pediatric Pathology & Laboratory Medicine 16, no. 1 (January 1996): 9–23. http://dx.doi.org/10.1080/15513819609168658.

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Huang, Xiaoyan, Jun Zhang, Li Lu, Lanlan Yin, Min Xu, Youqun Wang, Zuomin Zhou, and Jiahao Sha. "Cloning and expression of a novel CREB mRNA splice variant in human testis." Reproduction 128, no. 6 (December 2004): 775–82. http://dx.doi.org/10.1530/rep.1.00036.

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Identification of genes specifically expressed in adult and fetal testis is important in furthering our understanding of testis development and function. In this study, a novel human transcript, designated human testis cAMP-responsive element-binding protein (htCREB), was identified by hybridization of adult and fetal human testis cDNA probes with a human cDNA microarray containing 9216 clones. The htCREB transcript (GenBank Accession no. AY347527) was expressed at 2.35-fold higher levels in adult human testes than in fetal testes. Sequence and ntBLAST analyses against the human genome database indicated that htCREB was a novel splice variant of human CREB. RT-PCR-based tissue distribution experiments demonstrated that the htCREB transcript was highly expressed in adult human testis and in healthy sperm, but not in testes from patients with Sertoli cell-only syndrome. Taken together, these results suggest that the htCREB transcript is chiefly expressed in germ cells and is most likely involved in spermatogenesis.

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Mitchell, R. T., P. T. K. Saunders, A. J. Childs, C. Cassidy-Kojima, R. A. Anderson, W. H. B. Wallace, C. J. H. Kelnar, and R. M. Sharpe. "Xenografting of human fetal testis tissue: a new approach to study fetal testis development and germ cell differentiation." Human Reproduction 25, no. 10 (August 3, 2010): 2405–14. http://dx.doi.org/10.1093/humrep/deq183.

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Mitchell, Rod T., Philippa T. K. Saunders, Andrew J. Childs, Claire Cassidy-Kojima, Richard A. Anderson, W. Hamish B. Wallace, Chris J. H. Kelnar, and Richard M. Sharpe. "Xenografting of Human Fetal Testis Tissue: A New Approach to Study Fetal Testis Development and Germ Cell Differentiation." Obstetrical & Gynecological Survey 66, no. 1 (January 2011): 21–22. http://dx.doi.org/10.1097/ogx.0b013e3182168278.

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Niederberger, Craig. "Re: Xenografting of Human Fetal Testis Tissue: A New Approach to Study Fetal Testis Development and Germ Cell Differentiation." Journal of Urology 186, no. 1 (July 2011): 245. http://dx.doi.org/10.1016/s0022-5347(11)60337-6.

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Kilcoyne, Karen R., and Rod T. Mitchell. "Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data." Human Reproduction Update 25, no. 4 (March 14, 2019): 397–421. http://dx.doi.org/10.1093/humupd/dmz004.

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Abstract BACKGROUND Overall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance. OBJECTIVE AND RATIONALE The objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis. SEARCH METHODS For identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches. OUTCOMES A total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues. WIDER IMPLICATIONS Direct experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal–human differences in susceptibility.

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Lecluze, Estelle, Antoine D. Rolland, Panagiotis Filis, Bertrand Evrard, Sabrina Leverrier-Penna, Millissia Ben Maamar, Isabelle Coiffec, et al. "Dynamics of the transcriptional landscape during human fetal testis and ovary development." Human Reproduction 35, no. 5 (May 1, 2020): 1099–119. http://dx.doi.org/10.1093/humrep/deaa041.

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Abstract STUDY QUESTION Which transcriptional program triggers sex differentiation in bipotential gonads and downstream cellular events governing fetal testis and ovary development in humans? SUMMARY ANSWER The characterization of a dynamically regulated protein-coding and non-coding transcriptional landscape in developing human gonads of both sexes highlights a large number of potential key regulators that show an early sexually dimorphic expression pattern. WHAT IS KNOWN ALREADY Gonadal sex differentiation is orchestrated by a sexually dimorphic gene expression program in XX and XY developing fetal gonads. A comprehensive characterization of its non-coding counterpart offers promising perspectives for deciphering the molecular events underpinning gonad development and for a complete understanding of the etiology of disorders of sex development in humans. STUDY DESIGN, SIZE, DURATION To further investigate the protein-coding and non-coding transcriptional landscape during gonad differentiation, we used RNA-sequencing (RNA-seq) and characterized the RNA content of human fetal testis (N = 24) and ovaries (N = 24) from 6 to 17 postconceptional week (PCW), a key period in sex determination and gonad development. PARTICIPANTS/MATERIALS, SETTING, METHODS First trimester fetuses (6–12 PCW) and second trimester fetuses (13–14 and 17 PCW) were obtained from legally induced normally progressing terminations of pregnancy. Total RNA was extracted from whole human fetal gonads and sequenced as paired-end 2 × 50 base reads. Resulting sequences were mapped to the human genome, allowing for the assembly and quantification of corresponding transcripts. MAIN RESULTS AND THE ROLE OF CHANCE This RNA-seq analysis of human fetal testes and ovaries at seven key developmental stages led to the reconstruction of 22 080 transcripts differentially expressed during testicular and/or ovarian development. In addition to 8935 transcripts displaying sex-independent differential expression during gonad development, the comparison of testes and ovaries enabled the discrimination of 13 145 transcripts that show a sexually dimorphic expression profile. The latter include 1479 transcripts differentially expressed as early as 6 PCW, including 39 transcription factors, 40 long non-coding RNAs and 20 novel genes. Despite the use of stringent filtration criteria (expression cut-off of at least 1 fragment per kilobase of exon model per million reads mapped, fold change of at least 2 and false discovery rate adjusted P values of less than <1%), the possibility of assembly artifacts and of false-positive differentially expressed transcripts cannot be fully ruled out. LARGE-SCALE DATA Raw data files (fastq) and a searchable table (.xlss) containing information on genomic features and expression data for all refined transcripts have been submitted to the NCBI GEO under accession number GSE116278. LIMITATIONS, REASONS FOR CAUTION The intrinsic nature of this bulk analysis, i.e. the sequencing of transcripts from whole gonads, does not allow direct identification of the cellular origin(s) of the transcripts characterized. Potential cellular dilution effects (e.g. as a result of distinct proliferation rates in XX and XY gonads) may account for a few of the expression profiles identified as being sexually dimorphic. Finally, transcriptome alterations that would result from exposure to pre-abortive drugs cannot be completely excluded. Although we demonstrated the high quality of the sorted cell populations used for experimental validations using quantitative RT-PCR, it cannot be totally excluded that some germline expression may correspond to cell contamination by, for example, macrophages. WIDER IMPLICATIONS OF THE FINDINGS For the first time, this study has led to the identification of 1000 protein-coding and non-coding candidate genes showing an early, sexually dimorphic, expression pattern that have not previously been associated with sex differentiation. Collectively, these results increase our understanding of gonad development in humans, and contribute significantly to the identification of new candidate genes involved in fetal gonad differentiation. The results also provide a unique resource that may improve our understanding of the fetal origin of testicular and ovarian dysgenesis syndromes, including cryptorchidism and testicular cancers. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the French National Institute of Health and Medical Research (Inserm), the University of Rennes 1, the French School of Public Health (EHESP), the Swiss National Science Foundation [SNF n° CRS115_171007 to B.J.], the French National Research Agency [ANR n° 16-CE14-0017-02 and n° 18-CE14-0038-02 to F.C.], the Medical Research Council [MR/L010011/1 to P.A.F.] and the European Community’s Seventh Framework Programme (FP7/2007-2013) [under grant agreement no 212885 to P.A.F.] and from the European Union’s Horizon 2020 Research and Innovation Programme [under grant agreement no 825100 to P.A.F. and S.M.G.]. There are no competing interests related to this study.

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Harpelunde Poulsen, Katrine, and Anne Jørgensen. "Role of Nodal signalling in testis development and initiation of testicular cancer." Reproduction 158, no. 2 (August 2019): R67—R77. http://dx.doi.org/10.1530/rep-18-0641.

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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.

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Camacho-Moll, Maria E., Leendert H. J. Looijenga, Roland Donat, Chitranjan J. Shukla, Anne Jørgensen, and Rod T. Mitchell. "Expression of Intermediate Filaments in the Developing Testis and Testicular Germ Cell Cancer." Cancers 14, no. 22 (November 8, 2022): 5479. http://dx.doi.org/10.3390/cancers14225479.

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Cytokeratin and desmin expression have been associated with Sertoli cell maturity and the development of testicular germ cell cancer (TGCC). Thus, the present study aimed to characterize the expression of these intermediate filaments in normal testis development and TGCC. Cytokeratin and desmin were determined by immunohistochemistry and immunofluorescence in human fetal, and adult testis and tissue from patients with pre-invasive germ cell neoplasia in-situ (GCNIS) or invasive TGCC. Desmin was expressed in Sertoli cells of the human fetal testis, and the proportion of desmin expressing Sertoli cells was significantly reduced in the second trimester, compared with the first trimester (31.14% vs. 6.74%, p = 0.0016). Additionally, Desmin was expressed in the majority of Sertoli cells in the adult testis and TGCC samples. Cytokeratin was detected in Sertoli cells of human fetal testis but was not expressed in Sertoli cells of human adult testis. In patients with TGCC, cytokeratin was not expressed in Sertoli cells in tubules with active spermatogenesis but was detected in Sertoli cells in tubules containing GCNIS cells in patients with both pre-invasive and invasive TGCC. In conclusion, desmin was not associated with Sertoli cell maturation or progression to TGCC. However, cytokeratin appeared to be an indicator of impaired Sertoli cell maturation.

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Jannini, Emmanuele A., Anna Crescenzi, Nadia Rucci, Emiliano Screponi, Eleonora Carosa, Anna De Matteis, Enrico Macchia, Giulia d’Amati, and Massimino D’Armiento. "Ontogenetic Pattern of Thyroid Hormone Receptor Expression in the Human Testis." Journal of Clinical Endocrinology & Metabolism 85, no. 9 (September 1, 2000): 3453–57. http://dx.doi.org/10.1210/jcem.85.9.6803.

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Abstract We studied the spatiotemporal distribution of thyroid hormone nuclear receptors (TRs) α1 and α2 and β messenger RNA (mRNA) levels in normal human testicular tissue during development and in adulthood. Nonpathological specimens from five aborted fetuses (17 and 23 weeks of gestation, three and two cases, respectively) and from four patients undergoing orchiectomy (18 months old and 38-, 42-, and 52-yr-old, respectively) were analyzed by Northern blot, semiquantitative RT-PCR amplification using DNA sequences or specifically designed primers for the TR isoforms, and in situ hybridization. By using PCR amplification, we found that TRα1 and TRα2 are both expressed at different levels in fetal and adult testis. At all ages TRα2 is found at higher levels. Northern analysis showed hybridization signals corresponding to the expression of TRα2 and TRα1 in a ratio that increased from 2.6 at 17 weeks of gestation to 12.0 in adulthood. In fact, the expression of TRα1 dramatically decreased throughout development, being faintly detectable in the adult testis. Expression of TRβ was not detected at any age studied. This finding was further confirmed by PCR, which did not amplify TRβ either in fetal or in adult testis mRNAs. In situ hybridization studies showed the absence of TRβ and that TRα1 and TRα2 colocalized in Sertoli cells of prepubertal testis, whereas germ and interstitial cells appeared devoid of TR mRNA signals. From these results it can be concluded that the human testis exclusively expresses TRα, which is localized in Sertoli cells, TRβ being always undetectable. Fetal and prepubertal ages represent the period of maximal expression of TRα1 and TRα2. Theα 2/α1 ratio rises dramatically after development. These results confirm a critical window for the action of thyroid hormone in human testis, in the period of maximal expression of T3 binding isoform TRα1, and may account for the macroorchidism without virilization occurring when hyposecretion of thyroid hormones occurs before puberty.

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Drake, Amanda J., Sander van den Driesche, Hayley M. Scott, Gary R. Hutchison, Jonathan R. Seckl, and Richard M. Sharpe. "Glucocorticoids Amplify Dibutyl Phthalate-Induced Disruption of Testosterone Production and Male Reproductive Development." Endocrinology 150, no. 11 (October 9, 2009): 5055–64. http://dx.doi.org/10.1210/en.2009-0700.

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Common male reproductive abnormalities including cryptorchidism, hypospadias, and low sperm counts may comprise a testicular dysgenesis syndrome (TDS), resulting from fetal testis dysfunction during a critical developmental period involving reduced androgen production/action. The recent increase in TDS prevalence suggests environmental/lifestyle factors may be etiologically important. The developing fetus is exposed to multimodal challenges, and we hypothesized that exposure to a combination of factors rather than single agents may be important in the pathogenesis of TDS. We experimentally induced fetal testis dysfunction in rats via treatment of pregnant females daily from embryonic day (e) 13.5 to e21.5 with vehicle, 100 or 500 mg/kg · d dibutyl phthalate (DBP), 0.1 mg/kg · d dexamethasone (Dex), or a combination of DBP + Dex. In adulthood, penile length/normality, testis weight/descent, prostate weight, and plasma testosterone levels were measured plus anogenital distance (AGD) as a measure of androgen action within the masculinization programming window. Intratesticular testosterone and steroidogenic enzyme gene expression were measured in fetal testes at e17.5. High-dose DBP reduced fetal intratesticular testosterone and steroidogenic gene expression; induced mild hypospadias (31%) and cryptorchidism (53%); and reduced penile length, AGD, and testis and prostate weight in adulthood. Dex alone had no effect except to reduce birth weight but amplified the adverse effects of 500 mg/kg · d DBP and exacerbated the effects of 100 mg/kg · d DBP. All adverse effects were highly correlated to AGD, emphasizing the etiological importance of the masculinization programming window. These findings suggest that exposure to common environmental chemicals in combination with, for example, maternal stress, may increase the risk of common male reproductive abnormalities, with implications for human populations.

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Fowler, Paul A., Sarah Cassie, Stewart M. Rhind, Mark J. Brewer, J. Martin Collinson, Richard G. Lea, Paul J. Baker, Siladitya Bhattacharya, and Peter J. O’Shaughnessy. "Maternal Smoking during Pregnancy Specifically Reduces Human Fetal Desert Hedgehog Gene Expression during Testis Development." Journal of Clinical Endocrinology & Metabolism 93, no. 2 (February 1, 2008): 619–26. http://dx.doi.org/10.1210/jc.2007-1860.

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Abstract Context: Maternal cigarette smoking during gestation increases cryptorchidism and hypospadias and reduces testis size and fertility in sons by unknown mechanisms. Objective: The objective of the study was to determine whether maternal smoking is linked with changes in male human fetal endocrinology, testis gene expression, and liver concentrations of cigarette smoke chemicals. Design: This was an observational study of the male fetus, comparing pregnancies during which the mothers either did or did not smoke. Setting: The study was conducted at the universities of Aberdeen, Glasgow, and Nottingham and Macaulay Institute (Aberdeen). Patients/Participants: Testes, blood, and livers were collected from 69 morphologically normal human male fetuses of women undergoing elective termination of normal second-trimester pregnancies. Main Outcome Measures: Testosterone, human chorionic gonadotropin, LH, and cotinine; expression of 30 reproductive/developmental genes; liver concentrations of 16 polycyclic aromatic hydrocarbons; and Leydig, Sertoli. and germ cell numbers were determined. Results: There were no significant differences in fetal size, testis weight, cell numbers, seminiferous tubule diameter, or circulating LH and testosterone. Fetuses from smoking mothers had smoking range cotinine levels and liver concentrations of polycyclic aromatic hydrocarbons that were significant predictors of maternal smoking (P < 0.001). Only the Sertoli cell-specific gene, desert hedgehog (DHH), was significantly altered by maternal smoking (reduced 1.8-fold, P = 0.013). Conclusions: The consequences of reduced DHH signaling in men and mice are consistent with epidemiology for effects of gestational maternal smoking on sons. Given the absence of other observed effects of maternal smoking, we concluded that reduced DHH is part of a mechanism linking maternal gestational smoking with impaired reproductive development in male offspring.

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O’Shaughnessy, P. J., L. M. Fleming, G. Jackson, U. Hochgeschwender, P. Reed, and P. J. Baker. "Adrenocorticotropic Hormone Directly Stimulates Testosterone Production by the Fetal and Neonatal Mouse Testis." Endocrinology 144, no. 8 (August 1, 2003): 3279–84. http://dx.doi.org/10.1210/en.2003-0277.

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Abstract Adult Leydig cell steroidogenesis is dependent on LH but fetal Leydig cells can function independently of gonadotropin stimulation. To identify factors that may be involved in regulation of fetal Leydig cells expressed sequence tag libraries from fetal and adult testes were compared, and fetal-specific genes identified. The ACTH receptor [melanocortin type 2 receptor (Mc2r)] was identified within this fetal-specific group. Subsequent real-time PCR studies confirmed that Mc2r was expressed in the fetal testis at 100-fold higher levels than in the adult testis. Incubation of fetal or neonatal testes with ACTH in vitro stimulated testosterone production more than 10-fold, although ACTH had no effect on testes from animals aged 20 d or older. The steroidogenic response of fetal and neonatal testes to a maximally stimulating dose of human chorionic gonadotropin was similar to the response shown to ACTH. The ED50 for ACTH, measured in isolated fetal and neonatal testicular cells, was 5 × 10−10m and the lowest dose of ACTH eliciting a response was 2 × 10−11m. Circulating ACTH levels in fetal mice were around 8 × 10−11m. Neither α-MSH nor γ-MSH had any effect on androgen production in vitro at any age. Fetal testosterone levels were normal in mice that lack circulating ACTH (proopiomelanocortin-null) indicating that ACTH is not essential for fetal Leydig cell function. Results show that both LH and ACTH can regulate testicular steroidogenesis during fetal development in the mouse and suggest that fetal Leydig cells, but not adult Leydig cells, are sensitive to ACTH stimulation.

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Modi, D., C. Shah, G. Sachdeva, S. Gadkar, D. Bhartiya, and C. Puri. "Ontogeny and cellular localization of SRY transcripts in the human testes and its detection in spermatozoa." Reproduction 130, no. 5 (November 2005): 603–13. http://dx.doi.org/10.1530/rep.1.00413.

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The sex-determining region on the Y (SRY) gene is unequivocally designated as the testis-determining factor in mammals; however, its roles beyond sex determination, if any, have been hitherto unknown. To determine whether SRY has any roles beyond sex determination, herein the expression of SRY mRNA was investigated in the midtrimester human fetal, infantile and adult testes as well as in ejaculated spermatozoa. High levels of SRY transcripts werein situlocalized to the Sertoli cells of the developing testis at 9 weeks of gestation, and the expression persisted at comparable levels throughout the midtrimester (until 22 weeks) and also in the testis of an infant at 3 months of age. The germ cells and other somatic cells in the testes of fetuses and the infant were negative for SRY expression. The mRNA for SRY was detected in the spermatogenic cells, particularly the spermatogonia and the round spermatids; the expression was negligible in the meiotic stages. A single transcript of ~1.2 kb was detected in the adult testes and isolated spermatogonial cells. In the adult testis,in situhybridization (ISH) studies revealed a switch in the cellular localization of SRY transcripts. SRY transcripts were also demonstrable by RT-PCR of RNA from ejaculated human spermatozoa. ISH revealed the presence of SRY transcripts in the midpiece of 50% of ejaculated sperm. These results suggest that SRY may have extensive roles in male reproductive physiology, such as maturation of fetal testis, spermatogenesis, sperm maturation and early embryonic development.

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del Valle, Ignacio, Federica Buonocore, Andrew J. Duncan, Lin Lin, Martino Barenco, Rahul Parnaik, Sonia Shah, Mike Hubank, Dianne Gerrelli, and John C. Achermann. "A genomic atlas of human adrenal and gonad development." Wellcome Open Research 2 (April 7, 2017): 25. http://dx.doi.org/10.12688/wellcomeopenres.11253.1.

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Background: In humans, the adrenal glands and gonads undergo distinct biological events between 6-10 weeks post conception (wpc), such as testis determination, the onset of steroidogenesis and primordial germ cell development. However, relatively little is currently known about the genetic mechanisms underlying these processes. We therefore aimed to generate a detailed genomic atlas of adrenal and gonad development across these critical stages of human embryonic and fetal development. Methods: RNA was extracted from 53 tissue samples between 6-10 wpc (adrenal, testis, ovary and control). Affymetrix array analysis was performed and differential gene expression was analysed using Bioconductor. A mathematical model was constructed to investigate time-series changes across the dataset. Pathway analysis was performed using ClueGo and cellular localisation of novel factors confirmed using immunohistochemistry. Results: Using this approach, we have identified novel components of adrenal development (e.g. ASB4, NPR3) and confirmed the role of SRY as the main human testis-determining gene. By mathematical modelling time-series data we have found new genes up-regulated with SOX9 in the testis (e.g. CITED1), which may represent components of the testis development pathway. We have shown that testicular steroidogenesis has a distinct onset at around 8 wpc and identified potential novel components in adrenal and testicular steroidogenesis (e.g. MGARP, FOXO4, MAP3K15, GRAMD1B, RMND2), as well as testis biomarkers (e.g. SCUBE1). We have also shown that the developing human ovary expresses distinct subsets of genes (e.g. OR10G9, OR4D5), but enrichment for established biological pathways is limited. Conclusion: This genomic atlas is revealing important novel aspects of human development and new candidate genes for adrenal and reproductive disorders.

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del Valle, Ignacio, Federica Buonocore, Andrew J. Duncan, Lin Lin, Martino Barenco, Rahul Parnaik, Sonia Shah, Mike Hubank, Dianne Gerrelli, and John C. Achermann. "A genomic atlas of human adrenal and gonad development." Wellcome Open Research 2 (October 23, 2017): 25. http://dx.doi.org/10.12688/wellcomeopenres.11253.2.

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Background: In humans, the adrenal glands and gonads undergo distinct biological events between 6-10 weeks post conception (wpc), such as testis determination, the onset of steroidogenesis and primordial germ cell development. However, relatively little is currently known about the genetic mechanisms underlying these processes. We therefore aimed to generate a detailed genomic atlas of adrenal and gonad development across these critical stages of human embryonic and fetal development. Methods: RNA was extracted from 53 tissue samples between 6-10 wpc (adrenal, testis, ovary and control). Affymetrix array analysis was performed and differential gene expression was analysed using Bioconductor. A mathematical model was constructed to investigate time-series changes across the dataset. Pathway analysis was performed using ClueGo and cellular localisation of novel factors confirmed using immunohistochemistry. Results: Using this approach, we have identified novel components of adrenal development (e.g. ASB4, NPR3) and confirmed the role of SRY as the main human testis-determining gene. By mathematical modelling time-series data we have found new genes up-regulated with SOX9 in the testis (e.g. CITED1), which may represent components of the testis development pathway. We have shown that testicular steroidogenesis has a distinct onset at around 8 wpc and identified potential novel components in adrenal and testicular steroidogenesis (e.g. MGARP, FOXO4, MAP3K15, GRAMD1B, RMND2), as well as testis biomarkers (e.g. SCUBE1). We have also shown that the developing human ovary expresses distinct subsets of genes (e.g. OR10G9, OR4D5), but enrichment for established biological pathways is limited. Conclusion: This genomic atlas is revealing important novel aspects of human development and new candidate genes for adrenal and reproductive disorders.

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Lea, Richard G., Beatrice Mandon-Pépin, Benoit Loup, Elodie Poumerol, Luc Jouneau, Biola F. Egbowon, Adelle Bowden, et al. "Ovine fetal testis stage-specific sensitivity to environmental chemical mixtures." Reproduction 163, no. 2 (February 1, 2022): 119–31. http://dx.doi.org/10.1530/rep-21-0235.

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Exposure of the fetal testis to numerous individual environmental chemicals (ECs) is frequently associated with dysregulated development, leading to impaired adult reproductive competence. However, ‘real-life’ exposure involves complex mixtures of ECs. Here we test the consequences, for the male fetus, of exposing pregnant ewes to EC mixtures derived from pastures treated with biosolids fertiliser (processed human sewage). Fetal testes from continuously exposed ewes were either unaffected at day 80 or exhibited a reduced area of testis immunostained for CYP17A1 protein at day 140. Fetal testes from day 140 pregnant ewes that were exposed transiently for 80-day periods during early (0–80 days), mid (30–110 days), or late (60–140 days) pregnancy had fewer Sertoli cells and reduced testicular area stained for CYP17A1. Male fetuses from ewes exposed during late pregnancy also exhibited reduced fetal body, adrenal and testis mass, anogenital distance, and lowered testosterone; collectively indicative of an anti-androgenic effect. Exposure limited to early gestation induced more testis transcriptome changes than observed for continuously exposed day 140 fetuses. These data suggest that a short period of EC exposure does not allow sufficient time for the testis to adapt. Consequently, testicular transcriptomic changes induced during the first 80 days of gestation may equate with phenotypic effects observed at day 140. In contrast, relatively fewer changes in the testis transcriptome in fetuses exposed continuously to ECs throughout gestation are associated with less severe consequences. Unless corrected by or during puberty, these differential effects would predictably have adverse outcomes for adult testicular function and fertility.

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Moody, Sarah C., Shoichi Wakitani, Julia C. Young, Patrick S. Western, and Kate L. Loveland. "Evidence that activin A directly modulates early human male germline differentiation status." Reproduction 160, no. 1 (July 2020): 141–54. http://dx.doi.org/10.1530/rep-20-0095.

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Disrupted fetal germline development underpins testicular germ cell neoplasia, which is increasing worldwide. The complex signaling milieu during normal testis development includes TGFβ superfamily ligands; this study tests the hypothesis that, activin A, a TGFβ superfamily member, can influence gonocyte development. The human seminoma-derived cell line, TCam-2, a model of fetal gonocytes, was cultured with activin A (1.25–25 ng/mL) for 48 h, or with 5 ng/mL activin A for short- (6, 24, and 48 h) and long-term (13 days) exposures, and downstream targets measured by qRT-PCR. Transcripts that exhibited significant dose-dependent responses to activin A included the early germ cell markers KIT, NODAL, and CRIPTO (NODALl co-receptor and activin inhibitor) which all increased and the differentiation marker DNMT3L which decreased. After 48 h, KIT, NODAL, and CRIPTO levels were significantly higher, while the differentiation marker NANOS2 was significantly lower. Interestingly, activin A exposure also significantly reduced both transcript and protein levels of the PIWI/piRNA pathway component DNMT3L. Because TCam-2 cells produce the activin inhibitor CRIPTO, CRIPTO was reduced using siRNA prior to activin A exposure. This selectively increased KIT in response to activin A. Other ligands present in the fetal testis (BMP4, FGF9, TGFβ1, and TGFβ2) induced distinct effects on germline marker expression. This study showed that activin A can directly modulate germline markers in this human gonocyte-like cell, promoting a less-differentiated phenotype. Additional findings indicate evidence of signaling crosstalk between activin A and NODAL, leading to target-specific effects on gonocyte differentiation.

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Lambrot, Romain, Hervé Coffigny, Catherine Pairault, Anne-Claire Donnadieu, René Frydman, René Habert, and Virginie Rouiller-Fabre. "Use of Organ Culture to Study the Human Fetal Testis Development: Effect of Retinoic Acid." Journal of Clinical Endocrinology & Metabolism 91, no. 7 (July 2006): 2696–703. http://dx.doi.org/10.1210/jc.2005-2113.

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Kerr, Candace L., Christine M. Hill, Paul D. Blumenthal, and John D. Gearhart. "Expression of Pluripotent Stem Cell Markers in the Human Fetal Testis." Stem Cells 26, no. 2 (February 2008): 412–21. http://dx.doi.org/10.1634/stemcells.2007-0605.

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Ludbrook, Louisa M., Pascal Bernard, Stefan Bagheri-Fam, Janelle Ryan, Ryohei Sekido, Dagmar Wilhelm, Robin Lovell-Badge, and Vincent R. Harley. "Excess DAX1 Leads to XY Ovotesticular Disorder of Sex Development (DSD) in Mice by Inhibiting Steroidogenic Factor-1 (SF1) Activation of the Testis Enhancer of SRY-box-9 (Sox9)." Endocrinology 153, no. 4 (January 31, 2012): 1948–58. http://dx.doi.org/10.1210/en.2011-1428.

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Human DAX1 duplications cause dosage-sensitive sex reversal (DSS) whereby chromosomally XY individuals can develop as females due to gonadal dysgenesis. However, the mechanism of DSS-adrenal hypoplasia congenita on X, gene 1 (DAX1) action in the fetal testis is unknown. We show that in fetal testes from XY Dax1-overexpressing transgenic mice, the expression of the key testis-promoting gene sex-determining region on Y (SRY)-box-9 (Sox9) is reduced. Moreover, in XY Sox9 heterozygotes, in which testis development is usually normal, Dax1 overexpression results in ovotestes, suggesting a DAX1-SOX9 antagonism. The ovarian portion of the XY ovotestes was characterized by expression of the granulosa cell marker, Forkhead box-L2, with complete loss of the Sertoli cell markers, SOX9 and anti-Müllerian hormone, and the Leydig cell marker CYP17A1. However, the expression of SRY and steroidogenic factor-1 (SF1), two key transcriptional regulators of Sox9, was retained in the ovarian portion of the XY ovotestes. Using reporter mice, Dax1 overexpression reduced activation of TES, the testis enhancer of Sox9, indicating that DAX1 might repress Sox9 expression via TES. In cultured cells, increasing levels of DAX1 antagonized SF1-, SF1/SRY-, and SF1/SOX9-mediated activation of TES, due to reduced binding of SF1 to TES, providing a likely mechanism for DSS.

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Hutson, John M., Marilyn L. Baker, Amanda L. Griffiths, Yoshitaka Momose, Day Way Goh, William Middlesworth, Zhou Bai Yun, and Elizabeth Cartwright. "Endocrine and morphological perspectives in testicular descent." Reproductive Medicine Review 1, no. 2 (July 1992): 165–77. http://dx.doi.org/10.1017/s096227990000051x.

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Before sexual differentiation occurs at seven weeks, the urological ridges develop in the embryo. These contain the primitive gonads, the mesonephros (embryonic kidneys) and the paired Wolffian (mesonephric) ducts, along with the Müllerian (paramesonephric) ducts. The fundamental mechanism of fetal sexual development was elucidated by Alfred Jost and is determined by the development of the gonad: where testes form in response to the testis-determining gene, and the male testicular hormones cause development of the male phenotype. If ovaries develop or the gonads are absent, female secondary sex characteristics are produced. Recently, the cloning of the putative human testis-determining gene on the Y-chromosome was reported. Assuming this is the true controller of testicular development, an understanding of the initiation of sexual differentiation at the genetic level should emerge in the near future. Of great importance will be the isolation of the testis-determining gene product and identification of other genes that it regulates.

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Hutka, Marsida, Lee B. Smith, Ellen Goossens, W. Hamish B. Wallace, Jan-Bernd Stukenborg, and Rod T. Mitchell. "Exogenous Gonadotrophin Stimulation Induces Partial Maturation of Human Sertoli Cells in a Testicular Xenotransplantation Model for Fertility Preservation." Journal of Clinical Medicine 9, no. 1 (January 18, 2020): 266. http://dx.doi.org/10.3390/jcm9010266.

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The future fertility of prepubertal boys with cancer may be irreversibly compromised by chemotherapy and/or radiotherapy. Successful spermatogenesis has not been achieved following the xenotransplantation of prepubertal human testis tissue, which is likely due to the failure of somatic cell maturation and function. We used a validated xenograft model to identify the factors required for Leydig and Sertoli cell development and function in immature human testis. Importantly, we compared the maturation status of Sertoli cells in xenografts with that of human testis tissues (n = 9, 1 year-adult). Human fetal testis (n = 6; 14–21 gestational weeks) tissue, which models many aspects of prepubertal testicular development, was transplanted subcutaneously into castrated immunocompromised mice for ~12 months. The mice received exogenous human chorionic gonadotropin (hCG; 20IU, 3×/week). In xenografts exposed continuously to hCG, we demonstrate the maintenance of Leydig cell steroidogenesis, the acquisition of features of Sertoli cell maturation (androgen receptor, lumen development), and the formation of the blood–testis barrier (connexin 43), none of which were present prior to the transplantation or in xenografts in which hCG was withdrawn after 7 months. These studies provide evidence that hCG plays a role in Sertoli cell maturation, which is relevant for future investigations, helping them generate functional gametes from immature testis tissue for clinical application.

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Bird, Anthony D., Brittany M. Croft, Masayo Harada, Lingyun Tang, Liang Zhao, Zhenhua Ming, Stefan Bagheri-Fam, et al. "Ovotesticular disorders of sex development in FGF9 mouse models of human synostosis syndromes." Human Molecular Genetics 29, no. 13 (May 26, 2020): 2148–61. http://dx.doi.org/10.1093/hmg/ddaa100.

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Abstract In mice, male sex determination depends on FGF9 signalling via FGFR2c in the bipotential gonads to maintain the expression of the key testis gene SOX9. In humans, however, while FGFR2 mutations have been linked to 46,XY disorders of sex development (DSD), the role of FGF9 is unresolved. The only reported pathogenic mutations in human FGF9, FGF9S99N and FGF9R62G, are dominant and result in craniosynostosis (fusion of cranial sutures) or multiple synostoses (fusion of limb joints). Whether these synostosis-causing FGF9 mutations impact upon gonadal development and DSD etiology has not been explored. We therefore examined embryonic gonads in the well-characterized Fgf9 missense mouse mutants, Fgf9S99N and Fgf9N143T, which phenocopy the skeletal defects of FGF9S99N and FGF9R62G variants, respectively. XY Fgf9S99N/S99N and XY Fgf9N143T/N143T fetal mouse gonads showed severely disorganized testis cords and partial XY sex reversal at 12.5 days post coitum (dpc), suggesting loss of FGF9 function. By 15.5 dpc, testis development in both mutants had partly recovered. Mitotic analysis in vivo and in vitro suggested that the testicular phenotypes in these mutants arise in part through reduced proliferation of the gonadal supporting cells. These data raise the possibility that human FGF9 mutations causative for dominant skeletal conditions can also lead to loss of FGF9 function in the developing testis, at least in mice. Our data suggest that, in humans, testis development is largely tolerant of deleterious FGF9 mutations which lead to skeletal defects, thus offering an explanation as to why XY DSDs are rare in patients with pathogenic FGF9 variants.

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Samson, Michel, Franklin V. Peale, Gretchen Frantz, Nathalie Rioux-Leclercq, Ewa Rajpert-De Meyts, and Napoleone Ferrara. "Human Endocrine Gland-Derived Vascular Endothelial Growth Factor: Expression Early in Development and in Leydig Cell Tumors Suggests Roles in Normal and Pathological Testis Angiogenesis." Journal of Clinical Endocrinology & Metabolism 89, no. 8 (August 1, 2004): 4078–88. http://dx.doi.org/10.1210/jc.2003-032024.

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Angiogenesis is essential for tumor growth and metastasis. A new human angiogenic mitogen, endocrine gland-derived vascular endothelial growth factor (EG-VEGF), has been recently identified; its expression pattern is restricted to endocrine glands, with the highest expression in testis. We used in situ hybridization and newly generated monoclonal antibodies to investigate the expression of EG-VEGF in normal human prenatal and adult testis and in 48 human testicular tumors of different subtypes. We found that EG-VEGF was expressed from 14 wk until birth in human fetal testis. In the adult testis, EG-VEGF was strongly expressed only in Leydig cells. In testicular tumors, EG-VEGF was expressed specifically in Leydig cell tumors, whereas germ cell-derived neoplasms, including carcinoma in situ, seminoma, and nonseminomatous germ cell tumors, were negative for this antigen. In contrast, VEGF, another powerful angiogenic factor, was expressed in seminoma, but very weakly in Leydig cell tumors. Interestingly, we found that Leydig cell tumors presented vessel surface density 3.2-fold higher than seminoma. These findings argue that human EG-VEGF may play a role in angiogenesis both during the early endocrine development of testis and in the adult testis as well as in Leydig cell tumor growth.

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Jørgensen, Anne, Joni Macdonald, John E. Nielsen, Karen R. Kilcoyne, Signe Perlman, Lene Lundvall, Lea Langhoff Thuesen, et al. "Nodal Signaling Regulates Germ Cell Development and Establishment of Seminiferous Cords in the Human Fetal Testis." Cell Reports 25, no. 7 (November 2018): 1924–37. http://dx.doi.org/10.1016/j.celrep.2018.10.064.

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Klinefelter, Gary R., John W. Laskey, Witold M. Winnik, Juan D. Suarez, Naomi L. Roberts, Lillian F. Strader, Brandy W. Riffle, and D. N. Rao Veeramachaneni. "Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol." REPRODUCTION 144, no. 6 (December 2012): 747–61. http://dx.doi.org/10.1530/rep-12-0266.

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Significant research has been focused on phthalate-induced alterations in male reproductive development. Studies on rodents have prompted the notion that a syndrome exists in the human male which includes phenotypic alterations such as hypospadias, cryptorchidism, poor semen quality, and even testicular cancer. Each phenotype in this ‘testicular dysgenesis syndrome’ is predicated on reduction in testosterone production by the fetal Leydig cell. We sought to examine the relationship between dysgenesis and steroidogenic capacity in the fetal rat testis more stringently by incorporating lower exposures than those typically used, conducting a comprehensive, non-targeted quantitative evaluation of the fetal testis proteome, and relating alterations in individual proteins to the capacity of the fetal Leydig cell to produce testosterone, and histopathology of the fetal testis. Pregnant dams were dosed orally from gestation day (GD) 13–19 with 0, 10, or 100 mg diethylhexyl phthalate (DEHP)/kg body weight per day. Each endpoint was represented by 16 l. Clustering of Leydig cells occurred before any significant decrease in the capacity of the GD19 Leydig cell to produce testosterone. At 100 mg DEHP/kg, testosterone production was reduced significantly, Leydig cell clusters became quite large, and additional dysgenetic changes were observed in the fetal testis. Of 23 proteins whose expression was altered significantly at both DEHP exposure levels, seven were found to be correlated with and predictive of the quantified endpoints. None of these proteins have been previously implicated with DEHP exposure. Notably, pathway analysis revealed that these seven proteins fit a pathway network in which each is regulated directly or indirectly by estradiol.

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Archambeault, Denise R., Jessica Tomaszewski, Andrew J. Childs, Richard A. Anderson, and Humphrey Hung-Chang Yao. "Testicular Somatic Cells, not Gonocytes, Are the Major Source of Functional Activin A during Testis Morphogenesis." Endocrinology 152, no. 11 (September 27, 2011): 4358–67. http://dx.doi.org/10.1210/en.2011-1288.

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Proper development of the seminiferous tubules (or testis cords in embryos) is critical for male fertility. Sertoli cells, somatic components of the seminiferous tubules, serve as nurse cells to the male germline, and thus their numbers decide the quantity of sperm output in adulthood. We previously identified activin A, the protein product of the activin βA (Inhba) gene, as a key regulator of murine Sertoli cell proliferation and testis cord expansion during embryogenesis. Although our genetic studies implicated fetal Leydig cells as the primary producers of testicular activin A, gonocytes are another potential source. To investigate the relative contribution of gonocyte-derived activin A to testis morphogenesis, we compared testis development in the Inhba global knockout mouse, which lacks activin A production in all cells (including the gonocytes), and a steroidogenic factor 1 (Sf1)-specific conditional knockout model in which activin A expression in testicular somatic cells is disrupted but gonocyte expression of activin A remains intact. Surprisingly, testis development was comparable in these two models of activin A insufficiency, with similar reductions in Sertoli cell proliferation and minor differences in testis histology. Thus, our findings suggest activin A from male gonocytes is insufficient to promote Sertoli cell proliferation and testis cord expansion in the absence of somatic cell-derived activin A. Evaluation of adult male mice with fetal disruption of activin A revealed reduced testis size, lowered sperm production, altered testicular histology, and elevated plasma FSH levels, defects reminiscent of human cases of androgen-sufficient idiopathic oligozoospermia.

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Cowan, Gillian, Andrew J. Childs, Richard A. Anderson, and Philippa T. K. Saunders. "Establishment of long-term monolayer cultures of somatic cells from human fetal testes and expansion of peritubular myoid cells in the presence of androgen." REPRODUCTION 139, no. 4 (April 2010): 749–57. http://dx.doi.org/10.1530/rep-09-0532.

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The somatic (Sertoli cell (SC), Leydig cell (LC), and peritubular myoid (PTM) cell) cells play key roles in development of the fetal testis. We established monolayer cultures from second trimester human testes and investigated the pattern of expression of cell-lineage characteristic mRNAs. Expression of some SC-associated genes (SRY, SOX9, WT1, GATA4, and SF1) was detectable up to and including passage 3 (P3), while others (anti-Müllerian hormone; desert hedgehog) present prior to dissociation were not expressed in the cultured cells. Transcripts encoding the androgen receptor were expressed but addition of dihydrotestosterone (DHT) had no impact on expression of mRNAs expressed in SC or LC. Total concentrations of mRNAs encoding smooth muscle actin (ACTA2) and desmin increased from P1 to P3; an increasing proportion of the cells in the cultures were immunopositive for ACTA2 consistent with proliferation/differentiation of PTM cells. In conclusion, somatic cell monolayer cultures were established from human fetal testes; these cultures could form the basis for future studies based on isolation of purified populations of somatic cells and manipulation of gene expression that is difficult to achieve with organ culture systems. Our results suggest that fetal SC do not maintain a fully differentiated phenotype in vitro, yet PTM (ACTA2 positive) cells readily adapt to monolayer culture conditions in the presence of DHT. This culture system provides an opportunity to study the impact of regulatory factors on gene expression in PTM cells, a population thought to play a key role in mediating androgen action within the developing testis.

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van den Driesche, Sander, Chris McKinnell, Ana Calarrão, Laura Kennedy, Gary R. Hutchison, Lenka Hrabalkova, Matthew S. Jobling, et al. "Comparative Effects of Di( n -Butyl) Phthalate Exposure on Fetal Germ Cell Development in the Rat and in Human Fetal Testis Xenografts." Environmental Health Perspectives 123, no. 3 (March 2015): 223–30. http://dx.doi.org/10.1289/ehp.1408248.

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Jørgensen, A., J. E. Nielsen, S. Perlman, L. Lundvall, R. T. Mitchell, A. Juul, and E. Rajpert-De Meyts. "Ex vivoculture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development." Human Reproduction 30, no. 10 (August 6, 2015): 2351–63. http://dx.doi.org/10.1093/humrep/dev194.

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Lambrot, Romain, Vincent Muczynski, Charlotte Lécureuil, Gaëlle Angenard, Hervé Coffigny, Catherine Pairault, Delphine Moison, René Frydman, René Habert, and Virginie Rouiller-Fabre. "Phthalates Impair Germ Cell Development in the Human Fetal Testis in Vitro without Change in Testosterone Production." Environmental Health Perspectives 117, no. 1 (January 2009): 32–37. http://dx.doi.org/10.1289/ehp.11146.

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Harpelunde Poulsen, K., J. E. Nielsen, H. Frederiksen, C. Melau, K. Juul Hare, L. Langhoff Thuesen, S. Perlman, et al. "Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes." Human Reproduction 34, no. 11 (November 1, 2019): 2228–43. http://dx.doi.org/10.1093/humrep/dez191.

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Abstract STUDY QUESTION Does experimental manipulation of fibroblast growth factor 9 (FGF9)-signalling in human fetal gonads alter sex-specific gonadal differentiation? SUMMARY ANSWER Inhibition of FGFR signalling following SU5402 treatment impaired germ cell survival in both sexes and severely altered the developing somatic niche in testes, while stimulation of FGF9 signalling promoted Sertoli cell proliferation in testes and inhibited meiotic entry of germ cells in ovaries. WHAT IS KNOWN ALREADY Sex-specific differentiation of bipotential gonads involves a complex signalling cascade that includes a combination of factors promoting either testicular or ovarian differentiation and inhibition of the opposing pathway. In mice, FGF9/FGFR2 signalling has been shown to promote testicular differentiation and antagonize the female developmental pathway through inhibition of WNT4. STUDY DESIGN, SIZE, DURATION FGF signalling was manipulated in human fetal gonads in an established ex vivo culture model by treatments with recombinant FGF9 (25 ng/ml) and the tyrosine kinase inhibitor SU5402 (10 μM) that was used to inhibit FGFR signalling. Human fetal testis and ovary tissues were cultured for 14 days and effects on gonadal development and expression of cell lineage markers were determined. PARTICIPANTS/MATERIALS, SETTING, METHODS Gonadal tissues from 44 male and 33 female embryos/fetuses from first trimester were used for ex vivo culture experiments. Tissues were analyzed by evaluation of histology and immunohistochemical analysis of markers for germ cells, somatic cells, proliferation and apoptosis. Culture media were collected throughout the experimental period and production of steroid hormone metabolites was analyzed in media from fetal testis cultures by liquid chromatography–tandem mass spectrometry (LC-MS/MS). MAIN RESULTS AND THE ROLE OF CHANCE Treatment with SU5402 resulted in near complete loss of gonocytes (224 vs. 14 OCT4+ cells per mm2, P < 0.05) and oogonia (1456 vs. 28 OCT4+ cells per mm2, P < 0.001) in human fetal testes and ovaries, respectively. This was a result of both increased apoptosis and reduced proliferation in the germ cells. Addition of exogenous FGF9 to the culture media resulted in a reduced number of germ cells entering meiosis in fetal ovaries (102 vs. 60 γH2AX+ germ cells per mm2, P < 0.05), while in fetal testes FGF9 stimulation resulted in an increased number of Sertoli cells (2503 vs. 3872 SOX9+ cells per mm2, P < 0.05). In fetal testes, inhibition of FGFR signalling by SU5402 treatment altered seminiferous cord morphology and reduced the AMH expression as well as the number of SOX9-positive Sertoli cells (2503 vs. 1561 SOX9+ cells per mm2, P < 0.05). In interstitial cells, reduced expression of COUP-TFII and increased expression of CYP11A1 and CYP17A1 in fetal Leydig cells was observed, although there were no subsequent changes in steroidogenesis. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Ex vivo culture may not replicate all aspects of fetal gonadal development and function in vivo. Although the effects of FGF9 were studied in ex vivo culture experiments, there is no direct evidence that FGF9 acts in vivo during human fetal gonadogenesis. The FGFR inhibitor (SU5402) used in this study is not specific to FGFR2 but inhibits all FGF receptors and off-target effects on unrelated tyrosine kinases should be considered. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study suggest that dysregulation of FGFR-mediated signalling may affect both testicular and ovarian development, in particular impacting the fetal germ cell populations in both sexes. STUDY FUNDING/COMPETING INTEREST(S) This work was supported in part by an ESPE Research Fellowship, sponsored by Novo Nordisk A/S to A.JØ. Additional funding was obtained from the Erichsen Family Fund (A.JØ.), the Aase and Ejnar Danielsens Fund (A.JØ.), the Danish Government’s support for the EDMaRC programme (A.JU.) and a Wellcome Trust Intermediate Clinical Fellowship (R.T.M., Grant no. 098522). The Medical Research Council (MRC) Centre for Reproductive Health (R.T.M.) is supported by an MRC Centre Grant (MR/N022556/1). The authors have no conflict of interest to disclose.

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Sweeney, T., P. T. K. Saunders, M. R. Millar, and A. N. Brooks. "Ontogeny of anti-Mullerian hormone, 3β-hydroxysteroid dehydrogenase and androgen receptor expression during ovine fetal gonadal development." Journal of Endocrinology 153, no. 1 (April 1997): 27–32. http://dx.doi.org/10.1677/joe.0.1530027.

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Abstract Anti-Mullerian hormone (AMH) and androgenic steroids are key factors regulating the masculinisation of the internal and external genitalia during fetal development. AMH is produced in Sertoli cells and causes regression of the Mullerian ducts in the male. 3β-Hydroxysteroid dehydrogenase (3β-HSD) is one of the key steroidogenic enzymes regulating testosterone production in Leydig cells. The objective of this experiment was to elucidate the development of the ovine fetal testes by identifying the spatio-temporal expression of AMH, 3β-HSD and androgen receptor expression within them. Fetuses from days 30 and 40 of gestation were fixed intact, while the gonads were dissected from the fetuses on days 70, 100 and 130 of gestation. Tissue was fixed in Bouin's fixative for 6 h, processed into paraffin wax and sections immunostained using rabbit anti-human AMH, 3β-HSD or androgen receptor antibodies. While seminiferous cords were absent on day 30 of gestation, pre-cord organisation was apparent and the gonad could be clearly distinguished from surrounding tissue by the presence of AMH and 3β-HSD immunopositive cells. Androgen receptor expression was not apparent at this stage. By day 40 of gestation the testis was organised into distinct seminiferous cords and intense immunostaining for AMH and 3β-HSD was present in Sertoli cells within the cords and Leydig cells in the interstitium respectively. Androgen receptor immunopositive cells were present in the interstitium but cells destined to develop into rete testis were immunonegative. By day 70 of gestation, the rete testis was organised in the centre of the testis and was strongly androgen receptor immunopositive. AMH and 3β-HSD expression was present in Sertoli and Leydig cells respectively. The expression of AMH, 3β-HSD and androgen receptor in the 100 and 130 day gestation fetuses was similar to that identified in the 70 day fetuses. In conclusion, Sertoli and Leydig precursor cells are present in the gonad prior to seminiferous cord formation and contain AMH and 3β-HSD at all stages of gestation examined. While androgen receptor immunoexpression was present in nuclei of interstitial cells from day 40 of gestation and in the rete testis from day 70 of gestation, Sertoli cells were immunonegative for androgen receptor at all of the stages examined. Journal of Endocrinology (1997) 153, 27–32

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Curi, Tatiana Zauer, Gabriela Neubert da Silva, Marcella Tapias Passoni, Sara Emilia Lima Tolouei, Heloísa Meldola, Renata Marino Romano, Nicole Grechi, Paulo Roberto Dalsenter, and Anderson Joel Martino-Andrade. "In Utero and Lactational Exposure to Diisopentyl Phthalate Induces Fetal Toxicity and Antiandrogenic Effects in Rats." Toxicological Sciences 171, no. 2 (July 31, 2019): 347–58. http://dx.doi.org/10.1093/toxsci/kfz159.

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Abstract A previous study has demonstrated exposure of Brazilian pregnant women to diisopentyl phthalate (DiPeP), which reduces fetal rat testosterone production in a dose-responsive manner. In this study, we examined gene expression of steroidogenic proteins in rat fetal testes and investigated the effects of in utero and lactational DiPeP exposure on male rat reproductive development and function. For the prenatal experiment, we orally exposed pregnant Wistar rats to DiPeP or di-n-butyl phthalate (reference phthalate) at 0, 125, 250, and 500 mg/kg/day from gestation day 14–18 and the fetal testis was evaluated for transcript expression of Star, Cyp11a1, Cyp17a1, Cyp19a1, Insl3, Ar, Esr1, Esr2, and Gper1 by real-time quantitative PCR (RT-qPCR). Diisopentyl phthalate lowered mRNA levels of key steroidogenic proteins, lending support to the previously reported reductions in fetal testosterone production. Diisopentyl phthalate also lowered fetal testis transcript levels of Insl3 and changed gene expression of some steroid hormones receptors. For the postnatal experiment, pregnant rats were exposed orally to vehicle (canola oil) and 4 DiPeP doses (1, 10, 100, and 300 mg/kg/day) between gestation day 10 and postnatal day 21. Diisopentyl phthalate induced a range of reproductive and antiandrogenic effects that are typical of the rat phthalate syndrome, including reduced anogenital distance at the highest dose, reduced weight of seminal vesicles at 10 mg/kg/day and above, and testicular morphological and functional changes. Signs of fetal toxicity were observed at the highest dose. Together, our results indicate that DiPeP, a compound relevant to the human exposure scenario, is one of the most active antiandrogenic phthalates.

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Robinson, Lynne L. L., Norah A. Sznajder, Simon C. Riley, and Richard A. Anderson. "Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human fetal testis and ovary." MHR: Basic science of reproductive medicine 7, no. 7 (July 2001): 641–48. http://dx.doi.org/10.1093/molehr/7.7.641.

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Zafeiri, Aikaterini, and Paul A. Fowler. "Expression Patterns of Analgesic Metabolising Machinery in 1st and 2nd Trimester Human Fetal Liver and Gonads." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A488. http://dx.doi.org/10.1210/jendso/bvab048.998.

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Abstract Use of over-the-counter analgesics during pregnancy is widespread globally. Most analgesic compounds can freely diffuse through the placental feto-maternal interface and reach the developing fetus. Current literature suggests an endocrine disruptor (ED) potential of in utero exposure to these compounds. The liver is the primary site of contact with EDs in the fetus. Exposure of the fetal gonads can also alter reproductive function with potential intergenerational effects. We aimed to characterise the metabolic capability of these fetal organs. RNA sequencing was performed in 80 second trimester human fetal livers and 48 fetal gonads (balanced for fetal age and fetal sex). Samples were collected from elective terminations of normal pregnancies (liver 11-19 weeks, FeGo study: REC 04/S0802/21, and gonads 6-17 weeks, as previously described1. RNA was extracted and Illumina NextSeq was used to produce 76 bp single end (liver) or paired end 2x50 bp (gonads) sequencing reads. Reads were quality controlled, aligned to the human reference genome and quantified at gene regions. Statistical analyses involved an ANOVA model of two-way interactions between fetal sex and fetal age. All organs expressed phase I and II metabolising enzymes and drug transporters involved in the pharmacokinetic and pharmacodynamic pathways of over-the-counter analgesics. The human fetal liver expressed ABCC2, ABCC3, ABCC4 and ABCG2 receptors at similar levels between males and females. Expression of cytochrome p450 enzymes CYP2A6, CYP2C8, CYP2C9, CYP2E1, CYP3A4 involved in metabolism of the analgesics paracetamol and ibuprofen, all increased with gestational age in the liver. Expression of GSTM1, GSTP1, GSTT1, SULT1A1, SULT1A3, SULT1A4, SULT1E1, SULT2A1, UGT2B4, UGT2B7 and UGT2B15 metabolising enzymes also increased during gestation, while fetal hepatic GSTP1 expression showed a significant 2-way interaction between both sex and age. Fetal gonads expressed ABCC4 and ABCG2 transporters, with transcript levels demonstrating significant sex-specific and gestational age differences. Fewer analgesic metabolising enzymes were expressed in the gonads than the fetal liver, including CYP2E1, GSTP1 and SULT1A1, all significantly altered by gestation and fetal sex. Our results reveal expression of major analgesics metabolic and transport components within the human fetal liver, ovaries and testes between gestation weeks 7-19. Significant sex alterations in transcript levels also suggest sexually dimorphic metabolic activity of these organs during fetal life. In conclusion, analgesics can be transported into fetal liver and gonad cells and metabolised into bioactive forms, posing toxicity risks for the developing fetus.1. Lecluze E, Rolland AD, Filis P, et al. Dynamics of the transcriptional landscape during human fetal testis and ovary development. Hum Reprod. 2020;35(5):1099-1119.

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Eladak, Soria, Delphine Moison, Marie-Justine Guerquin, Gabriele Matilionyte, Karen Kilcoyne, Thierry N’Tumba-Byn, Sébastien Messiaen, et al. "Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis." PLOS ONE 13, no. 1 (January 31, 2018): e0191934. http://dx.doi.org/10.1371/journal.pone.0191934.

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Nishida, Hisayo, Shinichi Miyagawa, Maxence Vieux-Rochas, Monica Morini, Yukiko Ogino, Kentaro Suzuki, Naomi Nakagata, Hueng-Sik Choi, Giovanni Levi, and Gen Yamada. "Positive Regulation of Steroidogenic Acute Regulatory Protein Gene Expression through the Interaction between Dlx and GATA-4 for Testicular Steroidogenesis." Endocrinology 149, no. 5 (February 14, 2008): 2090–97. http://dx.doi.org/10.1210/en.2007-1265.

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Split hand/foot malformation (SHFM) is syndromic ectrodactyly often associated with mental retardation and/or craniofacial defects. Several clinical reports previously described urogenital dysplasia such as micropenis, hypospadias, and small testis in SHFM patients. Genetic lesions in the Dlx5 and Dlx6 (Dlx5/6) locus are associated with the human genetic disorder SHFM type 1. Although Dlx5/6 are expressed in the testis, their possible function of Dlx5/6 during testis differentiation has not been described. In this study, we show that Dlx5/6 are expressed in the fetal Leydig cells during testis development. We examined the effect of Dlx5 expression on the promoter activation of the steroidogenic acute regulatory protein (StAR) gene, which is essential for gonadal and adrenal steroidogenesis, in a Leydig cell line. Dlx5 efficiently activates the StAR promoter when GATA-4, another transcription factor essential for testicular steroidogenesis, was coexpressed. The transcriptional activation required the GATA-4-recognition element in the StAR promoter region and Dlx5 can physically interact with GATA-4. Furthermore, we herein show that the double inactivation of Dlx5 and Dlx6 in the mouse leads to decreased testosterone level and abnormal masculinization phenotype. These results suggest that Dlx5 and Dlx6 participate in the control of steroidogenesis during testis development. The findings of this study may open the way to analyze human congenital birth defects.

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Zhang, Lianjun, Min Chen, Qing Wen, Yaqiong Li, Yaqing Wang, Yanbo Wang, Yan Qin, et al. "Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation." Proceedings of the National Academy of Sciences 112, no. 13 (March 16, 2015): 4003–8. http://dx.doi.org/10.1073/pnas.1422371112.

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Sertoli and Leydig cells, the two major somatic cell types in the testis, have different morphologies and functions. Both are essential for gonad development and spermatogenesis. However, whether these cells are derived from the same progenitor cells and the mechanism regulating the differentiation between these two cell types during gonad development remains unclear. A previous study showed that overactivation of Ctnnb1 (cadherin-associated protein, beta 1) in Sertoli cells resulted in Sertoli cell tumors. Surprisingly, in the present study, we found that simultaneous deletion of Wilms’ Tumor Gene 1 (Wt1) and overactivation of Ctnnb1 in Sertoli cells led to Leydig cell-like tumor development. Lineage tracing experiments revealed that the Leydig-like tumor cells were derived from Sertoli cells. Further studies confirmed that Wt1 is required for the maintenance of the Sertoli cell lineage and that deletion of Wt1 resulted in the reprogramming of Sertoli cells to Leydig cells. Consistent with this interpretation, overexpression of Wt1 in Leydig cells led to the up-regulation of Sertoli cell-specific gene expression and the down-regulation of steroidogenic gene expression. These results demonstrate that the distinction between Sertoli cells and Leydig cells is regulated by Wt1, implying that these two cell types most likely originate from the same progenitor cells. This study thus provides a novel concept for somatic cell fate determination in testis development that may also represent an etiology of male infertility in human patients.

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Salonen, Jonna, Ewa Rajpert-De Meyts, Susanna Mannisto, John E. Nielsen, Niels Graem, Jorma Toppari, and Markku Heikinheimo. "Differential developmental expression of transcription factors GATA-4 and GATA-6, their cofactor FOG-2 and downstream target genes in testicular carcinoma in situ and germ cell tumors." European Journal of Endocrinology 162, no. 3 (March 2010): 625–31. http://dx.doi.org/10.1530/eje-09-0734.

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ObjectiveTesticular germ cell cancer is the most common malignancy among young males. The pre-invasive precursor, carcinoma in situ testis (CIS), presumably originates from arrested and transformed fetal gonocytes. Given that GATA transcription factors have essential roles in embryonic and testicular development, we explored the expression of GATA-4, GATA-6, cofactor friend of GATA (FOG)-2, and downstream target genes during human testis development and addressed the question whether changes in this pathway may contribute to germ cell neoplasms.MethodsFetal testis, testicular CIS, and overt tumor samples were analyzed by immunohistochemistry for GATA-4, GATA-6, FOG-2, steroidogenic factor 1 (NR5A1/SF1), anti-Müllerian hormone/Müllerian-inhibiting substance (AMH), and inhibin-α (INHα).ResultsGATA-4 was not expressed in normal germ cells, except for a subset of gonocytes at the 15th gestational week. The CIS cells expressed GATA-4 and GATA-6 heterogeneously, whereas most of the CIS cells expressed GATA-4 cofactor FOG-2. GATA target gene SF-1 was expressed heterogeneously in CIS cells, whereas INHα and AMH were mostly negative. Seminomas and yolk sac tumors were positive for GATA-4 and GATA-6, but mostly negative for FOG-2 and the GATA target genes. In contrast, pluripotent embryonal carcinomas and choriocarcinomas were GATA-4 and GATA-6 negative.ConclusionsDifferential expression of the GATA-4 target genes suggested cell-specific functions of GATA-4 in the germ and somatic cells. The GATA-4 expression in early fetal gonocytes, CIS, and seminoma cells but the absence in more mature germ cells is consistent with the early fetal origin of CIS cells and suggests that GATA-4 is involved in early germ cell differentiation.

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Kuopio, Teijo, Jorma Paranko, and Lauri J. Pelliniemi. "Basement membrane and epithelial features of fetal-type Leydig cells in rat and human testis." Differentiation 40, no. 3 (June 1989): 198–206. http://dx.doi.org/10.1111/j.1432-0436.1989.tb00599.x.

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Nistal, Manuel, Pilar González-Peramato, and Maria P. De Miguel. "Immunodetection of inhibin in the human testis and epididymis during normal development and in non-tumoural testicular lesions." Reproduction, Fertility and Development 22, no. 3 (2010): 558. http://dx.doi.org/10.1071/rd09179.

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Plasma concentrations of inhibin are correlated with spermatogenetic function. Inhibin is secreted mainly by the Sertoli and Leydig cells of the testis. In the human epididymis, the location and function of inhibin are contentious. Thus, the aim of the present study was to determine the location of inhibin in the human epididymis. Investigations were performed in samples with normal testicular function at different stages of development, as well as in samples in which testicular function or the testicular–epididymal connection were altered. In fetal, newborn and infant testes, Sertoli and Leydig cells stained positive for inhibin, whereas no such staining was detected in the epididymides. Inhibin was located in both the Sertoli and Leydig cells, as well as in the epididymis, in the apical pole of mainly secretory cells in the efferent ducts. This staining pattern was not correlated with the staining pattern for macrophages. The main duct of the epididymis was negative for inhibin staining. In ischaemic atrophic testes, the few tubules in which Sertoli cells were present stained positive for inhibin, whereas the epididymides stained negative. In paediatric cryptorchidism, Sertoli and Leydig cells stained positive for inhibin, whereas the epididymides were negative. In adult cryptorchidism, Sertoli and Leydig cells stained positive for inhibin, even in tubules containing Sertoli cells only. Interestingly, inhibin was absent from the efferent ducts. In three cases undergoing hormonal treatment prior to subsequent gender change, Sertoli and Leydig cells stained positive for inhibin. In contrast, the efferent ducts were negative or only faintly positive in cases of shorter hormonal treatment. In all cases studied, the presence of inhibin in the efferent ducts was associated with its production in the testis, suggesting that the epididymis is not responsible for the production of inhibin in men. The pattern of inhibin staining does not correlate with that of macrophages, suggesting that inhibin is not degraded in the human epididymis. The data suggest that, in humans, inhibin is secreted by Sertoli cells into the seminiferous tubules and then travels towards the efferent ducts, where it is reabsorbed into the bloodstream.

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Harris, Abigail, Pam Siggers, Silvia Corrochano, Nick Warr, Danielle Sagar, Daniel T. Grimes, Makoto Suzuki, et al. "ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling." Proceedings of the National Academy of Sciences 115, no. 21 (May 7, 2018): 5474–79. http://dx.doi.org/10.1073/pnas.1801223115.

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Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects. These abnormalities are associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human ZNRF3 variants in very rare cases of XY female presentation. We tested two missense variants and show that these disrupt ZNRF3 activity in both human cell lines and zebrafish embryo assays. Our data identify a testis-determining function for ZNRF3 and indicate a mechanism of direct molecular interaction between two mutually antagonistic organogenetic pathways.

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Sim, Helena, Anthony Argentaro, Daniel P. Czech, Stefan Bagheri-Fam, Andrew H. Sinclair, Peter Koopman, Brigitte Boizet-Bonhoure, Francis Poulat, and Vincent R. Harley. "Inhibition of SRY-Calmodulin Complex Formation Induces Ectopic Expression of Ovarian Cell Markers in Developing XY Gonads." Endocrinology 152, no. 7 (May 10, 2011): 2883–93. http://dx.doi.org/10.1210/en.2010-1475.

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The transcription factor sex-determining region of the Y chromosome (SRY) plays a key role in human sex determination, because mutations in SRY cause disorders of sex development in XY individuals. During gonadal development, Sry in pre-Sertoli cells activates Sox9 gene transcription, committing the fate of the bipotential gonad to become a testis rather than an ovary. The high-mobility group domain of human SRY contains two independent nuclear localization signals, one bound by calmodulin (CaM) and the other by importin-β. Although XY females carry SRY mutations in these nuclear localization signals that affect SRY nuclear import in transfected cells, it is not known whether these transport mechanisms are essential for gonadal development and sex determination. Here, we show that mouse Sry protein binds CaM and that a CaM antagonist reduces CaM binding, nuclear accumulation, and transcriptional activity of Sry in transfected cells. CaM antagonist treatment of cultured, sexually indifferent XY mouse fetal gonads led to reduced expression of the Sry target gene Sox9, defects in testicular cord formation, and ectopic expression of the ovarian markers Rspondin1 and forkhead box L2. These results indicate the importance of CaM for SRY nuclear import, transcriptional activity, testis differentiation, and sex determination.

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Mamsen, Linn Salto, Aikaterini Zafeiri, Jane Alrø Bøtkjær, Jonna Rasmussen Hardlei, Erik Ernst, Claus Oxvig, Paul A. Fowler, and Claus Yding Andersen. "Expression of the Insulin-like Growth Factor System in First- and Second-Trimester Human Embryonic and Fetal Gonads." Journal of Clinical Endocrinology & Metabolism 105, no. 9 (July 29, 2020): e3157-e3168. http://dx.doi.org/10.1210/clinem/dgaa470.

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Abstract Context Insulin-like growth factor (IGF) signaling is crucial for sex differentiation and development of Leydig and Sertoli cells in fetal mice testes. No such information is available for human embryonic and fetal testes and ovaries. Objective To investigate presence and activity of the IGF signaling system during human embryonic and fetal ovarian and testicular development. Design Human embryonic and fetal gonads were obtained following legal terminations of pregnancies. Gene expression was assessed by microarray and qPCR transcript analyses. Proteins of the IGF system components were detected with immunohistochemistry and immunofluorescence analyses. Specimens were included from 2010 to 2017. Setting University Hospital. Patients/Participants Ovaries and testes from a total of 124 human embryos and fetuses aged 5 to 17 postconception weeks were obtained from healthy women aged 16 to 47 years resident in Denmark or Scotland. Main Outcome Measures Gene expression analysis using microarray was performed in 46 specimens and qPCR analysis in 56 specimens, both sexes included. Protein analysis included 22 specimens (11 ovaries, 11 testes). Results IGF system members were detected in embryonic and fetal testes and ovaries, both at gene transcript and protein level. A higher expression of IGF regulators was detected in testes than ovaries, with a preferred localization to Leydig cells. Conclusions These data indicate that the IGF system is active during very early gestation, when it may have a regulatory role in Leydig cells.

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Journal articles on the topic 'Human fetal testis development'

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