Journal articles on the topic 'Testicule – Foetus'
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1
Varma, Santosh K., and Eric Bloch. "Effects of prenatal administration of mestranol and two progestins on testosterone synthesis and reproductive tract development in male rats." Acta Endocrinologica 116, no. 2 (October 1987): 193–99. http://dx.doi.org/10.1530/acta.0.1160193.
Abstract:
Abstract. The oestrogen mestranol (0, 0.01, 0.1 mg/kg body weight per day) and the progestins medroxyprogesterone-acetate and norethisterone (0, 2, 20 mg/kg body weight per day each) in sesame oil were intubated intragastrically daily during gestational days 14.5 through 19.5 to pregnant rats. Males were studied as 20.5-day-old foetuses and 4-month-old adults for serum testosterone and LH concentrations, in vitro testosterone synthesis, anogenital distance (foetuses only) and testes, seminal vesicle and ventral prostate weights. Administration of 0.1 mg mestranol decreased by 35 to 70% basal and LH-stimulated testosterone synthesis by both foetal and adult testes in vitro (P < 0.01). Foetal body weights (P < 0.05), but not anogenital distances, were significantly decreased. Testosterone content in adult sera was reduced significantly (P < 0.05) to less than 50% of control. Testes, ventral prostate, seminal vesicle and epididymal weights were unaffected by treatment. Medroxyprogesterone acetate or norethisterone administration did not alter testes endocrine function in foetal or adult offspring. In a small number of rats, pregnant for 10.5, 14.5 or 18.5 days, [3H]ethinyloestradiol was intubated and foetal and placental tissue examined for appearance and content of radioactivity. Radioactivity was detected in 10.5, 14.5 and 18.5 days old placentas, and 14.5 and 18.5 days old foetal liver, gonads and external genitalia. With [3H]medroxyprogesterone acetate, radioactivity was localized in 14.5 day placenta and foetal tissues. Thin-layer chromatographic analysis showed most of the activity to migrate as authentic ethinyloestradiol or medroxyprogesterone acetate. The results demonstrate inhibition of testicular testosterone synthesis by mestranol, presumably by being transferred across the placenta and acting in the foetus. The diminished activity of adult testes indicates a permanent effect of in utero mestranol exposure on testes function.
2
Grinspon, Romina P., and Rodolfo A. Rey. "Molecular Characterization of XX Maleness." International Journal of Molecular Sciences 20, no. 23 (December 3, 2019): 6089. http://dx.doi.org/10.3390/ijms20236089.
Abstract:
Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness.
3
van der Schoot, P. "Foetal testes control the prenatal growth and differentiation of the gubernacular cones in rabbits--a tribute to the late Professor Alfred Jost." Development 118, no. 4 (August 1, 1993): 1327–34. http://dx.doi.org/10.1242/dev.118.4.1327.
Abstract:
Gubernacular cones develop during foetal life in males of various species, including many of the common small laboratory animals. Postnatally these papilla-like organs invert and develop into the muscular cremaster sacs, providing space for testis descent. The mechanism governing male-specific development of these structures during foetal and postnatal life is unknown but foetal testicular androgens or anti-Mullerian hormone are unlikely to be involved. The present study of gubernacular cone development in 28-day-old rabbit foetuses castrated 5–9 days before questions whether foetal testis hormones play any role in these developmental processes. The study comprised an analysis of the microscopic slides in the legacy of the late Professor Alfred Jost in Paris. Castration at an earlier (19 days) or later (23/24 days) day of foetal life interfered with gubernacular cone growth and differentiation. Unilateral castration partially inhibited ipsilateral gubernacular cone growth. Implantation of a foetal testis close to the ovary could induce male-type gubernacular cone growth in females. Together the data unequivocally support the concept of foetal testicular hormonal control of male-specific gubernacular cone development. Further study is required to unravel the nature of the active foetal testicular agent.
4
Rey, Rodolfo. "Anti-Müllerian hormone in disorders of sex determination and differentiation." Arquivos Brasileiros de Endocrinologia & Metabologia 49, no. 1 (February 2005): 26–36. http://dx.doi.org/10.1590/s0004-27302005000100005.
Abstract:
Masculinisation of internal and external genitalia during foetal development depends on the existence of two discrete testicular hormones: Leydig cell-secreted testosterone drives the differentiation of the Wolffian ducts, the urogenital sinus and the external genitalia, whereas Sertoli cell-produced anti-Müllerian hormone (AMH) provokes the regression of Müllerian ducts. The absence of AMH action in early foetal life results in the formation of the Fallopian tubes, the uterus and the upper third of the vagina. In 46,XY foetuses, lack of AMH may result from testicular dysgenesis affecting both Leydig and Sertoli cell populations: in this case persistence of Müllerian remnants is associated with ambiguous or female external genitalia. Alternatively, defective AMH action may result from mutations of the genes encoding for AMH or its receptor: in this condition known as Persistent Müllerian Duct Syndrome, testosterone production is normal and external genitalia are normally virilised. Finally, AMH may be normally secreted in intersex patients with defects restricted to androgen synthesis or action, resulting in patients with female or ambiguous external genitalia with no Müllerian derivatives.
5
Veeramachaneni, D. N. Rao, and Gary R. Klinefelter. "Phthalate-induced pathology in the foetal testis involves more than decreased testosterone production." REPRODUCTION 147, no. 4 (April 2014): 435–42. http://dx.doi.org/10.1530/rep-13-0441.
Abstract:
Foetal exposure to phthalates is known to adversely impact male reproductive development and function. Developmental anomalies of reproductive tract have been attributed to impaired testosterone synthesis. However, species differences in the ability to produce testosterone have been noted; e.g., following foetal exposure, abnormal clustering of Leydig cells or decreased production of testosterone that is manifested in rats does not occur in mice or humans. Nonetheless, other facets of testicular dysgenesis occur in both rats and mice as well as in some other species tested. We recently published a comprehensive evaluation of the foetal rat testis proteome, following in utero exposure to diethylhexyl phthalate (DEHP), which revealed changes in individual proteins that are known to be factors in cellular differentiation and migration or related to the capacity of the foetal Leydig cell to produce testosterone and fit a pathway network in which each is regulated directly or indirectly by oestradiol. Plasma oestradiol indeed was found to be elevated approximately twofold in 19-day-old DEHP-exposed foetal male rats. In this brief review, we discuss our new findings vis-à-vis ‘oestrogen hypothesis’ as a cause for testicular dysgenesis syndrome.
6
Bertoldo, Joselma da Silva Cavalcanti, Apolônio Gomes Ribeiro, Liana Mesquita Vilela, Paola Teles Soares, Maria Juliana Coelho Dias da Silva Teixeira, and Júlio Cézar dos Santos Nascimento. "Male pseudohermaphroditism in a dog: case report." Acta Veterinaria Brasilica 17, no. 4 (December 31, 2023): 23–28. http://dx.doi.org/10.21708/avb.2023.17.4.11795.
Abstract:
Genital development disorders or anomalies have been described in several species of domestic animals. Sexual differentiation in mammals occurs sequentially and chronologically with the following distinct events in embryonic and faetal development: the determination of chromosomal sex at fertilisation, the development of gonadal sex and, finally, the development of the phenotypic sex in the foetus. Any errors in these processes lead to some form of intersexuality. In the literature, three types of intersexuality in companion animals are described: true hermaphroditism and male and female pseudohermaphroditism. The diagnosis is based on physical and imaging examinations, with confirmation by histopathological analysis and karyotyping. As there are few reports of this sexual anomaly, this case report addresses a case of male pseudohermaphroditism in a Shiba Inu canine. Clinical examination revealed the presence of a hypertrophied clitoris in the vaginal canal, without obstruction of the urethral canal. An abdominal ultrasound examination revealed splenomegaly, signs suggestive of chronic cystitis associated with bladder and urethral microuroliths, as well as a small tubular structure without cranial continuity. A blood count, serum biochemistry and the determination of the hormonal levels were performed pre- and post-surgery. Surgical treatment was instituted through exploratory laparotomy, revealing the presence of testicles in the abdominal cavity, a uterus, a cervix and uterine horns. The findings were sent for histopathological analysis, where diffuse testicular hypoplasia and endometrial hyperplasia, associated with neutrophilic and lymphoplasmacytic metritis, were evaluated. As these findings are associated with anamnesis, it is concluded that this case is a male pseudohermaphrodite.
7
Ngona, I. A., J. M. Beduin, A. B. F. Khang' Maté, and C. Hanzen. "Etude descriptive des caractéristiques morphométriques et génitales de la chèvre de Lubumbashi en République démocratique du Congo." Revue d’élevage et de médecine vétérinaire des pays tropicaux 65, no. 3-4 (March 1, 2012): 75. http://dx.doi.org/10.19182/remvt.10126.
Abstract:
L’étude a eu pour but de préciser les caractéristiques zootechniques et de reproduction des chèvres (n = 1 311) et des boucs (n = 346) abattus à Lubumbashi. La taille au garrot, la longueur corporelle et le poids vif ont été respectivement de 53 cm, 77 cm et 20,5 kg chez les femelles, et de 53 cm, 71 cm et 19 kg chez les mâles. Le poids des testicules gauche et droit, le diamètre moyen des testicules et le périmètre scrotal ont été respectivement de 67,3 g, 66,9 g, 12 cm et 21,1 cm. La longueur moyenne du tractus génital de la vulve à l’extrémité de la corne a été de 30,3 cm. Le poids moyen des ovaires, la longueur et la largeur des ovaires gauche et droit ont été respectivement de 1,1 g, 1,8 x 1,3 cm et 1,7 x 1,3 cm. Aucune structure kystique n’a été observée sur les ovaires. Quarante-quatre pourcent des femelles abattues se sont révélées gravides. A partir de la comparaison du nombre de corps jaunes et du nombre d’embryons ou de foetus présents dans l’utérus, les mortalités embryonnaires ont été estimées à 19,2 p. 100.
8
Dehkordi, R. F., A. Parchami, and P. Kheibari. "Studies on Foetal Testicular Development in Sheep." Asian Journal of Biological Sciences 1, no. 2 (June 15, 2008): 100–102. http://dx.doi.org/10.3923/ajbs.2008.100.102.
9
Engels, Manon, Paul N. Span, Rod T. Mitchell, Joop J. T. M. Heuvel, Monica A. Marijnissen-van Zanten, Antonius E. van Herwaarden, Christina A. Hulsbergen-van de Kaa, et al. "GATA transcription factors in testicular adrenal rest tumours." Endocrine Connections 6, no. 8 (November 2017): 866–75. http://dx.doi.org/10.1530/ec-17-0215.
Abstract:
Testicular adrenal rest tumours (TARTs) are benign adrenal-like testicular tumours that frequently occur in male patients with congenital adrenal hyperplasia. Recently, GATA transcription factors have been linked to the development of TARTs in mice. The aim of our study was to determine GATA expression in human TARTs and other steroidogenic tissues. We determined GATA expression in TARTs (n = 16), Leydig cell tumours (LCTs; n = 7), adrenal (foetal (n = 6) + adult (n = 10)) and testis (foetal (n = 13) + adult (n = 8)). We found testis-like GATA4, and adrenal-like GATA3 and GATA6 gene expressions by qPCR in human TARTs, indicating mixed testicular and adrenal characteristics of TARTs. Currently, no marker is available to discriminate TARTs from LCTs, leading to misdiagnosis and incorrect treatment. GATA3 and GATA6 mRNAs exhibited excellent discriminative power (area under the curve of 0.908 and 0.816, respectively), while immunohistochemistry did not. GATA genes contain several CREB-binding sites and incubation with 0.1 mM dibutyryl cAMP for 4 h stimulated GATA3, GATA4 and GATA6 expressions in a human foetal testis cell line (hs181.tes). Incubation of adrenocortical cells (H295RA) with ACTH, however, did not induce GATA expression in vitro. Although ACTH did not dysregulate GATA expression in the only human ACTH-sensitive in vitro model available, our results do suggest that aberrant expression of GATA transcription factors in human TARTs might be involved in TART formation.
10
Young, J. C., A. Jaiprakash, S. Mithraprabhu, C. Itman, S. Kitazawa, and K. L. Loveland. "170. TGFβ SIGNALING IN AN IN VITRO SEMINOMA MODEL." Reproduction, Fertility and Development 21, no. 9 (2009): 88. http://dx.doi.org/10.1071/srb09abs170.
Abstract:
Testicular cancer, the second most common malignancy in young men, has a 95% cure rate but can result in infertility or subfertility. Its incidence has increased significantly in recent decades (1). This cancer is thought to arise during embryogenesis, based on the persistence of embryonic germ cell markers such as Blimp1 (2), Oct3/4 (3) and Nanog (3) in adult seminoma cells. TCam2 cells are a recently characterised in vitro seminoma model (4). We show by Q-PCR and immunofluorescence that they also express these early germ cell markers. TGFβ signaling plays a key role during germ cell development, and is implicated in the development of testicular cancers (5, 6). To investigate this further, we first determined whether the pathway is active in TCam2 cells. By Q-PCR we demonstrate expression of the TGFβ downstream transcription factors Smad 2, 3 and 4, and Activin type I and II receptors. Importantly, ActRIIA, which is undetectable in adult testicular germ cells, but readily detected in human foetal germ cells (7) and clinical seminoma samples (6), is readily detectable at both the mRNA and protein level in TCam2 cells. Furthermore, 24 hour treatment with Activin (5 and 50ng/ml) or BMP4 (5 and 50ng/ml) induces a 3-4 fold increase in ActRIIA mRNA levels, but not ActRIA, ActRIB or ActRIIB. Strikingly, in TCam2 cells BMP4 and to a lesser extent retinoic acid, but not activin, support survival and proliferation of TCam2 cells in the absence of serum. This is consistent with known roles of BMP4 and retinoic acid in enhancing murine foetal germ cell proliferation/self-renewal and survival (8, 9), and activin inhibition of foetal murine germ cell proliferation (10). This study is the first to demonstrate a functional response in seminoma cells consistent with their foetal germ cell-like identity and forms the basis for future mechanistic analyses of the role of TGFβ signaling in human testicular cancer.
11
Habert, R., V. Muczynski, A. Lehraiki, D. Moison, R. Lambrot, C. Levacher, C. Lécureuil, R. Frydman, and V. Rouiller-Fabre. "Altérations environnementales du développement du testicule foetal: zoom sur les phtalates." Basic and Clinical Andrology 21, no. 1 (February 18, 2011): 24–33. http://dx.doi.org/10.1007/s12610-011-0121-8.
12
Lacham-Kaplan, Orly, and Alan Trounson. "Fertilization and embryonic developmental capacity of epididymal and testicular sperm and immature spermatids and spermatocytes." Reproductive Medicine Review 6, no. 1 (March 1997): 55–68. http://dx.doi.org/10.1017/s096227990000140x.
Abstract:
Spermatogenesis in mammalian species begins after birth. The gonocytes, arrested at G2 of the cell cycle in the foetus, resume mitotic proliferation after birth. As identified in the mouse, the gonocytes migrate towards the periphery of the seminiferous cords at day 4 to day 6 after birth and are located in close contact with the basal lamina. From this stage the gonocytes are referred to as primitive type A spermatogonia. These cells continue mitotic proliferation and differentiate to form type B spermatogonia. By day 10 after birth, many of the type B spermatogonia have formed preleptotene primary spermatocytes which undergo a final phase of DNA synthesis (leptotene) prior to entering meiotic prophase (zygotene).
13
Kapoor, D., and T. H. Jones. "Smoking and hormones in health and endocrine disorders." European Journal of Endocrinology 152, no. 4 (April 2005): 491–99. http://dx.doi.org/10.1530/eje.1.01867.
Abstract:
Smoking has multiple effects on hormone secretion, some of which are associated with important clinical implications. These effects are mainly mediated by the pharmacological action of nicotine and also by toxins such as thiocyanate. Smoking affects pituitary, thyroid, adrenal, testicular and ovarian function, calcium metabolism and the action of insulin. The major salient clinical effects are the increased risk and severity of Graves’ hyperthyroidism and opthalmopathy, osteoporosis and reduced fertility. Smoking also contributes to the development of insulin resistance and hence type 2 diabetes mellitus. An important concern is also the effect of smoking on the foetus and young children. Passive transfer of thiocyanate can cause disturbance of thyroid size and function. Furthermore, maternal smoking causes increased catecholamine production, which may contribute to under perfusion of the foetoplacental unit.
14
Wohlfahrt-Veje, Christine, Katharina M. Main, and Niels Erik Skakkebaek. "Testicular dysgenesis syndrome: foetal origin of adult reproductive problems." Clinical Endocrinology 71, no. 4 (September 7, 2009): 459–65. http://dx.doi.org/10.1111/j.1365-2265.2009.03545.x.
15
Wilharm, Anneke, Helena C. Brigas, Inga Sandrock, Miguel Ribeiro, Tiago Amado, Annika Reinhardt, Abdi Demera, et al. "Microbiota-dependent expansion of testicular IL-17-producing Vγ6+ γδ T cells upon puberty promotes local tissue immune surveillance." Mucosal Immunology 14, no. 1 (July 30, 2020): 242–52. http://dx.doi.org/10.1038/s41385-020-0330-6.
Abstract:
AbstractγδT cells represent the majority of lymphocytes in several mucosal tissues where they contribute to tissue homoeostasis, microbial defence and wound repair. Here we characterise a population of interleukin (IL) 17-producing γδ (γδ17) T cells that seed the testis of naive C57BL/6 mice, expand at puberty and persist throughout adulthood. We show that this population is foetal-derived and displays a T-cell receptor (TCR) repertoire highly biased towards Vγ6-containing rearrangements. These γδ17 cells were the major source of IL-17 in the testis, whereas αβ T cells mostly provided interferon (IFN)-γ in situ. Importantly, testicular γδ17 cell homoeostasis was strongly dependent on the microbiota and Toll-like receptor (TLR4)/IL-1α/IL-23 signalling. We further found that γδ17 cells contributed to tissue surveillance in a model of experimental orchitis induced by intra-testicular inoculation of Listeria monocytogenes, as Tcrδ−/− and Il17−/− infected mice displayed higher bacterial loads than wild-type (WT) controls and died 3 days after infection. Altogether, this study identified a previously unappreciated foetal-derived γδ17 cell subset that infiltrates the testis at steady state, expands upon puberty and plays a crucial role in local tissue immune surveillance.
16
Rey, Rodolfo A. "Recent advancement in the treatment of boys and adolescents with hypogonadism." Therapeutic Advances in Endocrinology and Metabolism 13 (January 2022): 204201882110656. http://dx.doi.org/10.1177/20420188211065660.
Abstract:
Clinical manifestations and the need for treatment varies according to age in males with hypogonadism. Early foetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in foetal life presents with micropenis, cryptorchidism and/or micro-orchidism. After the period of neonatal activation of the gonadal axis has waned, the diagnosis of hypogonadism is challenging because androgen deficiency is not apparent until the age of puberty. Then, the differential diagnosis between constitutional delay of puberty and central hypogonadism may be difficult. During infancy and childhood, treatment is usually sought because of micropenis and/or cryptorchidism, whereas lack of pubertal development and relative short stature are the main complaints in teenagers. Testosterone therapy has been the standard, although off-label, in the vast majority of cases. However, more recently alternative therapies have been tested: aromatase inhibitors to induce the hypothalamic-pituitary-testicular axis in boys with constitutional delay of puberty and replacement with GnRH or gonadotrophins in those with central hypogonadism. Furthermore, follicle-stimulating hormone (FSH) priming prior to hCG or luteinizing hormone (LH) treatment seems effective to induce an enhanced testicular enlargement. Although the rationale for gonadotrophin or GnRH treatment is based on mimicking normal physiology, long-term results are still needed to assess their impact on adult fertility.
17
Radhakrishnan, Karthika, Michael Luu, Josie Iaria, Jessie M. Sutherland, Eileen A. McLaughlin, Hong-Jian Zhu, and Kate L. Loveland. "Activin and BMP Signalling in Human Testicular Cancer Cell Lines, and a Role for the Nucleocytoplasmic Transport Protein Importin-5 in Their Crosstalk." Cells 12, no. 7 (March 24, 2023): 1000. http://dx.doi.org/10.3390/cells12071000.
Abstract:
Testicular germ cell tumours (TGCTs) are the most common malignancy in young men. Originating from foetal testicular germ cells that fail to differentiate correctly, TGCTs appear after puberty as germ cell neoplasia in situ cells that transform through unknown mechanisms into distinct seminoma and non-seminoma tumour types. A balance between activin and BMP signalling may influence TGCT emergence and progression, and we investigated this using human cell line models of seminoma (TCam-2) and non-seminoma (NT2/D1). Activin A- and BMP4-regulated transcripts measured at 6 h post-treatment by RNA-sequencing revealed fewer altered transcripts in TCam-2 cells but a greater responsiveness to activin A, while BMP4 altered more transcripts in NT2/D1 cells. Activin significantly elevated transcripts linked to pluripotency, cancer, TGF-β, Notch, p53, and Hippo signalling in both lines, whereas BMP4 altered TGF-β, pluripotency, Hippo and Wnt signalling components. Dose-dependent antagonism of BMP4 signalling by activin A in TCam-2 cells demonstrated signalling crosstalk between these two TGF-β superfamily arms. Levels of the nuclear transport protein, IPO5, implicated in BMP4 and WNT signalling, are highly regulated in the foetal mouse germline. IPO5 knockdown in TCam-2 cells using siRNA blunted BMP4-induced transcript changes, indicating that IPO5 levels could determine TGF-β signalling pathway outcomes in TGCTs.
18
Kortenkamp, Andreas, Martin Scholze, and Sibylle Ermler. "Mind the gap: can we explain declining male reproductive health with known antiandrogens?" REPRODUCTION 147, no. 4 (April 2014): 515–27. http://dx.doi.org/10.1530/rep-13-0440.
Abstract:
Several countries have experienced rises in cryptorchidisms, hypospadias and testicular germ cell cancer. The reasons for these trends are largely unknown, but Skakkebaek has proposed that these disorders form a testicular dysgenesis syndrome and can be traced to androgen insufficiency in foetal life. This suggests that antiandrogenic chemicals might contribute to risks, but few chemicals have been linked to these diseases in epidemiological studies. In animal studies with p,p′-dichlorodiphenyldichloroethylene, effects typical of disruptions of male sexual differentiation became apparent when the foetal levels of this androgen receptor (AR) antagonist approached values associated with responses in in vitro assays. This prompted us to analyse whether the 22 chemicals with AR antagonistic properties would produce mixture effects in an in vitro AR antagonism assay when combined at concentrations found in human serum. Other antiandrogenic modalities could not be considered. Two scenarios were investigated, one representative of average serum levels reported in European countries, the other in line with levels towards the high exposures. In both situations, the in vitro potency of the 22 selected AR antagonists was too low to produce combined AR antagonistic effects at the concentrations found in human serum, although the high exposure scenario came quite close to measurable effects. Nevertheless, our analysis exposes an explanation gap which can only be bridged by conjuring up as yet undiscovered high potency AR antagonists or, alternatively, high exposures to unknown agents of average potency.
19
Novotny, Guy Wayne, Kirstine C. Belling, Jesper Bertram Bramsen, John E. Nielsen, Jette Bork-Jensen, Kristian Almstrup, Si Brask Sonne, Jørgen Kjems, Ewa Rajpert-De Meyts, and Henrik Leffers. "MicroRNA expression profiling of carcinoma in situ cells of the testis." Endocrine-Related Cancer 19, no. 3 (March 14, 2012): 365–79. http://dx.doi.org/10.1530/erc-11-0271.
Abstract:
Testicular germ cell tumours, seminoma (SE) and non-seminoma (NS), of young adult men develop from a precursor cell, carcinomain situ(CIS), which resembles foetal gonocytes and retains embryonic pluripotency. We used microarrays to analyse microRNA (miRNA) expression in 12 human testis samples with CIS cells and compared it with miRNA expression profiles of normal adult testis, testis with Sertoli-cell-only that lacks germ cells, testis tumours (SE and embryonal carcinoma (EC), an undifferentiated component of NS) and foetal male and female gonads. Principal components analysis revealed distinct miRNA expression profiles characteristic for each of the different tissue types. We identified several miRNAs that were unique to testis with CIS cells, foetal gonads and testis tumours. These included miRNAs from the hsa-miR-371–373 and -302–367 clusters that have previously been reported in germ cell tumours and three miRNAs (hsa-miR-96, -141 and -200c) that were also expressed in human epididymis. We found several miRNAs that were upregulated in testis tumours: hsa-miR-9, -105 and -182–183–96 clusters were highly expressed in SE, while the hsa-miR-515–526 cluster was high in EC. We conclude that the miRNA expression profile changes during testis development and that the miRNA profile of adult testis with CIS cells shares characteristic similarities with the expression in foetal gonocytes.
20
Priskorn, L., M. Kreiberg, M. Bandak, J. Lauritsen, G. Daugaard, J. H. Petersen, L. Aksglaede, A. Juul, and N. Jørgensen. "Testicular cancer survivors have shorter anogenital distance that is not increased by 1 year of testosterone replacement therapy." Human Reproduction 36, no. 9 (July 5, 2021): 2443–51. http://dx.doi.org/10.1093/humrep/deab162.
Abstract:
Abstract STUDY QUESTION Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood? SUMMARY ANSWER AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone replacement therapy. WHAT IS KNOWN ALREADY Animal studies have shown that AGD is a postnatal ‘read-out’ of foetal androgen action, and short AGD in male offspring is considered a sign of feminization caused by in utero disruption of the reproductive system. Likewise, measurement of AGD in human studies has suggested AGD to be part of the testicular dysgenesis syndrome hypothesis, which proposes that male reproductive disorders, such as hypospadias, cryptorchidism, some cases of impaired semen quality and TC, all share a common foetal origin. STUDY DESIGN, SIZE, DURATION The aim was to assess AGD in men with a history of TC and controls, and furthermore to examine AGD during testosterone replacement therapy in adulthood. Study participants were TC survivors with a mild Leydig cell insufficiency who participated in a randomized double-blind study of testosterone replacement therapy versus placebo for 52 weeks (N = 69). Men from the general population were prospectively included from a study on testicular function as controls (N = 67). PARTICIPANTS/MATERIALS, SETTING, METHODS We measured two variants of AGD; as our primary outcome the anoscrotal distance (AGDas) measured from the centre of the anus to the posterior base of the scrotum, and secondarily the anopenile distance (AGDap) measured from the anus to the cephalad insertion of the penis. Using multiple regression analysis, the mean difference in AGD between TC survivors and men from the general population was assessed, adjusted for height, BMI and examiner. Next, AGD was measured before and after 52 weeks of treatment with testosterone or placebo, and with covariance analysis differences between the two groups at follow-up was assessed after adjustment for baseline AGD, examiner, BMI and change in BMI during treatment. MAIN RESULTS AND THE ROLE OF CHANCE TC survivors had a shorter AGDas (−0.84 cm, 95% CI: −1.31; −0.37) compared to men from the general population, and AGDas did not differ between the testosterone and placebo treated group at follow-up (0.11 cm, 95% CI: −0.22; 0.44). In contrast, AGDap was not shorter in TC survivors after adjustment (0.05 cm, 95% CI: −0.30; 0.39), and was 0.48 cm longer (95% CI: 0.13; 0.82) at follow-up in the testosterone treated compared to the placebo-treated group. LIMITATIONS, REASONS FOR CAUTION A limitation of the study is that the number of included men was limited, and results need confirmation in a larger study. Furthermore, TC survivors were significantly older than controls. For the comparison of AGD in TC survivors and controls, it was not possible to conduct the examinations with the examiner being blinded to which group he was examining, and it cannot be excluded that this can cause a bias. WIDER IMPLICATIONS OF THE FINDINGS The shorter AGDas in TC survivors compared to controls, which did not change upon adult testosterone replacement therapy, supports the hypothesis that reduced AGD is part of the testicular dysgenesis syndrome and may be a marker of disrupted foetal testicular development. By contrast, AGDap was not shorter in TC survivors and might be modestly sensitive to adult testosterone treatment, and thus inferior to AGDas as a constant postnatal marker of the foetal androgen environment. STUDY FUNDING/COMPETING INTEREST(S) Expenses were paid by the Department of Oncology, Copenhagen University Hospital, Rigshospitalet. Kiowa Kirin International covered expenses for Tostran and placebo. The Danish Cancer Society, The Danish Cancer Research Foundation, the Preben & Anna Simonsen Foundation, and Rigshospitalet have supported the study. L.P. was financed by the Research Fund of the Capital Region of Denmark. The authors have no competing interests. TRIAL REGISTRATION NUMBER Part of the study is based on men participating in a randomized controlled trial registered at ClinicalTrials.gov, NCT02991209, 25 November 2016.
21
Martino-Andrade, Anderson J., Rosana N. Morais, Giuliana G. K. Botelho, Graziela Muller, Simone W. Grande, Giovanna B. Carpentieri, Gabriel M. C. Leão, and Paulo R. Dalsenter. "Coadministration of active phthalates results in disruption of foetal testicular function in rats." International Journal of Andrology 32, no. 6 (December 22, 2008): 704–12. http://dx.doi.org/10.1111/j.1365-2605.2008.00939.x.
22
Giannandrea, Fabrizio, and Irene Figà Talamanca. "Increased availability of estrogens to the foetus and the risk of testicular cancer in later life: Does insulin have a role?" Medical Hypotheses 71, no. 1 (January 2008): 152–53. http://dx.doi.org/10.1016/j.mehy.2008.01.021.
23
Forand, A., S. Messiaen, R. Habert, and J. Bernardino-Sgherri. "Exposure of the mouse perinatal testis to radiation leads to hypospermia at sexual maturity." REPRODUCTION 137, no. 3 (March 2009): 487–95. http://dx.doi.org/10.1530/rep-08-0358.
Abstract:
The first round of mouse spermatogenesis begins from 3 to 4 days after birth through differentiation of gonocytes into spermatogonial-stem cells and type A spermatogonia. Consequently, this step of differentiation may determine generation of the original population of stem cells and the fertility potential of the adult mouse. We aimed to determine the effect of perinatal exposure to ionizing radiation on the testis at the end of the first wave of spermatogenesis and at sexual maturity. Our results show that, radiation sensitivity of the testis substantially decreases from late foetal life to the end of the first week after birth. In addition, partial or full recovery from radiation induced testicular weight loss occurred between the first round of spermatogenesis and sexual maturity, and this was associated with the stimulation of spermatogonial proliferation. Exposure of mice at 17.5 days after conception or at 1 day after birth to γ-rays decreased the sperm counts at sexual maturity, while exposure of 8 day-old mice had no effect. This suggests that irradiation of late foetal or early neonatal testes has a direct impact on the generation of the neonatal spermatogonial-stem cell pool.
24
Talsness, Chris E., Anderson J. M. Andrade, Sergio N. Kuriyama, Julia A. Taylor, and Frederick S. vom Saal. "Components of plastic: experimental studies in animals and relevance for human health." Philosophical Transactions of the Royal Society B: Biological Sciences 364, no. 1526 (July 27, 2009): 2079–96. http://dx.doi.org/10.1098/rstb.2008.0281.
Abstract:
Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A (TBBPA), are detected in humans. In addition to their utility in plastics, an inadvertent characteristic of these chemicals is the ability to alter the endocrine system. Phthalates function as anti-androgens while the main action attributed to BPA is oestrogen-like activity. PBDE and TBBPA have been shown to disrupt thyroid hormone homeostasis while PBDEs also exhibit anti-androgen action. Experimental investigations in animals indicate a wide variety of effects associated with exposure to these compounds, causing concern regarding potential risk to human health. For example, the spectrum of effects following perinatal exposure of male rats to phthalates has remarkable similarities to the testicular dysgenesis syndrome in humans. Concentrations of BPA in the foetal mouse within the range of unconjugated BPA levels observed in human foetal blood have produced effects in animal experiments. Finally, thyroid hormones are essential for normal neurological development and reproductive function. Human body burdens of these chemicals are detected with high prevalence, and concentrations in young children, a group particularly sensitive to exogenous insults, are typically higher, indicating the need to decrease exposure to these compounds.
25
Cancilla, B., A. Davies, M. Ford-Perriss, and GP Risbridger. "Discrete cell- and stage-specific localisation of fibroblast growth factors and receptor expression during testis development." Journal of Endocrinology 164, no. 2 (February 1, 2000): 149–59. http://dx.doi.org/10.1677/joe.0.1640149.
Abstract:
Fibroblast growth factors (FGFs) are a family of heparin binding proteins involved in many biological processes. These growth factors act through tyrosine kinase receptors (FGFRs); we have previously used immunohistochemistry to study FGFRs-1-4 in foetal, immature and adult rat testes, and found a discrete cell- and stage-specific localisation. Alternative mRNA splicing of FGFRs-1-3 leads to functional variants (IIIb and IIIc) with distinct ligand binding affinities, therefore we have identified the specific expression of functional FGFR variants and the expression and localisation of FGF ligands in testes from foetal, immature and adult rats. Using reverse transcriptase-polymerase chain reaction (RT-PCR), we found that mRNAs for FGFR-1 IIIb and IIIc, FGFR-2 IIIc, FGFR-3 IIIc and FGFR-4 were expressed in foetal, immature and adult testes. Ligands FGFs-1-5, and -8, which can signal through these receptors, were also expressed in testes at each age. Localisation of the ligands FGFs-1, -3 and -4 to rat testes by immunohistochemistry showed a discrete cell- and stage-specific localisation that altered during testis development. This study has shown that the ligands FGFs-1, -3 and -4 are expressed in the testis and have the capacity to signal through appropriate receptors that are also co-localised or expressed in adjacent cell types in the testis. Collectively, the expression profiles of the seven FGFR variants and FGFs-1-5 and -8 suggest a functional importance in testicular development and spermatogenesis. It is concluded that, future studies on the role of other FGF ligands, in particular FGFs-1-4, are warranted.
26
Dimitriadis, F., D. Giannakis, N. Pardalidis, K. Tsoukanelis, N. Kanakas, M. Saito, T. Watanabe, I. Miyagawa, P. Tsounapi, and N. Sofikitis. "Effects of primary testicular damage on sperm DNA oxidative status and embryonic and foetal development." Andrologia 41, no. 5 (October 2009): 282–96. http://dx.doi.org/10.1111/j.1439-0272.2009.00929.x.
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Bush, Stephen J., Rafail Nikola, Seungmin Han, Shinnosuke Suzuki, Shosei Yoshida, Benjamin D. Simons, and Anne Goriely. "Adult Human, but Not Rodent, Spermatogonial Stem Cells Retain States with a Foetal-like Signature." Cells 13, no. 9 (April 24, 2024): 742. http://dx.doi.org/10.3390/cells13090742.
Abstract:
Spermatogenesis involves a complex process of cellular differentiation maintained by spermatogonial stem cells (SSCs). Being critical to male reproduction, it is generally assumed that spermatogenesis starts and ends in equivalent transcriptional states in related species. Based on single-cell gene expression profiling, it has been proposed that undifferentiated human spermatogonia can be subclassified into four heterogenous subtypes, termed states 0, 0A, 0B, and 1. To increase the resolution of the undifferentiated compartment and trace the origin of the spermatogenic trajectory, we re-analysed the single-cell (sc) RNA-sequencing libraries of 34 post-pubescent human testes to generate an integrated atlas of germ cell differentiation. We then used this atlas to perform comparative analyses of the putative SSC transcriptome both across human development (using 28 foetal and pre-pubertal scRNA-seq libraries) and across species (including data from sheep, pig, buffalo, rhesus and cynomolgus macaque, rat, and mouse). Alongside its detailed characterisation, we show that the transcriptional heterogeneity of the undifferentiated spermatogonial cell compartment varies not only between species but across development. Our findings associate ‘state 0B’ with a suppressive transcriptomic programme that, in adult humans, acts to functionally oppose proliferation and maintain cells in a ready-to-react state. Consistent with this conclusion, we show that human foetal germ cells—which are mitotically arrested—can be characterised solely as state 0B. While germ cells with a state 0B signature are also present in foetal mice (and are likely conserved at this stage throughout mammals), they are not maintained into adulthood. We conjecture that in rodents, the foetal-like state 0B differentiates at birth into the renewing SSC population, whereas in humans it is maintained as a reserve population, supporting testicular homeostasis over a longer reproductive lifespan while reducing mutagenic load. Together, these results suggest that SSCs adopt differing evolutionary strategies across species to ensure fertility and genome integrity over vastly differing life histories and reproductive timeframes.
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Mall, E. M., N. Rotte, J. Yoon, R. Sandhowe-Klaverkamp, A. Röpke, J. Wistuba, K. Hübner, H. R. Schöler, and S. Schlatt. "A novel xeno-organoid approach: exploring the crosstalk between human iPSC-derived PGC-like and rat testicular cells." Molecular Human Reproduction 26, no. 12 (October 13, 2020): 879–93. http://dx.doi.org/10.1093/molehr/gaaa067.
Abstract:
Abstract Specification of germ cell-like cells from induced pluripotent stem cells has become a clinically relevant tool for research. Research on initial embryonic processes is often limited by the access to foetal tissue, and in humans, the molecular events resulting in primordial germ cell (PGC) specification and sex determination remain to be elucidated. A deeper understanding of the underlying processes is crucial to describe pathomechanisms leading to impaired reproductive function. Several protocols have been established for the specification of human pluripotent stem cell towards early PGC-like cells (PGCLC), currently representing the best model to mimic early human germline developmental processes in vitro. Further sex determination towards the male lineage depends on somatic gonadal cells providing the necessary molecular cues. By establishing a culture system characterized by the re-organization of somatic cells from postnatal rat testes into cord-like structures and optimizing efficient PGCLC specification protocols, we facilitated the co-culture of human germ cell-like cells within a surrogate testicular microenvironment. Specified conditions allowed the survival of rat somatic testicular and human PGCLCs for 14 days. Human cells maintained the characteristic expression of octamer-binding transcription factor 4, SRY-box transcription factor 17, and transcription factor AP-2 gamma and were recovered from the xeno-organoids by cell sorting. This novel xeno-organoid approach will allow the in vitro exploration of early sex determination of human PGCLCs.
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Gaytan, F., L. Pinilla, J. L. Romero, and E. Aguilar. "Differential effects of the administration of human chorionic gonadotropin to postnatal rats." Journal of Endocrinology 142, no. 3 (September 1994): 527–34. http://dx.doi.org/10.1677/joe.0.1420527.
Abstract:
Abstract Neonatal and prepubertal male rats were treated with human chorionic gonadotropin (hCG, 5 IU/g body weight per day) on days 2–4 or 20–22. Depending on the date of treatment, different groups of rats were sacrificed at 5, 23, 30 and 100 days of age, in order to study the short-and long-term effects of the treatment with hCG on the development of the testes and sex accessory organs. Rats treated with hCG on days 2–4 showed increased number and size of foetal Leydig cells at 5 days of age. However, long-term effects include decreased numbers of adult-type Leydig cells, decreased weight of the testes and sex accessory organs, decreased basal and hCG-stimulated testosterone secretion, and delayed balano-preputial separation. In contrast, animals treated with hCG on days 20–22 showed similar short- and long-term effects, consisting of increased number of adult-type Leydig cells and macrophages, increased weight of the testes and sex accessory organs and advanced balano-preputial separation. In adulthood, both groups showed normal reproductive function. These results seem to indicate that the effects of hCG treatment in prepubertal rats are dependent on the type of Leydig cell stimulated, and suggest that foetal Leydig cells play a regulatory role in the early postnatal testicular development. Journal of Endocrinology (1994) 142, 527–534
30
Kristensen, Dina G., Niels E. Skakkebk, Ewa Rajpert-De Meyts, and Kristian Almstrup. "Epigenetic features of testicular germ cell tumours in relation to epigenetic characteristics of foetal germ cells." International Journal of Developmental Biology 57, no. 2-3-4 (2013): 309–17. http://dx.doi.org/10.1387/ijdb.130142ka.
31
Read, Andrew J. "Reproductive seasonality in harbour porpoises, Phocoena phocoena, from the Bay of Fundy." Canadian Journal of Zoology 68, no. 2 (February 1, 1990): 284–88. http://dx.doi.org/10.1139/z90-042.
Abstract:
I examined the reproductive tracts from 244 harbour porpoises, Phocoena phocoena, captured incidentally in commercial fishing operations in the Bay of Fundy during June to September, 1985–1988. Evidence from follicular growth and the development of corpora lutea suggests that ovulation and conception occur in late June. This interpretation is supported by subtracting the duration of gestation from estimated mean birth date, and also by seasonal changes in testicular mass. Six or 7 weeks of preimplantation pregnancy follows conception and foetuses are first detectable in early August. Gestation lasts for approximately 10.6 months and parturition occurs during mid-May. Females that fail to conceive during the breeding season must wait 12 months for another opportunity to mate. Estimates of pregnancy rate must account for the seasonal nature of reproduction. The observed pattern of reproductive seasonality may reflect seasonal variation in prey quality, and perhaps availability.
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Gustin, Sonja E., Jessica M. Stringer, Kirsten Hogg, Andrew H. Sinclair, and Patrick S. Western. "FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model." Reproduction 152, no. 5 (November 2016): 529–43. http://dx.doi.org/10.1530/rep-16-0293.
Abstract:
Testis development is dependent on the key sex-determining factors SRY and SOX9, which activate the essential ligand FGF9. Although FGF9 plays a central role in testis development, it is unable to induce testis formation on its own. However, other growth factors, including activins and TGFβs, also present testis during testis formation. In this study, we investigated the potential of FGF9 combined with activin and TGFβ to induce testis development in cultured XX gonads. Our data demonstrated differing individual and combined abilities of FGF9, activin and TGFβ to promote supporting cell proliferation, Sertoli cell development and male germ line differentiation in cultured XX gonads. FGF9 promoted proliferation of supporting cells in XX foetal gonads at rates similar to those observed in vivo during testis cord formation in XY gonads but was insufficient to initiate testis development. However, when FGF9, activin and TGFβ were combined, aspects of testicular development were induced, including the expression of Sox9, morphological reorganisation of the gonad and deposition of laminin around germ cells. Enhancing β-catenin activity diminished the testis-promoting activities of the combined growth factors. The male promoting activity of FGF9 and the combined growth factors directly or indirectly extended to the germ line, in which a mixed phenotype was observed. FGF9 and the combined growth factors promoted male germ line development, including mitotic arrest, but expression of pluripotency genes was maintained, rather than being repressed. Together, our data provide evidence that combined signalling by FGF9, activin and TGFβ can induce testicular characteristics in XX gonads.
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Nowak, Radosława, Ewa A. Grzybowska, Anna Wilczyńska, Roman Pykało, and Janusz A. Siedlecki. "Low Expression of DNA Polymerase β in Human Testicular Germ Cell Tumours: Impact on Foetal Gonocytic Origin Theory." Acta Oncologica 41, no. 2 (January 2002): 188–91. http://dx.doi.org/10.1080/028418602753669580.
34
Gbore, F. A., E. O. Ewuola, J. T. Ogunlade, K. O. Idahor, A. O. Salako, and G. N. Egbunike. "Spermatogenesis, gonadal sperm reserves and fertility of rabbits fed micro doses of fumonisin." Nigerian Journal of Animal Production 34, no. 2 (January 9, 2021): 316–22. http://dx.doi.org/10.51791/njap.v34i2.1215.
Abstract:
The effects of micro doses of dietary fumonisin, a metabolite of Fusarium verticillioides, on spermatogenesis, gonadal sperm reserves and fertility of rabbits were studied. Relative paired testis weight; sperm production rate and sperm storage potential were not adversely affected in rabbits which were exposed to varied minute levels of dietary fumonisin of about 153-161 µg/kg body weight/day over a period of 8 weeks. The toxin also failed to exert any influence (P>0.05) on seminiferous tubular diameter and volume percent of testicular elements. Male fertility as evidenced by conception rate, litter size and embryo survival and normalcy was also not affected (P>0.05). However, the frequency of occurrence of stages II and VIII of the cycle of the seminiferous epithelium were significantly (P<0.05) influenced with increased dietary fumonisin levels. The results suggest that the ingestion of Fusarium-infected feed that would result in the liberation of about 153 µg of fumonisin/kg of body weight per day for a short time may not influence spermatogenesis, fertility in the male or the normalcy of the resulting foetuses.
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Boukari, K., G. Meduri, M. Lombès, and J. Young. "CO02 - L’absence de spermatogenèse dans le testicule foetal et néonatal est associée à une faible expression du récepteur aux androgènes dans la cellule de Sertoli." Annales d'Endocrinologie 67, no. 5 (October 2006): 380. http://dx.doi.org/10.1016/s0003-4266(06)72617-8.
36
Genovese, P., ME Núñez, C. Pombo, and A. Bielli. "Undernutrition During Foetal and Post-Natal Life Affects Testicular Structure and Reduces the Number of Sertoli Cells in the Adult Rat." Reproduction in Domestic Animals 45, no. 2 (April 2010): 233–36. http://dx.doi.org/10.1111/j.1439-0531.2008.01244.x.
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Chioccarelli, Teresa, Marina Migliaccio, Antonio Suglia, Francesco Manfrevola, Veronica Porreca, Nadia Diano, Sonia Errico, Silvia Fasano, and Gilda Cobellis. "Characterization of Estrogenic Activity and Site-Specific Accumulation of Bisphenol-A in Epididymal Fat Pad: Interfering Effects on the Endocannabinoid System and Temporal Progression of Germ Cells." International Journal of Molecular Sciences 22, no. 5 (March 3, 2021): 2540. http://dx.doi.org/10.3390/ijms22052540.
Abstract:
The objective of this work has been to characterize the estrogenic activity of bisphenol-A (BPA) and the adverse effects on the endocannabinoid system (ECS) in modulating germ cell progression. Male offspring exposed to BPA during the foetal-perinatal period at doses below the no-observed-adverse-effect-level were used to investigate the exposure effects in adulthood. Results showed that BPA accumulates specifically in epididymal fat rather than in abdominal fat and targets testicular expression of 3β-hydroxysteroid dehydrogenase and cytochrome P450 aromatase, thus promoting sustained increase of estrogens and a decrease of testosterone. The exposure to BPA affects the expression levels of some ECS components, namely type-1 (CB1) and type-2 cannabinoid (CB2) receptor and monoacylglycerol-lipase (MAGL). Furthermore, it affects the temporal progression of germ cells reported to be responsive to ECS and promotes epithelial germ cell exfoliation. In particular, it increases the germ cell content (i.e., spermatogonia while reducing spermatocytes and spermatids), accelerates progression of spermatocytes and spermatids, promotes epithelial detachment of round and condensed spermatids and interferes with expression of cell–cell junction genes (i.e., zonula occcludens protein-1, vimentin and β-catenin). Altogether, our study provides evidence that early exposure to BPA produces in adulthood sustained and site-specific BPA accumulation in epididymal fat, becoming a risk factor for the reproductive endocrine pathways associated to ECS.
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Calatayud, Natalie E., Andrew J. Pask, Geoffrey Shaw, Nadine M. Richings, Sue Osborn, and Marilyn B. Renfree. "Ontogeny of the oestrogen receptors ESR1 and ESR2 during gonadal development in the tammar wallaby, Macropus eugenii." REPRODUCTION 139, no. 3 (March 2010): 599–611. http://dx.doi.org/10.1530/rep-09-0305.
Abstract:
Oestrogen has wide ranging effects in development mediated mainly via the two oestrogen receptors, α (ESR1, also known as ERα) and β (ESR2, also known as ERβ). Oestrogen is the key factor that directs the indifferent gonad to become an ovary in many non-mammalian vertebrates. Oestrogen is not required for early ovarian differentiation in mammals but can disrupt normal testicular development in eutherians. Surprisingly, exogenous oestrogen can cause sex reversal of an XY gonad in two marsupials, the North American opossum and the tammar wallaby. To understand the mechanism by which oestrogen induces sex reversal, we characterised the genes for ESR1 and ESR2 and examined their expression during gonadal differentiation in the tammar wallaby, Macropus eugenii. Both receptors were expressed in the somatic cells and germ cells of the indifferent gonad in both XX and XY foetuses throughout all stages of development, and persisted in these cells into adulthood. ERs were also present in many other tissues including kidney, pituitary and mammary gland. ER mRNA was not significantly altered by exogenous oestrogen in cultured XY gonads but the receptors translocated to the nucleus in its presence. These findings confirm that there is conserved expression of the ERs in the indifferent gonad despite the lack of available ligand during early gonadal development. The receptors can respond to exogenous estrogen at this early stage and are capable of transducing signals in the early mammalian gonad. However, the selective forces that maintained conserved ER expression in this tissue remain unknown.
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Mendoza-Villarroel, Raifish E., Mickaël Di-Luoffo, Etienne Camiré, Xavier C. Giner, Catherine Brousseau, and Jacques J. Tremblay. "The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells." Journal of Molecular Endocrinology 53, no. 1 (April 29, 2014): 43–55. http://dx.doi.org/10.1530/jme-13-0290.
Abstract:
Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues. Although COUP-TFII-deficient mice had Leydig cell dysfunction and impaired fertility, it remained unknown whether Insl3 expression was directly regulated by COUP-TFII. In this study, we observed a significant decrease in Insl3 mRNA levels in MA-10 Leydig cells depleted of COUP-TFII. Furthermore, a −1087 bp mouse Insl3 promoter was activated fourfold by COUP-TFII in MA-10 Leydig cells. Using 5′ progressive deletions, the COUP-TFII-responsive element was located between −186 and −79 bp, a region containing previously uncharacterised direct repeat 0-like (DR0-like) and DR3 elements. The recruitment and direct binding of COUP-TFII to the DR0-like element were confirmed by chromatin immunoprecipitation and DNA precipitation assay respectively. Mutation of the DR0-like element, which prevented COUP-TFII binding, significantly decreased COUP-TFII-mediated activation of the −1087 bp Insl3 reporter in CV-1 fibroblast cells but not in MA-10 Leydig cells. Finally, we found that COUP-TFII cooperates with the nuclear receptor steroidogenic factor 1 (SF1) to further enhance Insl3 promoter activity. Our results identify Insl3 as a target for COUP-TFII in Leydig cells and revealed that COUP-TFII acts through protein–protein interactions with other DNA-bound transcription factors, including SF1, to activate Insl3 transcription in these cells.
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Viramontes, F., F. Filion, and L. C. Smith. "5 NEUTRAL SEGREGATION OF DONOR CELL MITOCHONDRIA IN FETAL AND ADULT TISSUES OF SOMATIC CELL CLONES IN CATTLE." Reproduction, Fertility and Development 17, no. 2 (2005): 153. http://dx.doi.org/10.1071/rdv17n2ab5.
Abstract:
Until now, animal cloning has been extremely inefficient: only 1–2% of nuclear transfer (NT) clones survive to birth. Some of these anomalies may be related to an incompatibility between nuclear and mitochondrial genes (Cummins JM 2001 Hum. Reprod. Update 7, 217–228). Controversy exists as to the levels of donor cell mitochondrial DNA (mtDNA) inheritance in somatic clones (heteroplasmy). Whereas some researchers found very low quantities (0.1–4%) (Steinborn R et al. 2000 Nat. Genet. 25, 255–257), others found levels of heteroplasmy ranging from 6 to 40% (Takeda et al. Mol. Reprod. Dev. 64, 429–437). Since it remains unclear whether mtDNA segregation is neutral or selective, the purpose of this study was to analyze the transmission of the mtDNA from donor somatic cells in fetal and adult clones using a particular mtDNA marker (mtDNA Bos taurus with one mutation in the D-loop of 40 base pairs plus than the wild type). Fibroblasts from a fetus of 60 days were used as donor cells. The fetus was produced by artificial insemination of a Holstein (Bos taurus) heifer carrying an mtDNA mutation with semen from a Zebu (Bos indicus) bull. Oocytes derived from slaughterhouse ovaries of Holstein cows carrying wild-type mtDNA were used as recipient cells. The presence of the mutated mtDNA from the donor cell (heteroplasmy) was analyzed in a male cloned fetus of 60 days and in three adult male clones at 18 months of age. Heteroplasmy was detected in 7 tissues in the foetus: muscle, skin, stomach, testicle, thymus, tongue, and umbilical cord. Three tissues were analyzed from the adult clones: semen, skin, and white blood cells. Heteroplasmy was detected in all the tissues by nested PCR amplification of the D-loop and analyzed by ANOVA and Tukey-Kramer multiple comparison test. The mean (%) of the mutated mtDNA of the donor cell in the seven tissues of the60-day-old fetus was 1.14 ± 0.34 (SEM). There was no differences in the means of heteroplasmy (%) between the tissues of the fetus (P > 0.05). The mean level of heteroplasmy in the three adult clones analyzed (clones A, B, and C) was 1.41 ± 0.18 (SEM). Analysis of heteroplasmy between the tissues of each clone showed no differences (P > 0.05) with the exception of clone B, where semen was different (P < 0.05) from white blood cells. There were significant differences (P < 0.05) between some clones (taking together all the results of all tissues of each clone). The heteroplasmy in clone B (%) (2.59 ± 0.18 SEM) was different (P < 0.05) from that of both clone A (1.04 ± 0.18) and clone C (1.46 ± 0.18). There was no difference between the heteroplasmy (%) of clone A and that of clone C (P > 0.05). These results show that the tissues of the fetus and the adult clones were heteroplasmic at similar levels, suggesting neutral segregation of the donor cell mtDNA during development and tissue differentiation.
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Fisher, B. G., A. Thankamony, J. Mendiola, C. J. Petry, H. Frederiksen, A. M. Andersson, A. Juul, et al. "Maternal serum concentrations of bisphenol A and propyl paraben in early pregnancy are associated with male infant genital development." Human Reproduction 35, no. 4 (April 2020): 913–28. http://dx.doi.org/10.1093/humrep/deaa045.
Abstract:
Abstract STUDY QUESTION Are maternal serum phthalate metabolite, phenol and paraben concentrations measured at 10–17 weeks of gestation associated with male infant genital developmental outcomes, specifically cryptorchidism, anogenital distance (AGD), penile length and testicular descent distance, at birth and postnatally? SUMMARY ANSWER Maternal serum bisphenol A (BPA) concentration at 10–17 weeks of gestation was positively associated with congenital or postnatally acquired cryptorchidism, and n-propyl paraben (n-PrP) concentration was associated with shorter AGD from birth to 24 months of age. WHAT IS KNOWN ALREADY Male reproductive disorders are increasing in prevalence, which may reflect environmental influences on foetal testicular development. Animal studies have implicated phthalates, BPA and parabens, to which humans are ubiquitously exposed. However, epidemiological studies have generated conflicting results and have often been limited by small sample size and/or measurement of chemical exposures outside the most relevant developmental window. STUDY DESIGN, SIZE, DURATION Case–control study of cryptorchidism nested within a prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at 10–17 postmenstrual weeks of gestation from a single UK maternity unit between 2001 and 2009 and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 330 mothers of 334 male infants (30 with congenital cryptorchidism, 25 with postnatally acquired cryptorchidism and 279 unmatched controls) were included in the present analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Maternal blood was collected at enrolment, and serum levels of 16 phthalate metabolites, 9 phenols (including BPA) and 6 parabens were measured using liquid chromatography/tandem mass spectrometry. Logistic regression was used to model the association of cryptorchidism with serum chemical concentrations, adjusting for putative confounders. Additionally, offspring AGD, penile length and testicular descent distance were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between serum chemical levels and these outcomes were tested using linear mixed models. MAIN RESULTS AND THE ROLE OF CHANCE Maternal serum BPA concentration was associated with offspring all-type cryptorchidism both when considered as a continuous exposure (adjusted odds ratio per log10 μg/l: 2.90, 95% CI 1.31–6.43, P = 0.009) and as quartiles (phet = 0.002). Detection of n-PrP in maternal serum was associated with shorter AGD (by 0.242 standard deviations, 95% CI 0.051–0.433, P = 0.01) from birth to 24 months of age; this reduction was independent of body size and other putative confounders. We did not find any consistent associations with offspring outcomes for the other phenols, parabens, and phthalate metabolites measured. LIMITATIONS, REASONS FOR CAUTION We cannot discount confounding by other demographic factors or endocrine-disrupting chemicals. There may have been misclassification of chemical exposure due to use of single serum measurements. The cohort was not fully representative of pregnant women in the UK, particularly in terms of smoking prevalence and maternal ethnicity. WIDER IMPLICATIONS OF THE FINDINGS Our observational findings support experimental evidence that intrauterine exposure to BPA and n-PrP during early gestation may adversely affect male reproductive development. More evidence is required before specific public health recommendations can be made. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), Newlife the Charity for Disabled Children, the Mothercare Group Foundation, Mead Johnson Nutrition and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. Visiting Fellowship (J.M.): Regional Programme ‘Jiménez de la Espada’ for Research Mobility, Cooperation and Internationalization, Seneca Foundation—Science and Technology Agency for the Region of Murcia (No. 20136/EE/17). K.O. is supported by the Medical Research Council (UK) (Unit Programme number: MC_UU_12015/2). The authors declare no conflict of interest.
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Meachem, S. J. "002.Sertoli cell terminal differentiation: doing a 'U' turn on a one way street." Reproduction, Fertility and Development 17, no. 9 (2005): 62. http://dx.doi.org/10.1071/srb05abs002.
Abstract:
The concept of terminal differentiation of Sertoli cells has been challenged and this new information has important implications for male fertility. The mammalian Sertoli cell has two distinct functions: (i) formation of the seminiferous cords and (ii) provision of nutritional and structural support to the developing germ cells. For these to occur successfully, Sertoli cells must undergo numerous maturational changes between foetal and adult life, the main switches occur around the onset of puberty, coincident with the rise in serum gonadotrophins. These switches include the loss of proliferative activity and the formation of the blood testis barrier. Follicle stimulating hormone (FSH) plays a key role in supporting Sertoli cell proliferation in early postnatal life and thus is critical in establishing sperm output in adulthood. After puberty, the size of the Sertoli cell population is considered to be stable and unmodifiable by hormones. This accepted view has been contested as data shows that the size of the adult Sertoli cell population is modifiable by hormone suppression, and that Sertoli cells can regain proliferative activity when stimulated by FSH in the Djungarian hamster1. The molecular mechanism(s) by which Sertoli cells re-enter proliferation are not known in this model however a study demonstrated that helix-loop-inhibitor of differentiation proteins can induce terminally differentiated Sertoli cells to re-enter the cell cycle and proliferate2. Thyroid hormone and testosterone may be involved in the cessation of Sertoli cell proliferation. Gonadotrophin suppression in the adult Djungarian hamster also results in the disruption of the blood testis barrier and spatial organisation of the inter Sertoli cell tight junction proteins and as a consequence the loss of all germ cells that reside inside the blood testis barrier. FSH restores the organisation of these tight junction proteins, which is associated with the appearance of more mature germ cells. It is expected that the integrity of the blood testis barrier is also re-established. It is suggested that this demonstrated plasticity of the adult Sertoli cell may be relevant in clinical settings, particularly to some types of infertility and testicular malignancies where Sertoli cells have failed to undergo these important maturational switches. (1)Chaudhary et al. (2005) Biol. Reprod. 72, 1205. (2)Meachem et al. (2005) Biol. Reprod. 72, 1187.
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Faden, Majed, Amir H. Salehi, Jeannine Simon, Moy Fong Chen, Atilla Omeroglu, and Richard Brown. "Hyperreactio luteinalis in association with multiple foetal malformations – a consequence of supra-physiological HCG?" Case Reports in Perinatal Medicine 3, no. 1 (January 1, 2014). http://dx.doi.org/10.1515/crpm-2013-0030.
Abstract:
AbstractHyperreactio luteinalis (HL) is characterised by ovarian cystic enlargement that is associated with high levels of human chorionic gonadotropin (hCG). Here the possible effects of abnormally high hCG levels on foetal development are demonstrated.We report a 28-year-old patient who was referred for evaluation of bilateral maternal ovarian enlargement in the second trimester. Abnormally elevated hCG (887,514 IU/L) was found with ultrasound examination identifying various foetal malformations. The karyotype was normal. Spontaneous abortion occurred at 20 weeks. Autopsy showed testicular hypertrophy with marked Leydig cell hyperplasia. The HL resolved with normalisation of the hCG levels following delivery.HL is a rare finding in normal pregnancies; the potential effects of abnormally elevated hCG on the foetus are discussed.
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Ciaputa, Rafał, Marcin Nowak, Stanisław Dzimira, Eleonora Brambilla, Małgorzata Kandefer-Gola, Alicja Tomaszek, Aneta Popiel-Kopaczyk, Piotr Dzięgiel, and Valeria Grieco. "Study on the expression of testin in the testes of dogs." Journal of Veterinary Research, October 31, 2023. http://dx.doi.org/10.2478/jvetres-2023-0055.
Abstract:
Abstract Introduction Testin is a protein involved in cell mobility, adhesion and colony formation. In rats, testin presence has been reported in the testes, and its possible role in spermatogenesis has been suggested. Studies in humans also suggest a possible role of testin as a cancer suppressor protein. In the dog, which represents both an important pet species and a good animal model for studying biological and pathological testicular processes, the presence of testin has never been reported. Material and Methods In the present study, the expression of testin in foetal, prepubertal, adult and aged canine testes was investigated. Testes from 5 adult and 3 aged dogs, from 2 one-month-old puppies and from 2 foetuses miscarried at the end of pregnancy were immunohistochemically examined with a commercial antibody against testin. Results Testin was intensely expressed in Sertoli cells in every testis examined. Spermatids were also positive for testin in mature dogs and in the testicular areas of the aged ones which were not atrophic. Weak expression of testin was also detected in all testes examined. Conclusion The present study, the first demonstrating the presence of testin in canine testes, provides the basis for further dog–human comparative research and for studies on the role of this protein in canine physiology, reproduction and testicular pathologies.
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Utama, Maulidya Rosa Putri, Dwi Ariani Yulihastuti, and Sang Ketut Sudirga. "KUALITAS SPERMATOZOA DAN BERAT ORGAN REPRODUKSI MENCIT (Mus musculus) SETELAH PEMBERIAN EKSTRAK BIJI KLABET (Trigonella foenum-graecum L.)." SIMBIOSIS, April 2, 2024, 32–41. http://dx.doi.org/10.24843/jsimbiosis.2024.v12.i01.p04.
Abstract:
Indonesia is one of the countries known to have the highest biodiversity in the world. There are 18 types of herbs that have the potential as antifertility in men, one of which is the klabet plant or fenugreek. Klabet is believed by ordinary people to have properties to increase the production and quality of spermatozoa. According to previous research klabet has toxic effects that can inhibit fertility due to the content of phytochemicals in it. This study aims to determine the effect of fenugreek seed extract on the quality of spermatozoa and the weight of the reproductive organs of mice. The mice used were 20 male mice weighing about 25-30 grams divided into 4 treatments namely control (P0), 56 mg/kgBB (P1), 112 mg/kgBB (P2), 168 mg/kgBB (P3) with 5 repetitions. Giving treatment for 24 days. The method used is RAL (Complete Randomized Design) and the resulting data is analyzed using ANOVA. The parameters studied were testicular weight, epididymis weight, motility, morphology and number of male mouse spermatozoa. The results showed that there was a real difference (p≤0.05) between the control and treatment of the klabet seed extract on the quality of spermatozoa and the weight of the testicle but not significantly different (p≥0.05) to the weight of the epididyimis. Concentration of mice spermatozoa decreased by 10.60%, progressive spermatozoa motility decreased by 55.61%, nomal morphology decreased by 57.92%, while testicular weight decreased by 38.46%. The most effective dose of fenugreek seed extract used as an antifertility agent was a dose of 168 mg/kgBW (P3).
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Al-Sharkawi, Mostafa, Verónica Calonga-Solís, Franz F. Dressler, Hauke Busch, Olaf Hiort, and Ralf Werner. "Persistence of foetal testicular features in patients with defective androgen signalling." European Journal of Endocrinology, January 31, 2023. http://dx.doi.org/10.1093/ejendo/lvad007.
Abstract:
Abstract Objective Congenital defects of androgen synthesis or action in 46, XY individuals can result in impaired virilisation, despite the apparent testicular development. In a recent case report of a young adult with complete androgen insensitivity syndrome (CAIS), tumorous gonadal tissue was shown to express HSD17B3 in Sertoli cells (SCs) and not in Leydig cells (LCs). This expression pattern differs from the typical adult human testis and resembles foetal mouse testis, suggesting an underlying testicular development and function defect. Here, we investigate the effect of altered androgen signalling in gonads from five 46, XY individuals with defects in androgen synthesis or action. Methods Gonadal tissue sections from four patients with CAIS, one with CYP17A1 deficiency, and one control were immunostained for LC developmental and steroidogenic markers. The expression of some of these markers during development was investigated by reanalysing previously published single-cell RNA sequencing (scRNA-seq) data from normal human testicular tissues. Results All gonadal tissues from the patients show exclusive expression of HSD17B3 in SCs and expression of the foetal/immature LC marker DLK1 in a subset of LCs, suggesting an androgen-dependent differentiation defect of adult SCs and LCs. Furthermore, reanalysis of scRNA-seq data reveals an expression of HSD17B3 in foetal and neonatal SCs that is downregulated in adult SCs. Conclusions Androgen signalling may affect the differentiation of adult but possibly not foetal SCs or LCs and may induce a shift of testosterone production from the tubular compartment in the foetal phase to the interstitial compartment in the adult phase.
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Tharmalingam, Melissa D., Gabriele Matilionyte, William H. B. Wallace, Jan-Bernd Stukenborg, Kirsi Jahnukainen, Elizabeth Oliver, Anne Goriely, et al. "Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer." BMC Medicine 18, no. 1 (December 2020). http://dx.doi.org/10.1186/s12916-020-01844-y.
Abstract:
Abstract Background Clinical studies indicate chemotherapy agents used in childhood cancer treatment regimens may impact future fertility. However, effects of individual agents on prepubertal human testis, necessary to identify later risk, have not been determined. The study aimed to investigate the impact of cisplatin, commonly used in childhood cancer, on immature (foetal and prepubertal) human testicular tissues. Comparison was made with carboplatin, which is used as an alternative to cisplatin in order to reduce toxicity in healthy tissues. Methods We developed an organotypic culture system combined with xenografting to determine the effect of clinically-relevant exposure to platinum-based chemotherapeutics on human testis. Human foetal and prepubertal testicular tissues were cultured and exposed to cisplatin, carboplatin or vehicle for 24 h, followed by 24–240 h in culture or long-term xenografting. Survival, proliferation and apoptosis of prepubertal germ stem cell populations (gonocytes and spermatogonia), critical for sperm production in adulthood, were quantified. Results Cisplatin exposure resulted in a significant reduction in the total number of germ cells (− 44%, p < 0.0001) in human foetal testis, which involved an initial loss of gonocytes followed by a significant reduction in spermatogonia. This coincided with a reduction (− 70%, p < 0.05) in germ cell proliferation. Cisplatin exposure resulted in similar effects on total germ cell number (including spermatogonial stem cells) in prepubertal human testicular tissues, demonstrating direct relevance to childhood cancer patients. Xenografting of cisplatin-exposed human foetal testicular tissue demonstrated that germ cell loss (− 42%, p < 0.01) persisted at 12 weeks. Comparison between exposures to human-relevant concentrations of cisplatin and carboplatin revealed a very similar degree of germ cell loss at 240 h post-exposure. Conclusions This is the first demonstration of direct effects of chemotherapy exposure on germ cell populations in human foetal and prepubertal testis, demonstrating platinum-induced loss of all germ cell populations, and similar effects of cisplatin or carboplatin. Furthermore, these experimental approaches can be used to determine the effects of established and novel cancer therapies on the developing testis that will inform fertility counselling and development of strategies to preserve fertility in children with cancer.
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Bensalah-Hammoutene, Meriem, and Guy Van Vliet. "Why should orchidopexy be performed in congenital hypogonadotropic hypogonadism, and when?" Hormone Research in Paediatrics, April 4, 2023. http://dx.doi.org/10.1159/000530520.
Abstract:
Background: In otherwise normal boys with undescended testes, early orchidopexy is recommended to preserve fertility, to decrease the risk of testicular cancer and to facilitate its detection. Indeed, compared to the general population, the risk of testicular cancer is increased two to eight-fold in isolated cryptorchidism and usually occurs before the age of 40 years. By contrast, when cryptorchidism is associated with congenital hypogonadotropic hypogonadism, the risk of testicular cancer is unknown. Objective: To determine the characteristics of testicular cancer when cryptorchidism is associated with congenital hypogonadotropic hypogonadism. Methods: PUBMED research without date limits including the following key words: hypogonadism, hypogonadotrophic hypogonadism, testicular cancer, testicular germ cell tumors, undescended testis, Kallmann syndrome, FSH, AFP (α foeto protein), βHCG. Results: Only three patients with testicular cancer and congenital hypogonadotropic hypogonadism have been published in the past four decades and cancer was diagnosed at 18.6, 50 and 64 years. Conclusion: Gonadotropin deficiency may protect against testicular cancer and orchidopexy in this context may be deferred.
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Naser, Abdullah An, Takehiro Miyazaki, Jun Wang, Shuji Takabayashi, Theeranukul Pachoensuk, and Toshinobu Tokumoto. "MC4R mutant mice develop ovarian teratomas." Scientific Reports 11, no. 1 (February 10, 2021). http://dx.doi.org/10.1038/s41598-021-83001-w.
Abstract:
AbstractTeratomas in mice, composed of different tissue types, are derived from primordial germ cells (PGCs) in the foetal gonads. The strongest candidate gene in the testicular teratoma locus (Ter) responsible for testicular teratoma formation was identified as mutation in Dnd1, Dnd1R178*. However, the phenotype of mice with a mutated Dnd1 gene was germ cell loss. This suggests that other genes are involved in teratoma formation. Testicular teratomas can also be induced experimentally (experimentally testicular teratomas: ETTs) in 129/Sv mice by transplanting E12.5 foetal testes into adult testes. Previously, we mapped the ett1 locus, which is the locus responsible for ETT formation on chromosome 18. By exome sequence analysis of the 129 and LTXBJ (LT) strains, we identified a missense mutation in the melanocortin 4 receptor (MC4R) gene among 8 genes in the ett1 region. The missense mutation causes a substitution of glycine 25 by serine. Thus, this gene is a candidate for ETT formation. We established the LT-ett1 congenic strain, which introduced the locus responsible for ETT formation genetically into the genomes of a testicular teratoma non-susceptible strain. In this study, we crossed LT-ett1 and a previously established LT-Ter strain to establish the double congenic strain LT-Ter-ett1. Also, we established a strain with a point mutation in the MC4R gene of the LT strain by genome editing, LT-MC4RG25S. Furthermore, double genetically modified strain LT-Ter-MC4RG25S was established to address the relation between Ter and MC4R. Surprisingly, highly developed ovarian teratomas (OTs), instead of testicular teratomas, appeared not only in the LT-Ter-MC4RG25S and LT-MC4RG25S strains but also in the LT-ett1 and LT-Ter-ett1 strains. The incidence of OT formation was high in double genetically modified strains. The results demonstrated that MC4R is one of the genes responsible for OT formation. It was suggested that the effect of the missense mutation in MC4R on teratoma formation was promoted by abnormal germ cell formation by the mutation in DND1.
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"Role of mammalian Y chromosome in sex determination." Philosophical Transactions of the Royal Society of London. B, Biological Sciences 322, no. 1208 (December 1988): 63–72. http://dx.doi.org/10.1098/rstb.1988.0114.
Abstract:
It has long been assumed that the mammalian Y chromosome either encodes, or controls the production of, a diffusible testis-determining molecule, exposure of the embryonic gonad to this molecule being all that is required to divert it along the testicular pathway. My recent finding that Sertoli cells in XX ↔ XY chimeric mouse testes are exclusively XY has led me to propose a new model in which the Y acts cell-autonomously to bring about Sertoli-cell differentiation. I have suggested that all other aspects of foetal testicular development are triggered by the Sertoli cells without further Y-chromosome involvement. This model thus equates mammalian sex determination with Sertoli-cell determination. Examples of natural and experimentally induced sex reversal are discussed in the context of this model.