Sexual Development最新文献

Introduction: Gonadal development and reproduction are under the control of the endocrine system, which acts along the brain-pituitary-gonad (BPG) axis. Besides well-known regulators of the BPG axis, such as the gonadotropin-releasing hormone, follicle-stimulating hormone, and luteinizing hormone, the anti-Müllerian hormone (Amh) came into the focus of research on the BPG axis. Amh is expressed differently in the gonads of dominant and subordinate Nile tilapia (Oreochromis niloticus) males and could be involved in the regulation of the differently developed gonads. In addition, the regulatory networks and the control of gene expression depend on microRNAs (miRNAs), an often not considered epigenetic mechanism in hormonal research.

Methods: We used a long-term, stable social hierarchy of Nile tilapia males as an experimental system to identify differentially expressed (DE) miRNAs in the testes of dominant and subordinate animals. A Dual-Luciferase Reporter Assay and in vitro analysis of amh expression in primary testis cells were used to demonstrate predicted interactions.

Results: We identified 23 DE miRNAs in the testes of dominant and subordinate males and predicted the targets in the pools of DE genes. Using these data, we placed the identified GO terms and KEGG pathways in the context of differently developed gonads under social control. The most DE miRNA, oni-miR-499, is upregulated in the testes of dominants and regulates amh expression.

Conclusion: We conclude that oni-miR-499 affects testis development via amh expression in Nile tilapia. Many miRNAs and biological processes identified in our study could be conserved mechanisms of testis development.

Introduction: Monorchidism is a rarely described condition in the horse and is not to be confused with cryptorchidism. The diagnosis is challenging and confirmed by surgery and histology in combination with hormonal assays. This report describes, to the best of the author's knowledge, the first case of monorchidism and abdominal cryptorchidism of the developed testicle in a horse.

Methods: An Irish Cob underwent laparoscopic castration for removal of bilateral cryptorchid testicles. At surgery, the horse was diagnosed as a monorchid with the testicle retained intra-abdominally. Histopathological, hormonal, molecular and cytogenetic analysis was performed. This included measuring testosterone and anti-Mullerian hormone (AMH) in serum blood, isolating genomic DNA from EDTA- and heparin-treated blood, PCR amplification of the SRY gene, metaphase chromosome preparation, and DAPI banding before metaphase analysis with fluorescence in situ hybridisation (FISH) analysis.

Results: The horse was positive for the SRY gene and had a mosaic 63,X/64,XY karyotype with the aneuploid cells being present in only 2% of metaphases. FISH showed that the missing sex chromosome of the aneuploid cell line was the Y chromosome embedded in micronuclei. An abnormal high rate of micronuclei (6.6%) was observed indicating genotoxic events and/or genome instability. Hormonal assay results confirmed that AMH was not significantly increased, suggesting that no further testicular tissue was present. Histopathology was consistent with testicular tissue displaying a Sertoli cell-only pattern with bipolar ductal structures.

Conclusion: The exact causes of monorchidism and cryptorchidism are unclear, but the elevated rate of micronuclei is clear evidence for genome instability which might have been involved in the failure of normal testicular development and descent. Future cases could further clarify the disease mechanism based on this report.

Background: 46,XX testicular/ovotesticular disorders of sexual development (T/OT DSD) are infrequent congenital conditions characterized by the presence of functional ovarian and testicular or only testicular parenchyma.

Objective: The aim of the study was to retrospectively describe clinical, hormonal, and genetic characteristics of 29 patients with 46,XX T/OT DSD (2000-2023), focusing on gonadal function, hormonal production, and long-term follow-up.

Results: Most patients (n = 25, 86.2%) presented with atypical genitalia that suggested DSD. Median age at first assessment was 0.38 years. Sex assignment was male in 21 patients without reports of discordant gender identity. Sex assignment was recommended before expert evaluation and without adequate studies in 64% of those patients with atypical genitalia (16/25). The median external masculinization score was 8 (range 4-12). During mini-puberty, LH, testosterone, AMH, and the LH/FSH ratio were above the female reference range and no different from the normal male reference range. Spontaneous puberty was observed in one female and 10 male-assigned subjects. Among the latter, pubertal virilization occurred with signs of hypergonadotropic hypogonadism and gynecomastia. Molecular studies identified the underlying mechanism in 7 patients: SRY gene was identified in two, WT1 gene variations were detected in three others, and 2 syndromic patients harbored complex chromosomal rearrangements.

Conclusion: Our findings underscore the clinical and biochemical variability in 46,XX T/OT DSD. Expert evaluation and accurate diagnostic work-up are essential prior to sex assignment and to prevent misdiagnosis and inappropriate treatments. Mini-puberty was characterized by a masculinized pattern of gonadotropin secretion. The potential for functional male pubertal development should be taken into account when making sex assignment decisions.

Introduction: The Dmrt1 gene is essential for sex determination and gonadal development across vertebrates. Despite its established role in model species, its functional dynamics and seasonal regulatory patterns remain uncharacterized in Gekko japonicus, a key species for understanding reptilian reproductive strategies. This study thus aimed to (1) elucidate its structural characteristics, (2) analyze seasonal expression profiles and sexual dimorphism of Dmrt1, and (3) define its physiological roles in reproductive cyclicity.

Methods: Total RNA was extracted from adult G. japonicus testes, and the full-length Dmrt1 transcript was obtained through 3' and 5' RACE. Bioinformatics predicted its properties, and phylogenetic analysis was conducted using PhyloSuite v1.2.3. RT-qPCR evaluated gjDmrt1 expression in male and female tissues and gonads.

Results: The gjDmrt1-encoded protein is a hydrophilic nuclear protein with a conserved 54-amino acid DM domain, exhibiting high conservation among vertebrates. RT-qPCR shows significant differential expression in male tissues, sex dimorphism favoring males, and expression peaks in April with notable periodic fluctuations.

Conclusion: This study offers critical insights into the characterization of the Dmrt1 gene in G. japonicus. The findings underscore its significant role in seasonal reproductive regulation and provide essential information for further investigation into the interactions between Dmrt1 and other candidate genes associated with gonad differentiation, as well as its regulatory mechanisms across varying environmental conditions.

Introduction: Although maternal microchimerism has been implicated in various disorders in children, its association with the risk of 46,XY disorders of sex development remains unknown.

Methods: We studied 22 boys with hypospadias using highly sensitive quantitative PCR assays. In seven cases with additional anomalies, microarray-based comparative genomic hybridization and whole-exome sequencing confirmed the lack of apparent pathogenic variants.

Results: Maternal microchimeric cells were detected in 2 patients (1.9 and 32.0 cells per 106 total cells). The results were comparable to our reference data.

Conclusion: This study argues against the significant role of maternal microchimerism in the risk of hypospadias.

Introduction: Transgender identity is a complex and multifactorial condition shaped by the effects of environmental and cultural factors as well as its biological basis. Genes involved in neurodevelopment and neuroplasticity may contribute to brain sexual differentiation, and rare variants in these genes could play a role in gender diversity. This study aimed to enhance explanations for the genetic component of transgender identity.

Methods: After the filtering process applied to the WES analysis data obtained from eight transgender men (TM), the gene list was generated. Previously reported genes were scanned in the gene list with a detailed literature review and data mining. Functional enrichment, protein classification, pathway, and genetic interaction network analysis were performed to determine the salient genes.

Results: A total of 30 variants were detected in 18 genes reported in the literature. The rs879121178 (GOLGA8J) variant, previously reported in 1 TW (transgender woman) and 1 TM, and the rs548940626 (PCDHA8) variant, previously reported in 1 TW, were present in two different individuals (individuals 5 and 6, respectively). In the functional enrichment analysis, the highest enrichment score in biological processes was detected in the cluster related to cell adhesion (enrichment score: 12.91) and the most enriched term was "homophilic cell adhesion via plasma membrane adhesion molecules" with 54 genes (p: 3.1E-11).

Conclusions: Our study shows that rare variants in cell adhesion genes, previously reported in TW, are also prominent in TM. These findings may help guide further investigations into genes that could be relevant to neurodevelopmental pathways, including those involved in brain sexual differentiation.

Introduction: SEMA3E is a secreted class 3 semaphorin that, in mice, plays roles in neuronal guidance, cardiovascular morphogenesis, angiogenesis, and vascular homeostasis. Adult male mice lacking SEMA3E exhibit reduced testicular size compared to wild-type littermates, indicating a potential role in reproductive function. In humans, heterozygous missense variants in SEMA3E were initially reported to be associated with CHARGE syndrome and hypogonadotropic hypogonadism with anosmia. However, these associations have since been questioned, and the contribution of SEMA3E variants to human disease is unclear.

Methods: We describe the results of exome sequencing of a 46,XY boy with unexplained bilateral testicular regression syndrome and optic nerve atrophy.

Results: Exome sequencing indicates that he carries a heterozygous frameshift variant (c.942del, p.Leu314PheTer11) in the SEMA3E gene. The variant is located within the functional SEMA domain of the protein and is predicted to trigger nonsense-mediated mRNA decay. This is the second reported loss-of-function (LoF) variant in the highly conserved SEMA3E gene. A previously described LoF variant was identified in a child presenting with severe intellectual disability and cognitive regression.

Conclusion: LoF SEMA3E variants may be associated with a broad and variable spectrum of clinical phenotypes.

Introduction: The MAPK genes are critical for gonadal differentiation in eutherian mammals, but their role in marsupial mammals is unknown. Characterisation and phylogenetic analyses of the tammar wallaby MAPK genes show these genes are highly conserved with their orthologues in mammalian and non-mammalian species.

Methods: We cultured sexually indifferent tammar gonads in the presence of p38α and -β MAPK inhibitor, SB202190.

Results: SB202190 downregulated SOX9 and AMH levels in XY-treated gonads when compared to controls, similar to the effects of oestrogen on the MAPK pathway in males. In contrast, XX gonads treated with the SB202190 inhibitor showed no change in mRNA expression between the control and treated gonads for any of the markers tested.

Conclusions: This study confirms that components of the MAPK pathway drive testis differentiation via the key downstream genes SOX9 and AMH in marsupials as is observed in eutherian mammals.

Background: Sex chromosomes evolve from an autosomal pair after the acquisition of a sex-determining gene. The primary sex chromosomes are homomorphic in both sexes and often undergo heteromorphism in either sex (XY in males or ZW in females) in association with chromosome rearrangements such as inversion, which creates a non-recombining region, called a stratum. Then, multiple strata may form by sequential inversions and extend the non-recombining region, where gene divergence accelerates, and degeneration of the Y or W chromosome progressively occurs.

Summary: In contrast to the conventional theory, we propose a shortcut in heteromorphic sex chromosome evolution, where an autosomal pair directly evolves into a heteromorphic sex chromosome pair. We illustrate this with two frog cases where Y chromosome or autosome, which is morphologically inverted, was introgressed from another species through interspecific hybridization, instantly forming a new heteromorphic sex chromosome pair. This event resulted in a distinct non-recombining region immediately after hybridization.

Key messages: The introduction of an inverted chromosome from a different species may be associated with benefits in morphology, breeding behavior, hybrid viability, sex determination, and recovery of the sex ratio of the hybrids. We discuss the molecular mechanisms driving preferential mutations in the introduced, inverted chromosome through interspecific hybridization.

Introduction: Explicit outcomes routinely measured across the life span following hypospadias surgery, defined by a core outcome set (COS), will harmonize and overcome reporting heterogeneity.

Methods: Age-specific outcomes identified in a literature review were presented in a three-round Delphi survey. Participants (professionals, parents, and patients) were encouraged to suggest outcomes in the first Delphi round. In subsequent rounds, participants were asked to choose and rank up to five preferred outcomes for each age. To be deemed core, an outcome needed over 70% of votes in a round.

Results: Professionals were mainly paediatric urologists (rounds 1, 2, 3: n = 57 [77%], 39 [78%], 35 [81%]). The response rates from parents/patients (rounds 1, 2, 3: n = 17, 5, 3) were low. In young boys (<6 years, 10-11 years), four core outcomes were identical (voiding, fistula, re-operation, and urethral stricture). Core outcomes in boys aged 11-16 years (cosmesis, curvature, voiding, stricture, and psychosocial status) and boys >16 years (cosmesis, curvature, erection, voiding, and psychosexual development) varied more.

Conclusion: Outcomes to include in a COS were consistent in younger boys. A larger variety was observed in older boys and reflects less clarity on relevant outcomes.