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Cell Communication and Signaling : CCS Jun 2024Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the...
Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.
Topics: Humans; Male; Wnt Signaling Pathway; Testis; Female; Sex Differentiation; Fetus; Cell Differentiation; Cell Proliferation; beta Catenin; Leydig Cells; Ovary
PubMed: 38879537
DOI: 10.1186/s12964-024-01704-9 -
Scientific Reports Jun 2024Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2... (Randomized Controlled Trial)
Randomized Controlled Trial
Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2 is encoded by SLC5A2 (Solute Carrier Family 5 Member 2), which is highly expressed in renal cortex, but also in the testes where glucose uptake may be essential for spermatogenesis and androgen synthesis. We postulated that in healthy males, SGLT2 inhibitor therapy may affect gonadal function. We examined the impact on gonadal and steroid hormones in a post-hoc analysis of a double-blind, randomized, placebo-controlled research including 26 healthy males who were given either placebo or empagliflozin 10 mg once daily for four weeks. After one month of empagliflozin, there were no discernible changes in androgen, pituitary gonadotropin hormones, or inhibin B. Regardless of BMI category, the administration of empagliflozin, a highly selective SGLT2 inhibitor, did not alter serum androgen levels in men without diabetes. While SGLT2 is present in the testes, its inhibition does not seem to affect testosterone production in Leydig cells nor inhibin B secretion by the Sertoli cells.
Topics: Male; Humans; Benzhydryl Compounds; Glucosides; Adult; Sodium-Glucose Transporter 2 Inhibitors; Double-Blind Method; Testis; Testosterone; Inhibins; Middle Aged; Sodium-Glucose Transporter 2; Androgens; Leydig Cells; Sertoli Cells
PubMed: 38877312
DOI: 10.1038/s41598-024-64684-3 -
Neuropeptides Jun 2024Chronic stress caused by prolonged emotional pressure can lead to various physiological issues, including reproductive dysfunction. Although reproductive problems can...
Chronic stress caused by prolonged emotional pressure can lead to various physiological issues, including reproductive dysfunction. Although reproductive problems can also induce chronic stress, the impact of chronic stress-induced reproductive dysfunction remains contentious. This study investigates the effects of chronic unpredictable stress (CUS) on reproductive neuropeptides, sperm quality, and testicular morphology. Sixteen twelve-week-old Sprague Dawley rats were divided into two groups: a non-stress control group and a CUS-induced group. The CUS regimen involved various stressors over 28 days, with both groups undergoing behavioural assessments through sucrose-preference and forced-swim tests. Hypothalamic gene expression levels of CRH, PNX, GPR173, kisspeptin, GnRH, GnIH, and spexin neuropeptides were measured via qPCR, while plasma cortisol, luteinizing hormone (LH), and testosterone concentrations were quantified using ELISA. Seminal fluid and testis samples were collected for sperm analysis and histopathological evaluation, respectively. Results showed altered behaviours in CUS-induced rats, reflecting stress impacts. Hypothalamic corticotropin-releasing hormone (CRH) expression and plasma cortisol levels were significantly higher in CUS-induced rats compared to controls (p < 0.05). Conversely, phoenixin (PNX) expression decreased in the CUS group (p < 0.05), while kisspeptin, spexin, and gonadotropin-inhibitory hormone (GnIH) levels showed no significant differences between groups. Despite a significant increase in GnRH expression (p < 0.05), plasma LH and testosterone concentrations were significantly lower (p < 0.05) in CUS-induced rats. Histopathological analysis revealed abnormal testis morphology in CUS-induced rats, including disrupted architecture, visible interstitial spaces between seminiferous tubules, and absence of spermatogenesis. In conclusion, CUS affects reproductive function by modulating PNX and GnRH expression, influencing cortisol levels, and subsequently reducing plasma LH and testosterone concentrations. This study highlights the complex interplay between chronic stress and reproductive health, emphasizing the significant impact of stress on reproductive functions.
PubMed: 38870753
DOI: 10.1016/j.npep.2024.102447 -
Ecotoxicology and Environmental Safety Jul 2024Polycyclic aromatic hydrocarbons (PAHs) are a large group of organic compounds which are comprised of two or more fused benzene rings. As a typical environmental... (Review)
Review
Polycyclic aromatic hydrocarbons (PAHs) are a large group of organic compounds which are comprised of two or more fused benzene rings. As a typical environmental pollutant, PAHs are widely distributed in water, soil, atmosphere and food. Despite extensive researches on the mechanisms of health damage caused by PAHs, especially their carcinogenic and mutagenic toxicity, there is still a lack of comprehensive summarization and synthesis regarding the mechanisms of PAHs on the gut-testis axis, which represents an intricate interplay between the gastrointestinal and reproductive systems. Thus, this review primarily focuses on the potential forms of interaction between PAHs and the gut microbiota and summarizes their adverse outcomes that may lead to gut microbiota dysbiosis, then compiles the possible mechanistic pathways on dysbiosis of the gut microbiota impairing the male reproductive function, in order to provide valuable insights for future research and guide further exploration into the intricate mechanisms underlying the impact of gut microbiota dysbiosis caused by PAHs on male reproductive function.
Topics: Polycyclic Aromatic Hydrocarbons; Male; Gastrointestinal Microbiome; Testis; Humans; Animals; Environmental Pollutants; Dysbiosis; Reproduction; Gastrointestinal Tract
PubMed: 38870734
DOI: 10.1016/j.ecoenv.2024.116539 -
Poultry Science May 2024Generation of transgenic birds can be achieved by temporal suppression of endogenous spermatogenesis in males prior to primordial germ cell implantation. One of many...
Generation of transgenic birds can be achieved by temporal suppression of endogenous spermatogenesis in males prior to primordial germ cell implantation. One of many established methods to induce male sterility is the intraperitoneal injection of busulfan, an alkylating agent. Nevertheless, the use of busulfan injections, which may also affect hematopoietic stem cells, carries the risk of potential lethality in animals. Given their safety and non-toxic nature, it has been demonstrated that intratesticular busulfan injections in mammals are less effective than intraperitoneal injections. This study aimed to compare, for the first time, the sterility and toxicity effects of intraperitoneal vs. intratesticular busulfan injections in quail and chickens. Our experimental design involved a previously established single intraperitoneal busulfan injection of 40 mg/kg of body weight (BW). In quail, busulfan was then administered intratesticularly at 3 different concentrations (6, 12, and 20 mg/kg BW), while in chickens, the working concentration was 20 mg/kg BW. We found that a single intraperitoneal busulfan injection of 40 mg/kg of BW resulted in 100% mortality in the treated roosters. In quails, however, this concentration only caused a temporary suppression of fertility for a 15-d period. Moreover, we found that a higher dose of intratesticular injection of busulfan is required to suppress spermatogenesis in quail (20 mg/kg BW) compared to mammals (4 mg/kg BW). Following these findings, we further confirmed that intratesticular injection of 20 mg/kg BW busulfan into roosters did not affect their overall viability. However, it induced a temporary state of male sterility, consistent with the effects observed with intraperitoneal injections. Hence, our data demonstrate that quail and chicken respond differently to busulfan administration. Furthermore, the present study provides evidence that direct injection into the rooster testes causes less physiological stress than intraperitoneal injection.
PubMed: 38870613
DOI: 10.1016/j.psj.2024.103890 -
Scientific Reports Jun 2024CRISPR-Cas9 technology has facilitated development of strategies that can potentially provide more humane and effective methods to control invasive vertebrate species,...
CRISPR-Cas9 technology has facilitated development of strategies that can potentially provide more humane and effective methods to control invasive vertebrate species, such as mice. One promising strategy is X chromosome shredding which aims to bias offspring towards males, resulting in a gradual and unsustainable decline of females. This method has been explored in insects with encouraging results. Here, we investigated this strategy in Mus musculus by targeting repeat DNA sequences on the X chromosome with the aim of inducing sufficient DNA damage to specifically eliminate X chromosome-bearing sperm during gametogenesis. We tested three different guide RNAs (gRNAs) targeting different repeats on the X chromosome, together with three male germline-specific promoters for inducing Cas9 expression at different stages of spermatogenesis. A modest bias towards mature Y-bearing sperm was detected in some transgenic males, although this did not translate into significant male-biasing of offspring. Instead, cleavage of the X chromosome during meiosis typically resulted in a spermatogenic block, manifest as small testes volume, empty tubules, low sperm concentration, and sub/infertility. Our study highlights the importance of controlling the timing of CRISPR-Cas9 activity during mammalian spermatogenesis and the sensitivity of spermatocytes to X chromosome disruption.
Topics: Animals; Male; Mice; CRISPR-Cas Systems; Spermatogenesis; X Chromosome; Female; RNA, Guide, CRISPR-Cas Systems; Spermatozoa; Mice, Transgenic; Meiosis
PubMed: 38866815
DOI: 10.1038/s41598-024-63706-4 -
Arquivos Brasileiros de Cardiologia 2024
Topics: Humans; Exercise Test; Oxygen Consumption; Pulmonary Ventilation
PubMed: 38865567
DOI: 10.36660/abc.20240184 -
PloS One 2024Cancer is a consequence of stochastic (mutations, genetic, and epigenetic instabilities) and deterministic (evolutionary bottlenecks) events. Stochastic events are less...
Cancer is a consequence of stochastic (mutations, genetic, and epigenetic instabilities) and deterministic (evolutionary bottlenecks) events. Stochastic events are less amenable to prediction, whereas deterministic events yield more predictable results. The relative contribution of these opposing forces determines cancer predictability, which affects the accuracy of our prognostic predictions and is critical for treatment planning. In this study, we attempted to quantify predictability. The predictability index (PI) was defined as the median overall-survival at any time point divided by the standard error at that time. Using data obtained from the SEER program, we found striking differences in the PI of different tumors. Highly predictable tumors were malignancies of the breast, thyroid, prostate, and testis (5-year PI of 3516, 1920, 1919, and 1805, respectively). Less predictable tumors were colorectal, melanoma, and bladder (5-year PI of 1264, 1197, and 760, respectively). Least predictable were pancreatic cancer and chronic myelogenous leukemia (5-year PI of 129, and 42). PI decreased during follow-up in all examined tumors and showed sex differences in some cases. Thyroid cancer was significantly more predictable in women (5-year PI of 2579 vs. 748, p = 0.00017) and bladder cancer more predictable in men (5-year PI of 723 vs. 385, p = 0.012), Predictability is a potentially new distinguishing feature of malignancy. This study sheds light on prognostic accuracy and provides insight into the relative roles of stochastic and deterministic forces during carcinogenesis.
Topics: Humans; Male; Neoplasms; Female; Prognosis; SEER Program; Middle Aged
PubMed: 38865416
DOI: 10.1371/journal.pone.0305181 -
Urology Journal Jun 2024Chromosome 7 open reading frame 61 (C7orf 61) was a testis-specific gene, and may be involved in the process of spermatogenesis. This study was aimed to investigate the...
PURPOSE
Chromosome 7 open reading frame 61 (C7orf 61) was a testis-specific gene, and may be involved in the process of spermatogenesis. This study was aimed to investigate the expression of C7orf61 in the testis and determine its role in spermatogenesis. Materials and Medhods: Reverse transcription-quantitative polymerase chain reaction, Western blot and immunofluorescence were performed to evaluate the expression characteristics of C7orf61 in mice and humans. In vitro fertilization assay was used to determine the role of the C7ORF61 protein in sperm-egg fusion.
RESULTS
The results demonstrated that C7orf61 was a testis-specific gene; the C7ofr61 mRNA expression level sharply increased in the fourth postnatal week and gradually increased until the adult stage. The C7ORF61 protein was located throughout the subacrosomal area and close to the nucleus in both mouse and human sperm. The incubation with the C7ORF61 antibody significantly decreased the fertilization rate of mouse eggs.
CONCLUSION
The present findings suggested that the C7ORF61 protein might be involved in sperm-egg fusion, and could serve as a useful target for contraceptives. However, further research is still needed to know the detailed molecular mechanism of its role.
PubMed: 38863317
DOI: 10.22037/uj.v21i.8073 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Jun 2024Over 5% of the global population (430 million people) require rehabilitation for hearing loss. Individuals with hearing impairments face significant challenges in...
BACKGROUND
Over 5% of the global population (430 million people) require rehabilitation for hearing loss. Individuals with hearing impairments face significant challenges in business, daily life, and social participation. Hearing loss (HL) and other permanent physical and sensory disabilities escalate dramatically in cases with brain damage and temporal bone trauma associated with head injuries. This study aims to identify the significant risk factors for hearing loss following head trauma, utilizing current data, and discuss the findings in the context of the literature. This could contribute to the development of standard approaches for assessing such cases.
METHODS
This retrospective study reviewed files and reports from individuals assessed for hearing loss at Dokuz Eylül University Faculty of Medicine, Department of Forensic Medicine. The study included cases that applied at least 12 months post-trauma, between January 1, 2016, and December 31, 2022, after their recovery process was completed. Sociodemographic data, types of temporal bone fractures, initial otoscopic examination findings, presence or absence of intracranial injury, type of hearing loss, and audiometry test results for air and bone conduction pure tone threshold averages were evaluated. Data analysis was conducted using SPSS 26.0 (Statistical Package for the Social Sciences).
RESULTS
Out of 244 cases, 177 (72.5%) were male and 67 (27.5%) were female. It was observed that the majority of trauma cases occurred in the 19-40 age group (49.2%; n=120). In the initial otoscopic examinations post-trauma, otorrhagia/otorrhea was the most common finding, both as an isolated symptom (n=59, 24.2%) and when accompanied by other symptoms. No temporal bone fractures were detected in 43 cases (17.6%). Longitudinal fractures were found in 141 cases (57.8%), transverse fractures in 48 (19.7%), and mixed-type fractures in 12 (4.9%). The statistical difference in air conduction and bone conduction pure tone threshold averages between groups with and without intracranial injury was significant (p<0.001).
CONCLUSION
Post-traumatic examinations should employ a multidisciplinary approach, adhering to standard medical improvement and assessment timelines. It is essential to verify whether each patient's medical improvement process has reached its maximum potential. We believe that adhering to these recommendations and utilizing standardized classifications for hearing loss will prevent the loss of rights.
Topics: Humans; Male; Female; Retrospective Studies; Adult; Hearing Loss; Middle Aged; Adolescent; Young Adult; Aged; Temporal Bone; Craniocerebral Trauma; Risk Factors; Child
PubMed: 38863291
DOI: 10.14744/tjtes.2024.63099