Systems Biology in Reproductive Medicine最新文献

Freshly ejaculated mammalian sperm have poor fertilizing ability, with fertility only gained after sperm undergo capacitation and the acrosome reaction. To visualize exposed Fc receptors (FcRs), which occur during the acrosome reaction and whose absence has been related to infertility, a novel sperm FcR binding assay (FcR assay) was developed to assess fertilizing potential of sperm in proof-of-concept studies. A competition binding assay between sperm FcR and exogenously added FcR was used to assess whether the FcR was a functioning ligand in bull sperm. Once FcR was confirmed as a functional ligand, time-based expression of FcR was then evaluated in bull and human sperm using the FcR assay. This FcR assay was then used to evaluate fertility outcomes in cattle with cryopreserved intrauterine insemination (IUI) sperm, and to evaluate sperm FcR expression in patients undergoing IUI treatment in a prospective observational study. Time-based analyses of ejaculates from bull and human sperm demonstrated characteristic, reproducible sinusoidal patterns of FcR expression that corresponded to high and low periods of fertility potential in each species. The pregnancy rate in cattle approached statistical significance using the FcR assay results to inform optimum insemination timing windows versus conventional untimed methods (73.0% vs. 68.4%, respectively; p = 0.06; 95% confidence interval [CI]: 0.98, 1.57) with a 4.4% increase in the overall pregnancy rate. In patients undergoing IUI treatment, FcR expression patterns were identified where sperm were at their optimal fertilizing state, with overall pregnancy rates increasing from 21% to 42% (p = 0.01) when inseminations occurred during the windows where the fertilizing potential of the sperm was deemed optimal. These results suggest that sperm fertility potential is quantifiable in semen samples using our novel sperm FcR assay. Importantly, the FcR assay has the ability to identify optimal fertility windows in real-time, and also in the procedure ejaculates.

This comprehensive review reflects our current knowledge of viral infections in the context of assisted reproduction, highlighting the latest research and guidelines. It focuses on the major viral pathogens that have a significant impact on human reproduction. It examines their impact on both male and female reproductive systems, fertility outcomes, and pregnancy, with a particular emphasis on managing the risks of transmission in assisted reproductive technologies (ART). State-of-the-art screening protocols and preventive measures are outlined, highlighting the progress made in minimizing viral transmission and ensuring safe reproductive outcomes. By presenting the current landscape of viral management in reproductive health, this review underscores the need for continued vigilance, research, and innovation to face viral threats.

Disruption of Dcaf17 in mice resulted in male infertility with severe spermatogenesis defects. To investigate the molecular basis of infertility phenotype, we examined testicular proteomes of wild-type (WT) and Dcaf17^-/- mice using a mass spectrometry-based approach. We identified 727 and 525 differentially expressed proteins (DEPs) in 3- and 8-week old testes of Dcaf17^-/- mice, respectively, with an adjusted p-value cut-off of ≤ 0.05. Among these, 299 and 298 DEPs had fold change of ≥ 1.5 between WT and Dcaf17^-/- testes at -3- and 8-week old, respectively. In the 3-week old Dcaf17^-/- testes, 59.5% of the DEPs were up-regulated, while 40.5% were down-regulated. Similarly, in the 8-week old Dcaf17^-/- testes, 83.9% and 16.1% DEPs were up-regulated and down-regulated, respectively. Functional annotation and network analyses highlighted that many DEPs were associated with key biological processes, including ubiquitination, RNA processing, translation, protein folding, protein stabilization, metabolic processes, oxidation-reduction processes and sper-matogenesis. Subsequent immunohistochemistry and immunoblotting analyses showed higher ubiquitin levels in Dcaf17^-/- testes compared to WT, suggesting potential impairment in ubiquitin proteasome system (UPS) due to DCAF17 loss of function. Our data provide a basis for further work to elucidate the molecular function(s) of DCAF17 in spermatogenesis and male fertility.

The placenta develops as a transient organ during pregnancy to nurture the growing fetus. It supplies nutrients and oxygen to the fetus, collects fetal waste, and safeguards the fetus from infections and adverse pregnancy conditions. Emerging evidence suggests that the placenta plays adaptive functions to protect the developing brain from injury in adverse maternal conditions. Inadequate placental support can impact the developmental process of the brain, which increases the risk of brain diseases among the offspring. There is a remarkable coordination in gene expression between the placenta and fetal brain of mice, suggesting a robust regulation of the brain-placental axis. The deregulation of the brain-placental axis can have adverse effects on the fetal programming of brain development. Defective neuronal development of the fetus due to the abnormal or non-optimal placental functions can lead to an increased risk of different neuropsychiatric diseases in the adult life of the offspring. Thus, there is a growing interest to understand placental influences on fetal brain development and its links to the risk of brain diseases. Research on the brain-placental axis, also referred to as neuroplacentology, is a rapidly emerging interdisciplinary field that integrates concepts and tools from diverse areas, including reproductive biology, neuroscience, epigenetics, systems biology, and data sciences, among others. Recently, large-scale multiomics data and systems biology approaches have been applied to investigate the functional links between the placenta and fetal brain, and to dissect the cellular and molecular mechanisms of the regulation of the brain-placental axis. The primary objective of this review is to outline the current status and the future avenues of this emerging research field that holds huge potential to advance our knowledge about the role of the placenta in the developmental origin of brain health and disease.

The role of sperm morphology in male fertilization potential remains unclear. This study aimed to evaluate the incidence of specific sperm morphological abnormalities in a cohort of Turkish men attending a single-center infertility clinic and to assess their associations with semen quality and sperm functionality. A total of 2,923 men aged 17-57 years were included in this cross-sectional study. Semen parameters and specific morphological abnormalities in the head, neck-midpiece, tail, and cytoplasmic residue were analyzed according to WHO criteria. Participants were categorized into normal and low semen parameter groups based on sperm count, motility, and normal morphology. Associations between semen parameters and morphological abnormalities were assessed using Spearman correlation and binary logistic regression analyses. Head defects were the most prevalent abnormalities, followed by tail, neck-midpiece, and cytoplasmic residue. Normal sperm morphology and specific abnormalities were significantly associated with semen quality, with normal forms demonstrating the strongest predictive potential. Head defects were primarily associated with teratozoospermia, whereas neck-midpiece and tail defects were linked to motility impairments. Notably, round and tapered heads, bent necks, and coiled or short tails showed the strongest associations with progressive and rapid progressive motility, which are critical determinants of fertilization capacity. Our findings indicate that different categories of sperm abnormalities have distinct predictive potentials for semen quality disorders and suggest that specific defects may arise from disruptions in different stages of sperm morphogenesis.

Endometriosis is a complex condition with a wide range of clinical manifestations, presenting significant challenges, particularly for young women. Its diverse and often perplexing presentations pose difficulties within the medical community. Laparoscopy remains the gold-standard diagnostic tool for endometriosis. However, alternative diagnostic methods are valuable for monitoring disease progression, assessing the likelihood of recurrence, reducing the need for surgical procedures, and facilitating timely decisions regarding fertility concerns. Recent research highlights the potential of microRNAs (miRNAs) as an alternative diagnostic test for endometriosis. A case-control study was conducted at the infertility unit of Arash Women's Hospital, involving 50 female participants, 25 with endometriosis and 25 without it. Plasma samples were collected and analyzed for the expression levels of 16 miRNAs using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Diagnostic accuracy measures were evaluated to establish a reliable and comparable diagnostic framework. Compared to the control group, downregulation of 11 miRNAs and upregulation of 5 miRNAs were observed in the case group. Regarding expression patterns, evidence from this study indicates that half of the evaluated miRNAs fall into the high-agreement category with similar studies. Sensitivity (SN) of the evaluated miRNAs ranged from 64.0% to 88.0%, while specificity (SP) ranged from 56.0% to 88.0%. The area under the curve (AUC) was reported between 0.619 (miR-135a) and 0.846 (miR-340). These findings suggest that the evaluated miRNAs demonstrate moderate to acceptable diagnostic accuracy for endometriosis.

Macrosomia (birth weight >4000 g) is a product of endocrine dysfunction in utero leading to fetal overgrowth and can lead to maternal and infant morbidity. Fibroblast growth factor 21 (FGF21) and its transcription factor, peroxisome proliferator-activated receptor alpha (PPARα), are found in the placenta and are associated with abnormal metabolic states. Their relationship to the placental dysregulation that leads to macrosomia is unknown. We sought to evaluate the relationship between protein expression of FGF21 and PPARα in placental samples from infants with macrosomia compared to controls (<4000 g) on both the maternal and fetal sides of the placenta. Placental specimens were collected at the time of delivery and protein levels of FGF21 and PPARα were quantified via Western Blot analysis and normalized to GAPDH. Student's t-test, Wilcoxon-Mann-Whitney test, Fisher's exact test, Chi-squared analysis, and Spearman's correlation were used for statistical analyses. Baseline characteristics were similar across both groups. FGF21 and PPARα levels on the maternal side of the placenta did not differ based on presence of macrosomia. PPARα expression was statistically significantly lower on the fetal side in infants with macrosomia. In controls alone, FGF21 and PPARα trended lower on the maternal side compared to the fetal side although this was not statistically significant. PPARα and FGF21 were positively correlated throughout the placenta. We found that lower PPARα expression on the fetal side of placenta was noted in infants with macrosomia, identifying a possible contribution to the growth discrepancy in this group. PPARα and FGF21 are strongly correlated in the human placenta.

Endometrial cancer is the most common malignant tumor of the uterus, but the underlying genetic mechanisms of EC remain unclear. To identify candidate genes and investigate genetic mechanisms for endometrial cancer, we utilized the summary-data-based Mendelian randomization (SMR) method to investigate causal associations between genetic variants, gene expression, DNA methylation, and endometrial cancer. Three main analyses were conducted utilizing cis-expression and methylation quantitative trait loci (eQTLs and mQTLs) as instrumental variables to examine causal relationships with endometrial cancer, and assessing the causal relationship between DNA methylation and gene expression. Data sources included genetic association data from O'Mara et al. eQTL data from the GTEx database, and mQTL data from McRae et al. Analysis involved the HEIDI test to distinguish pleiotropy, SMR analysis with multiple testing correction, and colocalization analysis to assess associations driven by linkage disequilibrium. Functional enrichment analysis was performed by the Metascape tool. Our study showed that three genes, SNX11, LINC00243, and EVI2A, were identified as causally related to endometrial cancer. SNX11 exhibited a positive causal relationship, while LINC00243 and EVI2A showed negative ones. Furthermore, 24 CpG sites were identified as causally related to endometrial cancer, with cg14424631 (CYP19A1) being the most significant. The study revealed common genes implicated in endometrial cancer, gene expression, and methylation sites, with LINC00243 playing a key role. Colocalization analysis confirmed significant causal relationships between LINC00243, SNX11, and endometrial cancer. Enrichment analysis uncovered pathways like interferon gamma signaling enriched in both endometrial cancer GWAS and e/mQTL. These findings shed light on the molecular mechanisms underlying endometrial cancer development. The study identified candidate genes and DNA methylation loci causally associated with endometrial cancer, which are expected to serve as potential targets for treatment.

Recurrent spontaneous miscarriage refers to the repeated loss of two or more clinically detected pregnancies occurring within 24 weeks of gestation. No identifiable cause has been identified for nearly 50% of these cases. This group is referred to as idiopathic recurrent spontaneous miscarriage (IRSM) or miscarriage of unknown origin. Due to lack of robust scientific evidence, guidelines on the diagnosis and management of IRSM are not well defined and often contradictory. This motivates us to explore the vibrational fingerprints of endometrial tissue in these women. Endometrial tissues were collected from women undergoing IRSM (n = 20) and controls (n = 20) corresponding to the window of implantation. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectra were obtained within the range of 400-4000 cm^-1 using Agilent Cary 630 FTIR spectrometer. Raman spectra were also generated within the spectral window of 400-4000 cm^-1 using Thermo Fisher Scientific, DXR Raman spectrophotometer. Based on the limited molecular information provided by a single spectroscopic tool, fusion strategy combining Raman and ATR-FTIR spectroscopic data of IRSM is proposed. The significant features were extracted applying principal component analysis (PCA) and wavelet threshold denoising (WTD) and fused spectral data used as input into support vector machine (SVM), adaptive boosting (AdaBoost) and decision tree (DT) models. Altered molecular vibrations associated with proteins, glutamate, and lipid metabolism were observed in IRSM using Raman spectroscopy. FTIR analysis indicated changes in the molecular vibrations of lipids and proteins, collagen dysregulation and impaired glucose metabolism. Combination of both spectroscopic data using mid-level fusion (MLF: 92% using AdaBoost and DT models) and high-level fusion (HLF: 92% using SVM models) methods showed improved IRSM classification accuracy as compared to individual spectral models. Our results indicate that spectral fusion technology hold promise in enhancing diagnostic accuracy of IRSM in clinical settings. Validation of these findings in a larger patient population is underway.