Systems Biology in Reproductive Medicine最新文献

The World Health Organization has considered the infertility as an international public health problem. Infertility affect nearly 1 in 7 couples and male component contributes to 50% of infertility cases. There is a clear link between male infertility and some cancers such as testicular germ cell, prostate and colon cancers. Two possibilities support this finding: 1) Cancer treatments can affect the fertility factors 2) Genetic profile of infertility genes have been altered in cancer patients. Although the previously published researches have mostly focused on the first factor, no article has yet confirmed the role of genetic factors. In this in silico study, we collected the large number of genes (n = 17703) involved in infertility. These genes were collected from NGS panel tests of male infertility and comprehensive literature review or online data base. The Prostate Adenocarcinoma genomic and transcriptomics raw data were downloaded from the cBioPortal Cancer dataset. This included with 494 patients of Prostate Cancer with 494 mutation data, 489 with CNA and 493 with RNA seqV2 data. TCGA RNA-Seq raw data was extracted in R using the cgdsr extension package with a threshold of ±2 relative to normal samples. The observed data showed that male infertility genes have been distributed through the human genome. Among the 17703 analyzed genes of this study, the genomic profile of three genes including OR9Q1, H4C6 and PSG7 were changed approximately in 100% of (n = 493) patients. In most of patients (>98%), genetic alteration was related to change in gene expression. In conclusion, this study showed that the genomic and transcriptomics patterns of some male-infertility genes are notably altered in patients of prostate cancer and suggested a possible role of genetic factors in occurrence of infertility in cancer patients. Our information can be used as a source for the design of genetic database of male-infertility.

Male infertility is a reproductive disorder, accounting for 40-50% of infertility. Currently, in about 70% of infertile men, the cause remains unknown. With the introduction of novel omics and advancement in high-throughput technology, potential biomarkers are emerging. The main purpose of our work was to overview different aspects of omics approaches in association with idiopathic male infertility and highlight potential genes, transcripts, non-coding RNA, proteins, and metabolites worth further exploring. Using the Gene Ontology (GO) analysis, we aimed to compare enriched GO terms from each omics approach and determine their overlapping. A PubMed database screening for the literature published between February 2014 and June 2022 was performed using the keywords: male infertility in association with different omics approaches: genomics, epigenomics, transcriptomics, ncRNAomics, proteomics, and metabolomics. A GO enrichment analysis was performed using the Enrichr tool. We retrieved 281 global studies: 171 genomics (DNA level), 21 epigenomics (19 of methylation and two histone residue modifications), 15 transcriptomics, 31 non-coding RNA, 29 proteomics, two protein posttranslational modification, and 19 metabolomics studies. Gene ontology comparison showed that different omics approaches lead to the identification of different molecular factors and that the corresponding GO terms, obtained from different omics approaches, do not overlap to a larger extent. With the integration of novel omics levels into the research of idiopathic causes of male infertility, using multi-omic systems biology approaches, we will be closer to finding the potential biomarkers and consequently becoming aware of the entire spectrum of male infertility, their cause, prognosis, and potential treatment.

The assessment of epigenetic profiles in sperm is sensitive to somatic cell contamination, which can influence methylation signals at gene promoters. This contamination is particularly problematic in the assessment of DNA methylation in samples with low sperm counts, where fractional amounts of somatic cell DNA can lead to significant shifts in measured methylation state. In this study, a new method of detecting possible somatic cell contamination is proposed through two multi-region bioinformatic models: a traditional differential methylation analysis and a machine learning logistic regression model. These models were trained on publicly available sperm (n = 489) and blood (n = 1029) DNA methylation array data and tested on a contamination set, wherein the sperm of four donors with normal sperm counts were run on a 450k methylation array with four permutations each, including pure blood, half blood and half sperm by DNA concentration, half blood and half sperm by cell count, and pure sperm (n = 16). The DMR and logistic regression model classified the contamination testing set with 100% and 94% accuracy, respectively. These new methods of detecting the effects of somatic cell contamination allow for more accurate differentiation between epigenetic profiles that contain a biological somatic-like shift and those that have somatic-like signatures because of contamination.

Despite the significant morphological changes that occur in the seminal vesicles with aging, the transcriptomic characteristics remain largely unexplored. To address this, we performed bulk RNA sequencing on seminal vesicle samples from mice aged 3, 13, and 21 months to uncover transcriptomic alterations. Our findings reveal that aged seminal vesicles display cystic dilatation, epithelial hypoplasia, disordered muscle layers, fibrosis, and reduced proliferation capability. A comparison between 3-month-old and 21-month-old mice indicated that leukocyte-mediated immunity and leukocyte migration were the most significantly upregulated biological processes among differentially expressed genes (DEGs). Notably, several DEGs associated with "leukocyte migration," such as Vcam1, Cxcl13, and Ccl8, exhibited an increasing trend in transcriptomic and protein expression at three different time points in the seminal vesicles of mice. Additionally, we identified multiple aging-associated DEGs, including P21 and Tnfrsf1b. Two genes (Cd209f and Ccl8) were consistently upregulated across all six regions of the male reproductive glands (testis, epididymis, and seminal vesicle) in the comparison of bulk RNA datasets from 3-month-old and 21-month-old mice. These analyses highlight an enhanced state of immune and inflammatory response in aged seminal vesicles. This study represents the first exploration of the overall transcriptome landscape of seminal vesicles in a murine model of natural aging, offering new insights into the mechanisms underlying aging-related seminal vesicle dysfunction.

Polyamines are polycationic molecules which contains two or more amino groups (-NH₃⁺) highly charged at physiological pH, and among them we found spermine, spermidine, putrescine, and cadaverine. They interact with proteins, nucleic acids, modulate Ca²⁺, K⁺, and Na⁺ channels, and protect sperm from oxidative stress. In this work, we evaluate the effect of spermine, spermidine, and putrescine on the total, progressive and kinematic parameters of motility, capacitation, acrosome reaction, also in presence and absence of the dbcAMP, an analogue of the cAMP, and the IBMX, a phosphodiesterase inhibitor. In addition, we evaluated the intracellular concentrations of cAMP [cAMP]i, and performed an in silico analysis between polyamines and the sAC from mouse to predict the possible interaction among them. Our results showed that all polyamines decrease drastically the total, progressive and the kinetic parameters of sperm motility, decrease the capacitation, and only spermidine and putrescine impeded the acquisition of acrosome reaction. Moreover, the effect of polyamines was attenuated but not countered by the addition of db-cAMP and IBMX, suggesting a possible inhibition of the sAC. Also, the presence of polyamines induced a decrease of the [cAMP]i, and the in silico analysis predicted a strong interaction among polyamines and the sAC. Overall, the evidence suggests that probably the polyamines interact and inhibit the activity of the sAC.

Effective treatments for nonobstructive azoospermia (NOA), which affects 1% of all men globally, are limited by undefined pathogenic mechanisms, especially in idiopathic NOA (iNOA). Here, we tried to identify the functional ferroptosis-related genes and phenotypes involved in iNOA. Differentially expressed ferroptotic genes were identified from iNOA mRNA microarray datasets by bioinformatic analyses, and these ferroptotic genes were subsequently filtered by various algorithms. Then, receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic ability of the abovementioned genes for iNOA. Generally, 11 differentially expressed ferroptotic genes were downregulated, and five genes were upregulated in iNOA samples. Four genes, including DUSP1, GPX4, HSD17B11, and SLC2A8, were technically selected and determined to be potential biomarkers for iNOA. Subsequently, similar expression levels were validated at both the RNA and protein levels in the iNOA specimens. Finally, morphologic and biochemical assays were applied to define the ferroptotic phenotypes in testes. The ferroptotic features, like shrunken mitochondria with electron-dense membranes and a reduction in cristae were observed across various cell types within iNOA patients, accompanied by the overload of ferrous ions and increased lipid peroxidation production. Our findings demonstrated that these ferroptosis genes could be involved in the underlying pathogenesis mechanisms of iNOA by regulating ferroptosis and serve as potential diagnostic biomarkers. Also, the ferroptotic phenotypes were identified in iNOA patients.

Cervical cancer (Cacx) is the second and endometrial cancer (Ec) is the third most common gynecological cancer worldwide. The present study aims to understand the complex and unexplored conditions occurring in cervix and endometrium of the female genital tract caused due to the infection of the human papilloma viruses (HPVs) and Chlamydia trachomatis (CT). A total of 300 tissue biopsy samples of cervix and endometrium were included in the present study and tested for the presence of HPV and CT deoxyribonucleic acid (DNA) by using polymerase chain reaction (PCR) technique. The odds ratios and 95% confidence interval were considered for the calculation of the association of HPV and CT infection with the risk of cervical or Ec. Among endometrial patients, samples were 5% positive for HPV and 5% positive for CT infection. Among endometrial control group, no sample was found positive for either HPV or CT infection. Among cervical patients, 72% samples were positive for only HPV infection and 1% samples were positive for only CT infection. Among control group, 7% of samples were positive for only HPV infection and 3% were positive for only CT infection. The co-infection of CT with HPV in 9% of Cacx cases and in 2% of cervical control samples was also observed. This is the first study in Indian women to detect the prevalence of HPV and CT infections in endometrium cases and control. An updated estimate regarding the HPV and CT prevalence in cervix cases and control samples was also provided.