Abstract
Background
Altered sperm DNA methylation patterns of imprinted genes as well as certain spermatogenesis-related genes has been proposed as a possible mechanism of male subfertility. Some ...reports suggest that there is an elevated risk of congenital diseases, associated with imprinted genes, in children conceived via intra-cytoplasmic sperm injection, due to the involvement of spermatozoa with aberrant imprinted genes obtained from infertile men.
Methods
In this study, the DNA methylation status of the promoter regions of six imprinted genes, namely potassium voltage-gated channel subfamily Q member 1 (
KCNQ1
), maternally expressed gene 3 (
MEG3
), insulin-like growth factor 2 (
IGF-2
), KCNQ1 overlapping transcript 1 (
KCNQ1OT1
), mesoderm specific transcript (
MEST
), and paternally expressed gene 3 (
PEG3
), were detected by a next generation sequencing-based multiple methylation-specific polymerase chain reaction analysis of sperm samples obtained from 166 men who sought fertility evaluation in our Reproductive Medicine Center. Thereafter, the semen samples were classified into subgroups according to sperm motility and DNA integrity status.
Results
As compared to the normozoospermic group, the samples of the asthenospermic group exhibited significant hypermethylation in two CpG sites of
IGF-2
and significant hypomethylation in one CpG site of
KCNQ1
as well as three CpG sites of
MEST
(
P
< 0.05). However, we did not observe any significant differences in the overall methylation levels of these six imprinted genes (
P
> 0.05). Additionally, we found that 111 of 323 CpG sites were hypomethylated in the group with DNA fragmentation index (DFI) ≥ 30% as compared to the group with DFI < 30% (
P
< 0.05). In this case, there were significant differences in the overall methylation levels of
MEG3
,
IGF-2
,
MEST
, and
PEG3
(
P
< 0.05), but not in that of
KCNQ1OT1
and
KCNQ1
(
P
> 0.05). Hence, aberrant methylation patterns of imprinted genes were more prevalent in males with poor sperm quality, especially in those with severe sperm DNA damage.
Conclusion
In conclusion, abnormal DNA methylation of some CpG sites of imprinted genes are associated with poor sperm quality, including asthenospermia and severe sperm DNA impairment.
•Each increase of 10 μg/m3 in PM2.5 was associated with decreased fecundity by 11%.•It was also associated with an 20% increased likelihood of infertility.•The association might explain the increased ...infertility rates in polluted areas.
Whether exposure to airborne particulate matter less than 2.5 μm (PM2.5) could impact human fecundity is unclear. We aimed to evaluate the potential impact of PM2.5 exposure on time to pregnancy (TTP) and the prevalence of infertility in the general Chinese population.
We collected reproductive information, sociodemographic characteristics, and lifestyle data of 10,211 couples at risk of pregnancy from a large-scale community-based fertility survey in China. Then, we estimated each participant’s 1-year, 3-year, and 5-year average PM2.5 exposure levels based on remote sensing information. After adjusting for demographic, lifestyle, and environmental co-variables, discrete-time Cox regression models were used to estimate the fecundability odds ratio (FOR) per 10 μg/m3 change of PM2.5. We also estimated the odds ratio (OR) of infertility per 10 μg/m3 change of PM2.5, using logistic regression models.
Among the 10,211 couples, 6,875 (67%) had conceived spontaneously, with a median TTP of 5 months (interquartile range: 2–10 months). The median PM2.5 exposure was 56.8 μg/m3, with a wide range of 9.2–93.5 μg/m3. In Cox regression models, each increase of 10 μg/m3 in the 1-year average PM2.5 exposure was associated with a significant decrease in fecundity by 11% (FOR: 0.89; 95% confidence interval CI: 0.86–0.92). In logistic regression models, it was also associated with an 20% increased likelihood of infertility (OR: 1.20; 95% CI: 1.13–1.27).
PM2.5 exposure was associated with reduced human fecundity, presented by a longer TTP and higher odds of infertility, which might explain the increased infertility rates in areas with heavy PM2.5 pollution.
This study aimed to establish a placental long non-coding RNA (lncRNA)-mRNA expression network for early-onset preeclampsia (early-onset PE).
The RNA sequencing data of the GSE14821 dataset were ...acquired. Several crucial lncRNAs and mRNAs were exerted based on the differential expression analysis of lncRNA and mRNA. By analyzing the differentially expressed lncRNA and mRNA, we constructed a regulatory network to explore the mechanism of the lncRNA in early onset preeclampsia.
A total of 4436 differentially expressed lncRNAs (DElncRNAs) were identified in early-onset PE placenta samples compared with control placenta samples. Pearson correlation analysis revealed significant correlations between 3659 DElncRNAs and 372 DEmRNAs. KEGG analysis showed that the DEmRNAs were enriched in cytokine-cytokine receptor and hypoxia-inducible factor (HIF)-1 pathways. Several well-known early-onset PE-related mRNAs, such as vascular endothelial growth factor A (VEGFA) and VEGF receptor 1 (FLT1), were involved in the two pathways. Weighted gene co-expression network analysis and cis-regulatory analysis further suggested the involvement of the two pathways and potential DElncRNA-DEmRNA interactions in early-onset PE. Moreover, the upregulation of representative DElncRNAs, such as RP11-211G3.3 and RP11-65J21.3, and DEmRNAs, such as VEGFA and FLT1, were validated in clinical placenta samples from patients with early-onset PE by quantitative reverse transcription PCR. Importantly, overexpression of RP11-65J21.3 significantly promoted the proliferation of HTR-8 trophoblast cells at 72 h after transfection.
In conclusion, we identified placental DElncRNAs of early-onset PE and established a DElncRNA-DEmRNA network that was closely related to the cytokine-cytokine receptor and HIF-1 pathways. Our results provide potential diagnostic markers and therapeutic targets for early-onset PE management.
Based on a medical record or questionnaire survey approach, previous epidemiological studies have investigated associations between maternal antibiotic exposure during pregnancy and childhood ...allergic diseases. However, biomonitoring studies on the prenatal low-dose antibiotic exposure, mainly from the environment and contaminated food, and in relation to children allergic diseases, are missing.
This research aimed to examine the associations between prenatal low-dose antibiotic exposure measured at multiple time points and children current allergic diseases at 4 years of age.
The current study including 2453 mother-child pairs was based on the Ma’anshan Birth Cohort study. Selected 41 antibiotics and their two metabolites, which including human antibiotics (HAs), preferred as human antibiotics (PHAs), veterinary antibiotics (VAs) and preferred as veterinary antibiotics (PVAs), in urine samples from 2453 pregnant women were biomonitored through liquid chromatography-triple quadrupole tandem mass spectrometry. Information on children current allergic diseases were collected via validated questionnaires. Generalized estimating equation were used to explore the associations between the repeated measurements of maternal urinary antibiotic over three trimesters and current allergic diseases in children.
The detection rates of nine individual antibiotics in the three trimester during pregnancy are greater than 10%, and the 90th percentile concentration of the detected antibiotics ranges from 0.07 to 22.34 µg/g, and the 95th percentile concentration ranges from 0.17 to 59.57 µg/g. Among the participants, each one-unit concentration increment of sulfamethazine (adjusted OR=1.28, 95% CI: 1.10, 1.49, P-FDR=0.014) in the first trimester and ciprofloxacin (adjusted OR=1.17, 95% CI: 1.07, 1.28, P-FDR=0.008) in the second trimester were associated with an increased risk of current eczema in children. In the third trimester, each one-unit concentration increment of oxytetracycline (adjusted OR=1.90, 95% CI: 1.30, 2.78, P-FDR=0.014) was associated with an increased risk of current asthma in children. Gender-stratified analyses demonstrated that no gender differences were observed in the associations between prenatal antibiotic exposure and current allergic diseases in children.
Maternal exposure to certain specific VAs or PVAs (sulfamethazine, ciprofloxacin and oxytetracycline) in different trimesters was associated with an increased risk of current asthma and current eczema in 4-year-old children. No gender differences were found in these associations. Further studies are warranted to confirm our findings and explore the potential mechanisms.
Display omitted
•Pregnant women were commonly exposed to low-dose antibiotics during pregnancy.•Sulfamethazine exposure (1st trimester) increases the risk of eczema in children.•Ciprofloxacin exposure (2nd trimester) elevates the risk of eczema in children.•Oxytetracycline exposure (3nd trimester) increases the risk of asthma in children.•No gender differences were found in these associations.
Toxic and essential trace elements are reported to have impact on female fertility. However, studies on the potential synergistic or antagonistic effects of metal mixtures on IVF outcomes remain ...limited.
To evaluate whether serum concentrations of metals, individually and as mixtures, are associated with pregnancy outcomes in women undergoing IVF.
In a prospective birth cohort study about IVF from the First Affiliated Hospital of Anhui Medical University (n = 1184), we measured the concentrations of serum metals by ICP-MS according to a previously established method. Oocyte/embryo development indicators and follow-up results were also collected. The individual and joint effects of metals were estimated using logistic regressions and Bayesian kernel machine regressions (BKMR).
At embryonic stage, we found negative associations between the serum lead (Pb) (β = −0.14, 95%CI: −0.32, −0.04) and cadmium (Cd) (β = −0.24, 95%CI: −0.39, −0.09) concentrations and the high-quality embryos rate; and positive associations between the serum cobalt (Co) (β = 0.18, 95%CI: 0.05, 0.31) and selenium (Se) (β = 0.17, 95%CI: 0.06, 0.41) concentrations and the MII rate. Regarding to the pregnancy outcomes, the serum Pb was negatively related with successful implantation (OR=0.85, 95%CI: 0.77, 0.94) and clinical pregnancy (OR=0.95, 95%CI: 0.91, 0.99); and positively associated with spontaneous abortion (OR=1.39, 95% CI: 1.02, 1.91). The BKMR analysis showed linear or parabolic associations between the metal mixtures and pregnancy outcomes, with Pb showing the highest posterior inclusion probabilities.
The toxic (Pb, Cd) and essential (Co, Se) metals could be incorporated as simultaneous predictors of IVF outcomes including potential antagonistic effects, in which Pb exhibits major contributions.
•Pb and Cd were adversely associated with embryo development and pregnancy outcomes.•The Pb & Cd and Co & Se existed potential antagonistic effects.•Pb exhibits major contributions in the adverse mixture effects.
The aim of this study was to uncover the underlying mechanisms of cervical cancer progression and provide potential therapeutic targets for its treatment in clinic.
Real-Time qPCR was used to ...determine the expression levels of Linc00483, miR-508-3p and RGS17 mRNA in cervical cancer tissues and cell lines. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) assay was conducted to determine cell apoptosis. Western Blot was performed to detect protein expression levels. Wound healing and Transwell assay were employed to determine cell migration and invasion respectively. Online software (TargetScan, miRDB and miR TarBase) were used to predict the regulating mechanisms of Linc00483, miR-508-3p and RGS17, which were validated by dual-luciferase reporter gene system. In vivo tumor-bearing mice models were established to validate the cellular results.
Linc00483 aberrantly overexpressed in both cervical cancer tissues and cell lines comparing to the Control groups. Knock-down of Linc00483 inhibited cervical cancer cell proliferation, invasion as well as migration, and promoted cell apoptosis. In addition, miR-508-3p was identified as the downstream target of Linc00483, and miR-508-3p inhibitor abrogated the inhibiting effects of downregulated Linc00483 on cervical cancer cell viability. Furthermore, the expression levels of Linc00483 was positively correlated with RGS17 in the clinical samples and overexpressed Linc00483 increased RGS17 expression levels in cervical cancer cells by sponging miR-508-3p. The in vivo experiments showed that knock-down of Linc00483 inhibited cervical cancer cell tumorigenesis and lung metastasis in mice models.
Knock-down of Linc00483 inhibited the development of cervical cancer by regulating miR-508-3p/RGS17 axis.
Background
To find the factors impacting overall survival (OS) prognosis in patients with endometrioid endometrial carcinoma (EEC) and adenocarcinoma and to establish a nomogram model to validate the ...2023 International Federation of Obstetrics and Gynecology (FIGO) staging system for endometrial cancer.
Methods
Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) training cohort. An independent validation cohort was obtained from the First Affiliated Hospital of Anhui Medical University between 2008 and 2023. Cox regression analysis identified independent prognostic factors for OS in EEC and adenocarcinoma patients. A nomogram predicting OS was developed and validated utilizing the C‐index, calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). The relationship between the tumor grade and prognosis of EEC and adenocarcinoma was quantified using net reclassification improvement (NRI), propensity score matching (PSM), and Kaplan–Meier curves.
Results
Cox regression analysis identified age, race, marital status, tumor grade, tumor stage, tumor size, and chemotherapy as independent prognostic factors for OS. A nomogram for predicting OS was developed based on these factors. The C‐indexes for the OS nomogram was 0.743 and 0.720 for the SEER training set and external validation set, respectively. The area under the ROC (AUC) for the OS nomogram was 0.755, 0.757, and 0.741 for the SEER data subsets and 0.844, 0.719, and 0.743 for the external validation subsets. Calibration plots showed high concordance between the nomogram‐predicted and observed OS. DCA also demonstrated the clinical utility of the OS nomogram. NRI, PSM, and survival analyses revealed that tumor grade was the most important histopathological factor for EEC and adenocarcinoma prognosis.
Conclusion
Seven independent prognostic variables for the OS of patients with EEC and adenocarcinoma were identified. The established OS nomogram has good predictive ability and clinical utility and validates the 2023 endometrial cancer FIGO staging system.
Ovarian damage and follicle loss are major side effects of chemotherapy in young female patients with cancer. However, effective strategies to prevent these injuries are still lacking. The purpose of ...this study was to verify low-intensity pulsed ultrasound (LIPUS) can reduce ovarian injury caused by chemotherapy and to explore its underlying mechanisms in mice model.
The mice were randomly divided into the Control group, Cisplatin group, and Cisplatin + LIPUS group. The Cisplatin group and Cisplatin + LIPUS group were intraperitoneally injected with cisplatin every other day for a total of 10 injections, and the Control group was injected with saline. On the second day of each injection, the Cisplatin + LIPUS group received irradiation, whereas the other two groups received sham irradiation. We used a variety of biotechnologies to detect the differences in follicle count, granulosa cell apoptosis, fibrosis, transcriptome level, oxidative damage, and inflammation in differently treated mice.
LIPUS was able to reduce primordial follicle pool depletion induced by cisplatin and inhibit the apoptosis of granulosa cells. Transcriptomic results confirmed that LIPUS can reduce ovarian tissue injury. We demonstrated that LIPUS can relieve ovarian fibrosis by inhibiting TGF-β1/Smads pathway. Meanwhile, it can reduce the oxidative damage and reduced the mRNA levels of proinflammatory cytokines caused by chemotherapy.
LIPUS can reduce the toxic effects of chemotherapy drugs on ovaries, inhibit ovarian fibrosis, reduce the inflammatory response, and redcue the oxidative damage, reduce follicle depletion and to maintain the number of follicle pools.
Singleton pregnancy is encouraged to reduce pregnancy complications. In addition to single embryo transfer (SET), selective and spontaneous fetal reduction (SEFR and SPFR) can also achieve singleton ...pregnancies. After SEFR or SPFR, an inanimate fetus remains in the uterus. It is unclear whether the inanimate fetus would adversely affect another fetus or the mother. Previous studies have focused on the differences between pre- and post-reduction. However, studies focusing on the influence of SEFR and SPFR on the remaining fetal development and maintenance of pregnancy are rare.
Materials from 5922 patients whose embryo transfer dates ranged from March 2011 to January 2021 were collected. Both the SEFR group (n = 390) and SPFR group (n = 865) had double embryos transferred (DET) and got twin pregnancies, but subsequent selective or spontaneous fetal reduction occurred. The SET group (n = 4667) had only one embryo transferred. All were singleton pregnancies on the 65th day after embryo transfer. Clinical outcomes, including pregnancy outcomes, pregnancy complications, and newborn outcomes, were compared among the three groups.
After adjusting for age, infertility duration, types of infertility, states of embryos, body mass index, and factors affecting SET or DET decisions, multivariate regression analysis revealed that SEFR increased the risk of miscarriage (OR 2.368, 95% CI 1.423-3.939) and preterm birth (OR 1.515, 95% CI 1.114-2.060), and reduced the gestational age (βeta -0.342, 95% CI -0.544- -0.140). SPFR increased the risk of gestational diabetes mellitus (GDM) (OR 1.657, 95% CI 1.215-2.261), preterm premature rupture of membranes (PPROM) (OR 1.649, 95% CI 1.057-2.574), and abnormal amniotic fluid volume (OR 1.687, 95% CI 1.075-2.648). Both SEFR and SPFR were associated with reduced live birth rate (OR 0.522, 95% CI 0.330-0.825; OR 0.671, 95% CI 0.459-0.981), newborn birth weight (βeta -177.412, 95% CI -235.115--119.709; βeta -42.165, 95% CI -83.104--1.226) as well as an increased risk of low-birth-weight newborns (OR 2.222, 95% CI 1.490-3.313; OR 1.510, 95% CI 1.092-2.087).
DET with subsequent fetal reduction was related to poor clinical outcomes. We recommend that DET with subsequent fetal reduction should only be considered as a rescue method for multiple pregnancy patients with potential complications, and SET is more advisable.
The axonemal dynein arms (outer (ODA) and inner dynein arms (IDAs)) are multiprotein structures organized by light, intermediate, light intermediate (LIC), and heavy chain proteins. They hydrolyze ...ATP to promote ciliary and flagellar movement. Till now, a variety of dynein protein deficiencies have been linked with asthenospermia (ASZ), highlighting the significance of these structures in human sperm motility. Herein, we detected bi-allelic DNALI1 mutations c.663_666del (p.Glu221fs), in an ASZ patient, which resulted in the complete loss of the DNALI1 in the patient's sperm. We identified loss of sperm DNAH1 and DNAH7 rather than DNAH10 in both DNALI1
patient and Dnali1
mice, demonstrating that mammalian DNALI1 is a LIC protein of a partial IDA subspecies. More importantly, we revealed that DNALI1 loss contributed to asymmetries in the most fibrous sheath (FS) of the sperm flagellum in both species. Immunoprecipitation revealed that DNALI1 might interact with the cytoplasmic dynein complex proteins in the testes. Furthermore, DNALI1 loss severely disrupted the transport and assembly of the FS proteins, especially AKAP3 and AKAP4, during flagellogenesis. Hence, DNALI1 may possess a non-classical molecular function, whereby it regulates the cytoplasmic dynein complex that assembles the flagella. We conclude that a DNALI deficiency-induced IDAs injury and an asymmetric FS-driven tail rigid structure alteration may simultaneously cause flagellum immotility. Finally, intracytoplasmic sperm injection (ICSI) can effectively resolve patient infertility. Collectively, we demonstrate that DNALI1 is a newly causative gene for AZS in both humans and mice, which possesses multiple crucial roles in modulating flagellar assembly and motility.
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