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BACKGROUND: Mild hypothyroidism, including subclinical hypothyroidism (SCH) and isolated maternal hypothyroxinemia (IMH), is fairly common in pregnant women, but its impact on pregnancy outcomes is less clear, especially mild hypothyroidism in late pregnancy. OBJECTIVE: To evaluate the impact of SCH and IMH in the first and third trimesters, respectively, on obstetric and perinatal outcomes. STUDY DESIGN: This large prospective study was conducted at the International Peace Maternity and Child Health Hospital (IPMCH) in Shanghai. 52,027 pregnant women who underwent the first-trimester antenatal screening at IPMCH were consecutively enrolled from January 2013 to December 2016. To evaluate the impact of maternal SCH and IMH in the first trimester on pregnancy outcomes, participants were divided into three groups according to thyroid function in the first trimester: first-trimester euthyroidism group (n= 33,130), first-trimester SCH group (n= 884), and first-trimester IMH group (n= 846). Then, to evaluate the impact of maternal SCH and IMH in the third trimester on pregnancy outcomes, the first-trimester euthyroidism group was subdivided into three groups according to thyroid function in the third trimester: third-trimester euthyroidism group (n= 30,776), third-trimester SCH group (n= 562), and third-trimester IMH group (n= 578). Obstetric and perinatal outcomes, including preterm birth (PTB), preeclampsia, gestational hypertension, gestational diabetes mellitus (GDM), large for gestational age (LGA), small for gestational age, macrosomia, cesarean section, and fetal demise were measured and compared between those in either SCH/IMH group and euthyroid group. Binary logistic regression was used to assess the association of SCH or IMH with these outcomes. RESULTS: 34,860 pregnant women who had first (weeks 8-14) and third trimester (weeks 30-35) thyrotropin and free thyroxine concentrations available were included in the final analysis. Maternal SCH in the first trimester was linked to a lower risk of GDM (aOR 0.64, 95% CI 0.50-0.82) compared with the euthyroid group. However, third-trimester SCH is associated with heightened rates of PTB (aOR 1.56, 95%CI 1.10-2.20), preeclampsia (aOR 2.23, 95%CI 1.44-3.45), and fetal demise (aOR 7.00, 95%CI 2.07-23.66) compared with the euthyroid group. IMH in the first trimester increased risks of preeclampsia (aOR 2.14, 95% CI 1.53-3.02), GDM (aOR 1.45, 95%CI 1.21-1.73), LGA (aOR 1.64, 95%CI 1.41-1.91), macrosomia (aOR 1.85, 95%CI 1.49-2.31) and cesarean section (aOR 1.35, 95%CI 1.06-1.74), while IMH in the third trimester increased risks of preeclampsia (aOR 2.85, 95%CI 1.97-4.12), LGA (aOR 1.49, 95%CI 1.23-1.81) and macrosomia (aOR 1.60, 95%CI 1.20-2.13) compared with the euthyroid group. CONCLUSION: This study indicates that while first-trimester SCH did not elevate the risk for adverse pregnancy outcomes, third-trimester SCH was linked to several adverse pregnancy outcomes. IMH in the first and third trimesters was associated with adverse pregnancy outcomes, yet the impact varied by trimester. These results suggest the timing of mild hypothyroidism in pregnancy may be pivotal in determining its effects on adverse pregnancy outcomes and underscore the importance of trimester-specific evaluations of thyroid function.
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RESEARCH QUESTION: Does frozen embryo transfer (FET) increase the risk of allergic diseases in offspring? DESIGN: This study followed up 653 singleton children: 166 born through FET and 487 born through natural conception. Demographic characteristics, perinatal information and allergic diseases of children and their parents were collected through clinical medical systems and questionnaires. Among these 653 children, allergen-specific immunoglobulin E (IgE) testing was performed using peripheral blood samples collected from 207 children: 145 in the FET group and 62 in the natural conception group. The prevalence of allergic diseases and positive rates of allergen-specific IgE testing were compared between the two groups with adjustments for confounding factors. RESULTS: The prevalence of food allergy was significantly higher in children born through FET compared with children born through natural conception (adjusted ORâ¯=â¯3.154, 95% CI 1.895-5.250; P < 0.001). In addition, positive rates of food allergen sensitization were higher in children in the FET group compared with children in the natural conception group (adjusted ORâ¯=â¯5.769, 95% CI 2.859-11.751, P < 0.001). Children in the FET group had a higher positive sensitization rate to at least one allergen compared with children in the natural conception group (adjusted ORâ¯=â¯3.127, 95% CI 1.640-5.961, P < 0.001). No association was observed between FET and other allergic diseases, including asthma (Pâ¯=â¯0.136), atopic dermatitis (Pâ¯=â¯0.130) and allergic rhinitis (Pâ¯=â¯0.922). Allergen sensitization IgE testing indicated no differences between the two groups in terms of positive sensitization rates of other common allergens, including animal and insect allergens (Pâ¯=â¯0.627), inhaled outdoor allergens (Pâ¯=â¯0.915) and inhaled outdoor allergens (Pâ¯=â¯0.544). CONCLUSION: This study suggests that children born through FET have increased risk of developing food allergy in early childhood.
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BACKGROUND: In recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms. METHODS: Given the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET). RESULTS: Reduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups. CONCLUSION: Based on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.
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Criopreservación , Transferencia de Embrión , Placenta , Criopreservación/métodos , Femenino , Embarazo , Animales , Ratones , Transferencia de Embrión/métodos , Placenta/metabolismo , Embrión de Mamíferos , Implantación del Embrión/genética , Desarrollo Fetal/genética , Blastocisto/metabolismoRESUMEN
BACKGROUND: Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified. METHODS: Pregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon. RESULTS: Short-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation. CONCLUSIONS: Short-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Diabetes Gestacional , Hiperglucemia , Músculo Esquelético , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Efectos Tardíos de la Exposición Prenatal , Transducción de Señal , Animales , Femenino , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Embarazo , Ratones , Masculino , Músculo Esquelético/metabolismo , Diabetes Gestacional/metabolismo , Hiperglucemia/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocondrias/metabolismo , Glucemia/metabolismoRESUMEN
Background: Assisted reproductive technology (ART) has been reported to have negative effects on maternal and neonatal health. Ovulation induction (OI) was reported to be associated with alteration of epigenetic modification of mice embryos, and extinguishing the influence of ovulation induction and in vitro operations on maternal and neonatal health will bring benefits for reducing side effects. The present study aimed to determine whether ovulation induction alone and ART are associated with adverse pregnancy outcomes and whether ART could induce a higher risk than ovulation induction alone. Methods: A total of 51,172 cases with singleton live birth between Jan 2016 and May 2019 at the International Peace Maternal and Child Health Hospital were included in this study. Conception modes documented during registration were classified into natural conception (NC), OI, and ART. Pregnancy outcomes of the three groups with balanced baseline characteristics by propensity score matching were compared. The relative risks of maternal and neonatal outcomes were calculated by logistic regression analysis. Results: Compared with natural conception, infertility treatments are associated with gestational diabetes (OI: OR 1.72, 95% CI 1.31-2.27; ART: OR 1.67, 95% CI 1.26-2.20), preeclampsia/eclampsia (OI: OR 1.86, 95% CI 1.03-3.36; ART: OR 2.23, 95% CI 1.26-3.92). Even if gestational diabetes, gestational hypertension, and placental problems were adjusted, infertility treatments are associated with birth before 37 weeks (OI: OR 1.99, 95% CI 1.28-3.12; ART: OR 1.70, 95% CI 1.08-2.69), low birth weight (OI: OR 2.19, 95% CI 1.23-3.91; ART: OR 1.90, 95% CI 1.05-3.45), and SGA (OI: OR 2.42, 95% CI 1.20-4.87; ART: OR 2.56, 95% CI 1.28-5.11). ART but not OI is associated with a higher risk of birth before 34 weeks (OR:3.12, 95% CI 1.21-8.05). By comparing the OI group with the ART group, we only found that ART could induce a higher ratio of placental problems (5.0%, 26/518 vs 2.1%, 11/519, p<0.05). Conclusion: Both OI and ART are associated with adverse pregnancy outcomes. ART induced comparable negative effects with OI on gestational complications, birth weight, and premature birth (<37 weeks). However, ART resulted in a higher risk of placental problems than group NC and OI. The incidence of birth before 34 weeks of gestation in the ART group tends to be higher than in the OI group, but not statistically significant. The side effects of ART may originate from OI.
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Diabetes Gestacional , Infertilidad , Complicaciones del Embarazo , Humanos , Niño , Embarazo , Femenino , Animales , Ratones , Resultado del Embarazo/epidemiología , Estudios Retrospectivos , Puntaje de Propensión , Placenta , Complicaciones del Embarazo/epidemiología , Infertilidad/terapiaRESUMEN
Small nucleolar RNA host genes (SNHGs) have been implicated in various biological processes, yet their involvement in polycystic ovary syndrome (PCOS) remains elusive. Specifically, SNHG5, a long non-coding RNA implicated in several human cancers, shows elevated expression in granulosa cells (GCs) of PCOS women and induces PCOS-like features when overexpressed in mice. In vitro, SNHG5 inhibits GC proliferation and induces apoptosis and cell-cycle arrest at G0/G1 phase, with RNA-seq indicating its impact on DNA replication and repair pathways. Mechanistically, SNHG5 acts as a competing endogenous RNA by binding to miR-92a-3p, leading to increased expression of target gene CDKN1C, which further suppresses GC proliferation and promotes apoptosis. These findings elucidate the crucial role of SNHG5 in the pathogenesis of PCOS and suggest a potential therapeutic target for this condition. Additional investigations such as large-scale clinical studies and functional assays are warranted to validate and expand upon these findings.
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Accumulating evidence has shown that inflammation is a key process in polycystic ovary syndrome (PCOS). Nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasomes play an essential role in inflammation. We investigated the expression of NLRP3 inflammasome in PCOS and its underlying mechanisms. Human granulosa cells (GCs) were isolated from patients with PCOS and control women who underwent in vitro fertilization and embryo transfer. Ovarian specimens were collected from mice with polycystic ovarian changes induced by a high-fat diet and letrozole. RNA sequencing (RNA-Seq) was performed on a granulosa cell line (KGN) overexpressing NLRP3. Polymerase chain reaction (PCR) was performed to quantify the differentially expressed genes of interest. NLRP3 and caspase-1 expression was significantly higher in GCs from patients with PCOS than in GCs from the control group. Increased NLRP3 and caspase-1 expression was also detected by immunohistochemistry in the GCs of a mouse model of polycystic ovarian changes. The serum IL-18 concentration in PCOS-like mice was significantly higher than that in control mice. Following NLRP3 overexpression in KGN cells, the genes involved in N-glycan processing, steroidogenesis, oocyte maturation, autophagy, and apoptosis were upregulated. The RT-qPCR results revealed that the expression levels of GANAB, ALG-5, HSD3B2, ULK1, PTK2B, and Casp7 in KGN cells after NLRP3 overexpression were significantly higher than those in control cells, which was consistent with the RNA-Seq results. Taken together, the NLRP3 inflammasome-dependent pathway is involved in the pathogenesis of PCOS not only by mediating pyroptosis, but also by regulating glycan synthesis, sex hormone synthesis, autophagy, and apoptosis in GCs.
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Inflamasomas , Síndrome del Ovario Poliquístico , Animales , Femenino , Humanos , Ratones , Caspasas/metabolismo , Células de la Granulosa/metabolismo , Inflamasomas/metabolismo , Inflamación/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Polisacáridos/metabolismoRESUMEN
Background: To assess the relationship of genetically predicted sexual behavior (age at first sex (AFS) and the number of sexual partners (NSP)) on cardiovascular diseases (CVDs). Methods and results: We performed two-sample Mendelian randomization (MR) with publicly available datasets from the UK Biobank and FinnGen Study, and analyzed genome-wide association results for sexual behaviors and twelve types of CVDs. The univariable MR method provided a total effect of AFS and NSP on CVDs, and showed evidence that early AFS rather than NSP was associated with CVDs, including angina pectoris (AP), atrial fibrillation and flutter (AFF), coronary atherosclerosis (CAS), deep vein thrombosis of the lower extremity (DVT-LE), heart failure (HF), hypertension (HTN), ischaemic stroke (IS), and myocardial infarction (MI). Given sex as a social determinant of CVD risk, we used gender-stratified SNPs to investigate gender differences in the development of CVDs. These results showed a stronger causal relationship of AFS on CVDs in females than in males. Further multivariable MR analyses indicated a direct effect after accounting for insomnia, number of days of vigorous physical activity 10 + minutes (VPA 10 + min), and time spent watching television (TV). Two-step MR demonstrated these three risk factors act as a mediator in AFS associated AP/HTN/HF. Conclusions: We provide evidence that early AFS increased the risk of CVDs. These associations may be partly caused by VPA 10 + min, insomnia, and the time spent on TV. The causality of AFS on CVDs in females was stronger than in males. Conversely, genetically predicted NSP was not associated with CVDs.
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Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.
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Hormona Folículo Estimulante , Islotes Pancreáticos , Ratones , Animales , Humanos , Hormona Folículo Estimulante/farmacología , Hormona Folículo Estimulante/metabolismo , Secreción de Insulina , Glucosa/farmacología , Glucosa/metabolismo , Receptores de HFE/genética , Receptores de HFE/metabolismo , Islotes Pancreáticos/metabolismo , Transducción de Señal , Insulina/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Mamíferos/metabolismoRESUMEN
BACKGROUND: Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. METHODS: Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. RESULTS: Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C+ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C+ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14++CD16- monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. CONCLUSIONS: Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.
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Lesiones Cardíacas , Infarto del Miocardio , Síndrome del Ovario Poliquístico , Embarazo , Femenino , Humanos , Ratones , Animales , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/diagnóstico , Remodelación Ventricular , Infarto del Miocardio/complicaciones , Inflamación/complicaciones , NorepinefrinaRESUMEN
Skeletal muscle plays a crucial role in maintaining metabolic function, energy homeostasis, movement function, as well as endocrine function. The gestation period is a critical stage for the myogenesis and development of skeletal muscle. Adverse environmental exposures during pregnancy would impose various effects on the skeletal muscle health of offspring. Maternal obesity during pregnancy can mediate lipid deposition in skeletal muscle of offspring by affecting fetal skeletal muscle metabolism and inflammation-related pathways. Poor dietary habits during pregnancy, such as high sugar and high fat intake, can affect the autophagy function of skeletal muscle mitochondria and reduce the quality of offspring skeletal muscle. Nutritional deficiencies during pregnancy can affect the development of offspring skeletal muscle through epigenetic modifications. Gestational diabetes may affect the function of offspring skeletal muscle by upregulating the levels of miR-15a and miR-15b in offspring. Exposure to environmental endocrine disruptors during pregnancy may impair skeletal muscle function by interfering with insulin receptor-related signaling pathways in offspring. This article reviews the research progress on effects and possible mechanisms of adverse maternal exposures during pregnancy on offspring skeletal muscle function in clinical and animal studies, aiming to provide scientific evidence for the prevention and treatment strategy of birth defects in skeletal muscle.
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Background: Although numerous studies have investigated the potential correlation between follicular fluid (FF) steroid concentrations and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes, few have accounted for the effect of controlled ovarian hyperstimulation regimes on FF steroid concentrations. Objective: To comprehensively compare follicular steroid concentrations between women stimulated with gonadotropin-releasing hormone agonist (GnRHa) and antagonist (GnRHant) protocols and to explore the associations between FF steroid concentrations and IVF/ICSI outcomes. Methods: A total of 295 infertile women undergoing IVF/ICSI from January 2018 to May 2020 were enrolled. Eighty-four and 211 women received GnRHa and GnRHant protocols, respectively. Seventeen steroids in FF were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the correlation of follicular steroids with clinical pregnancy was explored. Results: Follicular steroid concentrations were similar between the GnRHa and GnRHant groups. Follicular cortisone levels were adversely associated with clinical pregnancy in fresh embryo transfers. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve (AUC) of 0.639 (95% confidence interval = 0.527-0.751, p = 0.025) for predicting non-pregnancy, with an optimal cutoff value of 15.81 ng/mL (sensitivity = 33.3%, specificity = 94.1%). Women with FF cortisone concentrations ≥15.81 ng/mL were fifty times less likely to achieve clinical pregnancy in fresh embryo transfers than those with FF cortisone levels below this threshold (adjusted OR = 0.019, 95% confidence interval = 0.002-0.207, p = 0.001) after adjusting for age, body mass index, baseline serum progesterone levels, serum levels of luteinizing hormone, estradiol and progesterone on human chorionic gonadotropin day, ovarian stimulation protocols, and the number of transferred embryos. Conclusions: There was no significant difference in intrafollicular steroid levels between GnRHa and GnRHant protocols, and intrafollicular cortisone level ≥15.81 ng/mL was found to be a strong negative predictor of clinical pregnancy in fresh embryo transfers with high specificity.
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Objectives: Several studies have indicated a potential association between early life course-related traits and neurological and psychiatric disorders in adulthood, but the causal link remains unclear. Methods: Instrumental variables (IVs) that have been shown to be strongly associated with exposure were obtained from summary data of genome-wide association studies (GWASs). Four early life course-related traits [i.e., birthweight (BW), childhood body mass index (BMI), early body size, and age at first birth (AFB)] were used as exposure IVs to estimate their causal associations with three neurological and psychiatric diseases [i.e., Alzheimer's disease (AD), major depressive disorder (MDD), and attention-deficit hyperactivity disorder (ADHD)]. Four different statistical methods, i.e., inverse-variance weighting (IVW), MR-Egger (MRE), weighted median (WM), and weighted mode (Wm), were performed in our MR analysis. Sensitivity analysis was performed by using the leave-one-out method, and horizontal pleiotropy was assessed using the MR-PRESSO package. Results: There was evidence suggesting that BW has a causal effect on AD (ORMR-PRESSO = 1.05, p = 1.14E-03), but this association was not confirmed via multivariable Mendelian randomization (MVMR) (ORMVMR = 0.97, 95% CI 0.92-1.02, p = 3.00E-01). A strong relationship was observed between childhood BMI and ADHD among both sexes; a 1-SD increase in BMI significantly predicted a 1.46-fold increase in the OR for ADHD (p = 9.13E-06). In addition, a similar relationship was found between early life body size and ADHD (ORMR-PRESSO = 1.47, p = 9.62E-05), and this effect was mainly driven by male participants (ORMR-PRESSO = 1.50, p = 1.28E-3). Earlier AFB could significantly predict a higher risk of MDD (ORMR-PRESSO = 1.19, p = 1.96E-10) and ADHD (ORMR-PRESSO = 1.45, p = 1.47E-15). No significant causal associations were observed between the remaining exposures and outcomes. Conclusion: Our results reveal the adverse effects of childhood obesity and preterm birth on the risk of ADHD later in life. The results of MVMR also show that lower BW may have no direct relationship with AD after adjusting for BMI. Furthermore, AFB may predict a higher risk of MDD.
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Emerging evidence shows that the lncRNA THOR is deeply involved in the development of various cancers. However, the effects and underlying molecular mechanisms of THOR in breast cancer (BRCA) initiation and progression have not been fully elucidated. Here we show that THOR is critical for BRCA tumorigenesis by interacting with hnRNPD to regulate downstream signaling pathways. THOR expression was significantly higher in BRCA tissues than in normal tissues, and THOR upregulation was associated with a poor prognosis in BRCA patients. Functionally, THOR knockdown impaired cell proliferation, migration and invasion in BRCA cells in vitro and inhibited tumorigenesis and metastasis in a tumor xenograft model and THOR-deficient MMTV-PyMT model in vivo. Mechanistically, THOR bound to the hnRNPD protein and increased hnRNPD protein levels by maintaining hnRNPD protein stability through inhibition of the proteasome-dependent degradation pathway. The increased hnRNPD protein levels led to stabilization of its target mRNAs, including pyruvate dehydrogenase kinase 1 (PDK1), further activating downstream PI3K-AKT and MAPK signaling pathways to regulate BRCA cell proliferation and metastasis. Together, our findings indicate that THOR is a promising prognostic predictor for BRCA patients and that the THOR-hnRNPD-PDK1-MAPK/PI3K-AKT axis might be a potential therapeutic target for BRCA treatment.
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Neoplasias de la Mama , ARN Largo no Codificante , Femenino , Humanos , Neoplasias de la Mama/genética , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Nuclear Heterogénea D0 , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/metabolismoRESUMEN
The prevalence of gestational diabetes mellitus (GDM) is increasing rapidly. In addition to the metabolic disease risks, GDM might increase the risks of cryptorchidism in children. However, its mechanism involved in abnormalities of the male reproductive system is still unclear. The purpose of this study was to study the effects of GDM on the development of mouse fetal Leydig cells (FLCs) and Sertoli cells (SCs). Pregnant mice were treated on gestational days 6.5 and 12.5 with streptozotocin (100 mg/kg) or vehicle (sodium citrate buffer). Leydig cell and SC development and functions were evaluated by investigating serum testosterone levels, cell number and distribution, genes, and protein expression. GDM decreased serum testosterone levels, the anogenital distance, and the level of desert hedgehog in SCs of testes of male offspring. FLC number was also decreased in testes of GDM offspring by delaying the commitment of stem Leydig cells into the Leydig cell lineage. RNA-seq showed that FOXL2, RSPO1/ß-catenin signaling was activated and Gsk3ß signaling was inhibited in GDM offspring testis. In conclusion, GDM disrupted reproductive tract and testis development in mouse male offspring via altering genes related to development.
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Diabetes Gestacional , Testículo , Animales , Diabetes Gestacional/metabolismo , Femenino , Desarrollo Fetal , Humanos , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Embarazo , Células de Sertoli/metabolismo , Testículo/metabolismo , TestosteronaRESUMEN
Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.
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Dioxigenasas , Intolerancia a la Glucosa , Hiperglucemia , Oocitos , Adulto , Animales , Dioxigenasas/metabolismo , Femenino , Glucosa/metabolismo , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/genética , Hiperglucemia/metabolismo , Herencia Materna , Ratones , Oocitos/metabolismoRESUMEN
RESEARCH QUESTION: Is advanced paternal age (APA) associated with preterm birth overall and with the subtypes of preterm birth? DESIGN: A total of 66,167 pregnancies were included. Linear regression and logistic regression models were used to analyse the association between paternal age and subtypes of preterm birth. RESULTS: APA was associated with a higher risk of preterm birth (35-44 years: odds ratio [OR] 1.16 [1.04-1.28], Pâ¯=â¯0.006; >44 years: OR 1.40 [1.10-1.78], Pâ¯=â¯0.007) and very early preterm birth (VPTB; <34 weeks) (35-44 years: OR 1.46 [1.17-1.81], Pâ¯=â¯0.002; >44 years: OR 1.65 [1.01-2.69], Pâ¯=â¯0.045). The increased risk of preterm birth was mostly associated with preterm birth with premature rupture of membranes (PROM-PTB) (35-44 years: OR 1.23 [1.03-1.48], Pâ¯=â¯0.021) and medically induced preterm birth (MI-PTB) (>44 years: OR 1.55 [1.12-2.15], Pâ¯=â¯0.008). For women who carried a male fetus, having the father in the 35- to 44-year-old group carried a 1.29-fold risk of PROM-PTB (OR 1.29 [1.02-1.63], Pâ¯=â¯0.031) and a 1.26-fold risk of MI-PTB (OR 1.26 [1.04-1.52], Pâ¯=â¯0.017). There was no evidence of a higher risk of PROM-PTB among women carrying a female fetus, but there was a 1.67-fold higher risk of MI-PTB for the 45-or-older paternal age group (OR 1.67 [1.04-2.67], Pâ¯=â¯0.035). CONCLUSIONS: These results suggest that APA is associated with a higher risk of preterm birth and VPTB, mainly related to PROM-PTB and MI-PTB. The study also indicates a fetal sex-specific association between APA and a higher risk of PROM-PTB for male fetuses.
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Rotura Prematura de Membranas Fetales , Nacimiento Prematuro , Adulto , Femenino , Rotura Prematura de Membranas Fetales/epidemiología , Humanos , Recién Nacido , Masculino , Edad Paterna , Embarazo , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/etiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Diabetes is a complex metabolic disorder which can adversely affect reproductive function. SGK1 is found to be up-regulated in multiple tissues of diabetic patients. However, the effects of diabetes on endometrial SGK1 expression and endometrial receptivity remain unknown. In this study, we established a streptozotocin-induced diabetic mouse model and observed reduced implantation sites, retarded development of pinopodes, increased SGK1, and aberrant expression of LIF and MUC1 in the endometrial epithelium. We injected the uterine lumen of normal mice with high-glucose solution and cultured endometrial cells in high-glucose medium to mimic intrauterine hyperglycemia. Both studies provided compelling evidence that hyperglycemia could lead to diminished embryo implantation and dysregulated SGK1, LIF and MUC1. Additionally, through over-expression of SGK1 in vivo and in vitro, we found that enhanced SGK1 also decreased LIF expression, increased MUC1 expression, and attenuated embryo implantation rate. We further identified that hyperglycemia-activated SMAD2/3 might be responsible for the enhancement of SGK1 and verified directly the interaction between SMAD3 and corresponding SMAD binding elements within SGK1 promoter. Taken together, our study confirmed the association between diabetes-related hyperglycemia and endometrial receptivity defects. Hyperglycemia-induced SGK1 has a tremendous role in this pathological process, rendering it as an attractive therapeutic target for diabetes-related reproductive disorders.
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Diabetes Mellitus , Hiperglucemia , Animales , Diabetes Mellitus/metabolismo , Implantación del Embrión/fisiología , Endometrio , Femenino , Glucosa/metabolismo , Hiperglucemia/genética , RatonesRESUMEN
Growing evidence suggests that adverse intrauterine environments could affect the long-term health of offspring. Recent evidence indicates that gestational diabetes mellitus (GDM) is associated with neurocognitive changes in offspring. However, the mechanism remains unclear. Using a GDM mouse model, we collected hippocampi, the structure critical to cognitive processes, for electron microscopy, methylome and transcriptome analyses. Reduced representation bisulfite sequencing (RRBS) and RNA-seq in the GDM fetal hippocampi showed altered methylated modification and differentially expressed genes enriched in common pathways involved in neural synapse organization and signal transmission. We further collected fetal mice brains for metabolome analysis and found that in GDM fetal brains, the metabolites displayed significant changes, in addition to directly inducing cognitive dysfunction, some of which are important to methylation status such as betaine, fumaric acid, L-methionine, succinic acid, 5-methyltetrahydrofolic acid, and S-adenosylmethionine (SAM). These results suggest that GDM affects metabolites in fetal mice brains and further affects hippocampal DNA methylation and gene regulation involved in cognition, which is a potential mechanism for the adverse neurocognitive effects of GDM in offspring.