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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
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
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
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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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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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
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
Gestational and postpartum high-fat diets (HFDs) have been implicated as causes of obesity in offspring in later life. The present study aimed to investigate the effects of gestational and/or postpartum HFD on obesity in offspring. We established a mouse model of HFD exposure that included gestation, lactation and post-weaning periods. We found that gestation was the most sensitive period, as the administration of a HFD impaired lipid metabolism, especially fatty acid oxidation in both foetal and adult mice, and caused obesity in offspring. Mechanistically, the DNA hypermethylation level of the nuclear receptor, peroxisome proliferator-activated receptor-α (Pparα), and the decreased mRNA levels of ten-eleven translocation 1 (Tet1) and/or ten-eleven translocation 2 (Tet2) were detected in the livers of foetal and adult offspring from mothers given a HFD during gestation, which was also associated with low Pparα expression in hepatic cells. We speculated that the hypermethylation of Pparα resulted from the decreased Tet1/2 expression in mothers given a HFD during gestation, thereby causing lipid metabolism disorders and obesity. In conclusion, this study demonstrates that a HFD during gestation exerts long-term effects on the health of offspring via the DNA demethylation of Pparα, thereby highlighting the importance of the gestational period in regulating epigenetic mechanisms involved in metabolism.
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Desmetilación , Dieta Alta en Grasa/efectos adversos , Obesidad/patología , PPAR alfa/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Animales , Femenino , Edad Gestacional , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/metabolismo , PPAR alfa/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
The number of children born after assisted reproductive technology (ART) is accumulating rapidly, and the health problems of the children are extensively concerned. This study aims to evaluate whether ART procedures alter behaviours in male offspring. Mouse models were utilized to establish three groups of offspring conceived by natural conception (NC), in vitro fertilization and embryo transfer (IVF-ET), and frozen-thawed embryo transfer (IVF-FET), respectively. A battery of behaviour experiments for evaluating anxiety and depression levels, including the open field test (OFT), elevated plus maze (EPM) test, light/dark transition test (L/DTT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) was carried out. Aged (18 months old), but not young (3 months old), male offspring in the IVF-ET and IVF-FET groups, compared with those in the NC group, exhibited increased anxiety and depression-like behaviours. The protein expression levels of three neurotrophins in PFC or hippocampus in aged male offspring from the IVF-ET and IVF-FET groups reduced at different extent, in comparison to NC group. RNA sequencing (RNA-Seq) was performed in the hippocampus of 18 months old offspring to further explore the gene expression profile changes in the three groups. KEGG analyses revealed the coexisted pathways, such as PI3K-Akt signalling pathway, which potentially reflected the similarity and divergence in anxiety and depression between the offspring conceived by IVF-ET and IVF-FET. Our research suggested the adverse effects of advanced age on the psychological health of children born after ART should be highlighted in the future.
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Depresión , Fosfatidilinositol 3-Quinasas , Animales , Ansiedad/etiología , Depresión/etiología , Fertilización In Vitro/efectos adversos , Masculino , Ratones , Técnicas Reproductivas Asistidas/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Previous studies have focused on pregnancy outcomes after frozen embryo transfer (FET) performed using different endometrial preparation protocols. Few studies have evaluated the effect of endometrial preparation on pregnancy-related complications. This study was designed to explore the association between different endometrial preparation protocols and adverse obstetric and perinatal complications after FET. METHODS: We retrospectively included all FET cycles (n = 12,950) in our hospital between 2010 and 2017, and categorized them into three groups, natural cycles (NC), hormone replacement therapy (HRT) and ovarian stimulation (OS) protocols. Pregnancy-related complications and subsequent neonatal outcomes were compared among groups. RESULTS: Among all 12,950 FET cycles, the live birth rate was slightly lower for HRT cycles than for NC (HRT vs. NC: 28.15% vs. 31.16%, p < 0.001). The pregnancy loss rate was significantly higher in OS or HRT cycles than in NC (HRT vs. NC: 17.14% vs. 10.89%, p < 0.001; OS vs. NC: 16.44% vs. 10.89%, p = 0.001). Among 3864 women with live birth, preparing the endometrium using OS or HRT protocols increased the risk of preeclampsia, and intrahepatic cholestasis of pregnancy (ICP) in both singleton and multiple deliveries. Additionally, OS and HRT protocols increased the risk of low birth weight (LBW) and small for gestational age (SGA) in both singletons and multiples after FET. CONCLUSION: Compared with HRT or OS protocols, preparing the endometrium with NC was associated with the decreased risk of pregnancy-related complications, as well as the decreased risk of LBW and SGA after FET.
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Transferencia de Embrión/efectos adversos , Endometrio/fisiología , Terapia de Reemplazo de Hormonas/efectos adversos , Inducción de la Ovulación/métodos , Complicaciones del Embarazo/etiología , Adulto , China , Colestasis Intrahepática/etiología , Femenino , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Nacimiento Vivo , Modelos Logísticos , Preeclampsia/etiología , Embarazo , Resultado del Embarazo , Índice de Embarazo , Estudios RetrospectivosRESUMEN
OBJECTIVE: To study the effect of aging on ovarian circadian rhythm. DESIGN: Human and animal study. SETTING: University hospital and research laboratory. PATIENTS/ANIMALS: Human granulosa cells were obtained by follicular aspiration from women undergoing in vitro fertilization (IVF), and ovarian and liver tissues were obtained from female C57BL/6 mice. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Expression of circadian genes in young and older human granulosa cells and circadian rhythm in ovaries and livers of young and older mice. RESULT(S): All examined circadian clock genes in human granulosa cells showed a downward trend in expression with aging, and their mRNA expression levels were negatively correlated with age (P < 0.05). Older patients (≥ 40 years of age) had significantly reduced serum anti-Müllerian hormone (AMH) levels. Except for Rev-erbα, all other examined circadian clock genes were positively correlated with the level of AMH (P < 0.05). The circadian rhythm in the ovaries of older mice (8 months) was changed significantly relative to that in ovaries of young mice (12 weeks), although the circadian rhythm in the livers of older mice was basically consistent with that of young mice. CONCLUSION(S): Lower ovarian reserve in older women is partially due to ovarian circadian dysrhythmia as a result of aging.
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Envejecimiento/genética , Ritmo Circadiano/genética , Hígado/metabolismo , Ovario/metabolismo , Envejecimiento/patología , Animales , Hormona Antimülleriana/sangre , Femenino , Fertilización In Vitro , Células de la Granulosa/metabolismo , Humanos , Ratones , Reserva Ovárica/genética , Ovario/crecimiento & desarrollo , Ovario/patología , ARN Mensajero/genéticaRESUMEN
Primary ovarian insufficiency (POI) leads to infertility and premature menopause in young women. The genetic etiology of this disorder remains unknown in most patients. Using whole exome sequencing of a large Chinese POI pedigree, we identified a heterozygous 5 bp deletion inducing a frameshift in BNC1, which is predicted to result in a non-sense-mediated decay or a truncated BNC1 protein. Sanger sequencing identified another BNC1 missense mutation in 4 of 82 idiopathic patients with POI, and the mutation was absent in 332 healthy controls. Transfection of recombinant plasmids with the frameshift mutant and separately with the missense mutant in HEK293T cells led to abnormal nuclear localization. Knockdown of BNC1 was found to reduce BMP15 and p-AKT levels and to inhibit meiosis in oocytes. A female mouse model of the human Bnc1 frameshift mutation exhibited infertility, significantly increased serum follicle-stimulating hormone, decreased ovary size and reduced follicle numbers, consistent with POI. We report haploinsufficiency of BNC1 as an etiology of human autosomal dominant POI.
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Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mutación Missense , Insuficiencia Ovárica Primaria/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto , Anciano , Animales , Pueblo Asiatico/genética , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Linaje , Insuficiencia Ovárica Primaria/metabolismo , Secuenciación del Exoma , Adulto JovenRESUMEN
Increased granulosa cell (GC) proliferation may contribute to abnormal folliculogenesis in patients with polycystic ovary syndrome (PCOS), which affects approximately 10% reproductive aged women. However, the mechanisms underlying increased GC proliferation in PCOS remain incompletely understood. In this study, we identified miR-3940-5p as a hub miRNA in GC from PCOS using weighted gene co-expression network analysis (WGCNA), and real-time polymerase chain reaction (RT-PCR) analysis confirmed that miR-3940-5p was significantly increased in GC from PCOS. Enrichment analysis of predicted target genes of miR-3940-5p indicated potential roles of miR-3940-5p in follicular development and cell proliferation regulation. Consistently, functional study confirmed that miR-3940-5p overexpression promoted granulosa cell proliferation. Integrated analysis of mRNA expression profiling data and predicted target genes of miR-3940-5p identified potassium voltage-gated channel subfamily A member 5 (KCNA5) as a potential target of miR-3940-5p, and was validated by luciferase reporter assay. Finally, functional analysis suggested that miR-3940-5p promoted GC proliferation in a KCNA5 dependent manner. In conclusion, miR-3940-5p was a hub miRNA upregulated in GC from PCOS, and promoted GC proliferation by targeting KCNA5.
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Regulación Neoplásica de la Expresión Génica , Células de la Granulosa/metabolismo , Canal de Potasio Kv1.5/genética , MicroARNs/genética , Proteínas de Neoplasias/genética , Síndrome del Ovario Poliquístico/genética , Adulto , Antagomirs/genética , Antagomirs/metabolismo , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Genes Reporteros , Células de la Granulosa/patología , Humanos , Canal de Potasio Kv1.5/antagonistas & inhibidores , Canal de Potasio Kv1.5/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Anotación de Secuencia Molecular , Proteínas de Neoplasias/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Cultivo Primario de Células , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de SeñalRESUMEN
Polycystic ovary syndrome (PCOS) is a complicated reproductive endocrine disease characterized by hyperandrogenism, polycystic ovaries, and anovulation. Previous studies have revealed that androgen receptors (ARs) are strongly associated with hyperandrogenism and abnormalities in folliculogenesis in patients with PCOS. However, the kinases responsible for androgen receptor activity, especially in granulosa cells, and the role of casein kinase 2α (CK2α) specifically in the pathogenesis of PCOS, remain unknown. Here, we show that both CK2α protein and mRNA levels were higher in luteinized granulosa cells of patients with PCOS compared with non-PCOS, as well as in the ovarian tissues of mice with a dehydroepiandrosterone-induced PCOS-like phenotype, compared with controls. In addition, CK2α not only interacted with AR in vivo and in vitro, but it also phosphorylated and stabilized AR, triggering AR and ovulation related genes excessive expression. CK2α also promoted cell proliferation in the KGN cell line and inhibited apoptosis. Collectively, the finding highlighted that the CK2α-AR axis probably caused the etiology of the PCOS. Thus, CK2α might be a promising clinical therapeutic target for PCOS treatment.
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Brown adipose tissue (BAT) is an exclusive tissue of nonshivering thermogenesis. It is fueled by lipids and glucose and involved in energy and metabolic homeostasis. Intrauterine exposure to hyperglycemia during gestational diabetes mellitus may result in abnormal fetal development and metabolic phenotypes in adulthood. However, whether intrauterine hyperglycemia influences the development of BAT is unknown. In this study, mouse embryos were exposed to the intrauterine hyperglycemia environment by injecting streptozocin into pregnant mice at 1 d post coitum (dpc). The structure of BAT was examined by hematoxylin and eosin staining and immunohistochemical analysis. The glucose uptake in BAT was measured in vivo by [18F]-fluoro-2-deoxyglucose-micro-positron emission tomography. The gene expression in BAT was determined by real-time PCR, and the 5'-C-phosphate-G-3' site-specific methylation was quantitatively analyzed. Intrauterine hyperglycemia exposure resulted in the impaired structure of BAT and decreased glucose uptake function in BAT in adulthood. The expressions of the genes involved in thermogenesis and mitochondrial respiratory chain in BAT, such as Ucp1, Cox5b, and Elovl3, were down-regulated by intrauterine hyperglycemia exposure at 18.5 dpc and at 16 wk of age. Furthermore, higher methylation levels of Ucp1, Cox5b, and Elovl3 were found in offspring of mothers with streptozotocin-induced diabetes. Our results provide the evidence for enduring inhibitory effects of intrauterine hyperglycemia on BAT development in offspring. Intrauterine hyperglycemia is associated with increased DNA methylation of the BAT specific genes in offspring, which support an epigenetic involvement.-Yu, D.-Q., Lv, P.-P., Yan, Y.-S., Xu, G.-X., Sadhukhan, A., Dong, S., Shen, Y., Ren, J., Zhang, X.-Y., Feng, C., Huang, Y.-T., Tian, S., Zhou, Y., Cai, Y.-T., Ming, Z.-H., Ding, G.-L., Zhu, H., Sheng, J.-Z., Jin, M., Huang, H.-F. Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue.
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Tejido Adiposo Pardo/fisiopatología , Hiperglucemia/fisiopatología , Útero/fisiopatología , Tejido Adiposo Pardo/metabolismo , Animales , Metilación de ADN/fisiología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diabetes Gestacional/inducido químicamente , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatología , Transporte de Electrón/fisiología , Femenino , Expresión Génica/fisiología , Glucosa/metabolismo , Hiperglucemia/metabolismo , Ratones , Ratones Endogámicos ICR , Embarazo , Estreptozocina/farmacología , Termogénesis/fisiología , Útero/metabolismoRESUMEN
RESEARCH QUESTION: Fat accumulation is present in most post-menopausal women, but the underlying mechanism remains unclear. Aquaporin 7 (AQP7) is the most important glycerol channel facilitating glycerol efflux in adipocytes. High circulating FSH in post-menopausal women may play an independent role in regulation of the lipogenic effect of AQP7 in adipocytes. This study explored the role of AQP7 in the pathophysiology of post-menopausal lipogenesis mediated by high concentrations of circulating FSH. DESIGN: Primary adipocytes from post-menopausal and childbearing women were analysed. An in-vivo post-menopausal animal model was established. AQP7 expression, lipid accumulation and glycerol concentration in adipocytes were measured. Luciferase reporter assay and chromatin immunoprecipitation were performed to identify transcriptional crosstalk in AQP7 promoter. RESULTS: It was found that FSH down-regulated AQP7 expression and glycerol efflux function in mature adipocytes of post-menopausal women and ovariectomized (OVX) mice. In vitro, FSH inhibited lipid accumulation in primary cultured mature adipocytes in a dose-dependent manner and the mechanism was down-regulating AQP7 expression via a FSH receptor pathway. The effect of FSH on AQP7 in adipocytes was through activation of cAMP response element-binding (CREB) protein, which could bind to activator protein-1 (AP-1) sites in the AQP7 promoter, and therefore inhibited the transcriptional activation elicited by c-Jun. CONCLUSIONS: Down-regulation of AQP7 by FSH mediated post-menopausal lipogenesis, and the role of FSH was based on binding competition for AP-1 sites between CREB and c-Jun.
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Acuaporinas/fisiología , Hormona Folículo Estimulante/farmacología , Lipogénesis/genética , Posmenopausia , Factor de Transcripción AP-1/metabolismo , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adulto , Anciano , Animales , Acuaporinas/genética , Acuaporinas/metabolismo , Sitios de Unión/efectos de los fármacos , Sitios de Unión/genética , Estudios de Casos y Controles , Células Cultivadas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Posmenopausia/genética , Posmenopausia/metabolismoRESUMEN
Blastomere loss is a common issue during frozen-thawed embryo transfer (FET). Our previous study showed that blastomere loss was associated with an increased risk of small-for-gestational-age (SGA) neonates. The present study assessed the impact of blastomere loss during cryopreservation by comparing the mRNA profiles of umbilical cord blood of FET offspring from the prospective cohort study. Umbilical cord blood samples were collected from 48 neonates, including 12 from the loss group, 11 from the intact group, and 25 from the matched spontaneous pregnancy group. RNA-seq technology was used to compare the global gene expression profiles of the lymphocytes. Then, we used TopHat software to map the reads and quantitative real-time PCR to validate some important differentially expressed genes (DEGs). We identified 92 DEGs between the loss group and the spontaneous pregnancy group, including IGF2 and H19. Ingenuity Pathway Analysis (IPA) showed that the DEGs were most affected in the blastomere loss group. Downstream analysis also predicted the activation of organismal death pathways. In conclusions, our pilot study sheds light on the mechanism underlying how human blastomere loss may affect offspring at the gene expression level. These conclusions are, however, only suggestive, as the current study is based on a very limited sample size and type or nature of biological samples. Additional studies with larger sample sizes and independent experiments with placental samples should be conducted to verify these findings.
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Blastómeros/metabolismo , Criopreservación/métodos , Transferencia de Embrión/métodos , Fertilización In Vitro/métodos , Sangre Fetal/metabolismo , Transcriptoma , Adulto , Análisis por Conglomerados , Metilación de ADN , Femenino , Redes Reguladoras de Genes , Humanos , Recién Nacido , Factor II del Crecimiento Similar a la Insulina/genética , Proyectos Piloto , Embarazo , Estudios Prospectivos , RNA-Seq/métodosRESUMEN
PURPOSE: Higher serum estradiol levels occur in women undergoing assisted reproductive technology (ART) owing to ovarian stimulation. Here, we investigated the association between maternal serum estradiol levels and the intellectual development of offspring conceived with ART. METHODS: A total of 204 singletons born after fresh embryo transfer were recruited for this cohort study. Among them, 102 children were born from mothers with high serum estradiol levels (> 12,000 pmol/L) on the day that human chorionic gonadotropin was administered. Another 102 children, matched by gestational age and age of the children, were recruited as controls from mothers with low serum estradiol (≤ 12,000 pmol/L). The Wechsler Preschool and Primary Scale of Intelligence was used to evaluate the intellectual development of the children. RESULTS: Children from mothers with higher serum estradiol levels scored lower in the verbal intelligence quotient (IQ) tests and verbal comprehension than children whose mothers had lower estradiol levels. The main difference between the two groups was in verbal subtests including information, vocabulary, and sorting. Partial correlation analysis revealed that the logarithm of maternal serum estradiol level negatively correlated with verbal IQ, performance IQ, and full scale IQ. CONCLUSION: Our data demonstrate that a high maternal serum estradiol level may negatively associate the verbal ability of children conceived via ART.
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Estradiol/sangre , Discapacidad Intelectual/sangre , Inteligencia/fisiología , Técnicas Reproductivas Asistidas/efectos adversos , Adulto , Niño , Preescolar , Gonadotropina Coriónica/administración & dosificación , Estudios de Cohortes , Transferencia de Embrión/efectos adversos , Femenino , Fertilización In Vitro/efectos adversos , Humanos , Discapacidad Intelectual/etiología , Discapacidad Intelectual/fisiopatología , Pruebas de Inteligencia , Masculino , Inyecciones de Esperma Intracitoplasmáticas/efectos adversosRESUMEN
BACKGROUND: Exposure to early-life undernutrition is closely related to higher risks of adverse immunologic outcomes in adulthood. Although it has been suggested that asthma has its origins in early life, its underlying mechanisms remain largely unknown. OBJECTIVE: We characterized the effects of early-life undernutrition on T lymphocytes, which play a pivotal role in immune diseases, and we investigated whether this contributes to susceptibility to asthma in adulthood. METHODS: Pregnant mice were fed a protein restriction diet (PRD) to establish an early-life undernutrition model. Naive CD4+ T cells (CD4+CD62LhiCD44-) from offspring were used throughout the study. TH2 differentiation was examined by using fluorescence-activated cell sorting and ELISA under TH2-polarized conditions in vitro and through ovalbumin-induced experimental asthma in vivo. T-cell metabolism was measured with a Seahorse XF96 Analyzer. DNA methylation levels were measured by using bisulfite sequencing. RESULTS: PRD CD4+ T cells displayed increased activation and proliferation and were prone to differentiate into TH2 cells both in vitro and in vivo, leading to susceptibility to experimental asthma. Mechanistically, early-life undernutrition upregulated mechanistic target of rapamycin 1-dependent glycolysis and induced conserved noncoding DNA sequence 1 DNA hypomethylation in the TH2 cytokine locus of CD4+ T cells. Glycolysis blockades undermined increased TH2 skewing and alleviated experimental asthma in PRD mice. CONCLUSION: Early-life undernutrition induced mechanistic target of rapamycin 1-dependent glycolysis upregulation and TH2 cytokine locus hypomethylation in CD4+ T cells, resulting in increased T-cell activation, proliferation, and TH2 skewing and further susceptibility to experimental asthma.
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Asma/genética , Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Desnutrición/genética , Desnutrición/inmunología , Alérgenos/inmunología , Animales , Citocinas/genética , Citocinas/inmunología , Epigénesis Genética , Femenino , Glucólisis , Pulmón/inmunología , Pulmón/fisiopatología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/inmunología , Diana Mecanicista del Complejo 2 de la Rapamicina/inmunología , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , EmbarazoRESUMEN
High circulating androgen in women with polycystic ovary syndrome (PCOS) may increase the risk of cardiovascular disease in offspring. The aim of the present study is to investigate whether maternal androgen excess in the rat PCOS model would lead to cardiac hypertrophy in offspring. Maternal testosterone propionate (maternal-TP)-treated adult female offspring displayed cardiac hypertrophy associated with local high cardiac dihydrotestosterone (DHT). The molecular markers of cardiac hypertrophy along with androgen receptor (AR) and PKCδ, were increased in the Maternal-TP group. Treatment of primary neonatal rat ventricular cardiomyocytes (NRCMs) and H9c2 cells with DHT significantly increased cell size and upregulated PKCδ expression, which could be attenuated by AR antagonist. Treatment with phorbol 12-myristate 13-acetate (PMA), a PKC activator, significantly increased cell size and upregulated myh7 level. Rottlerin, that may inhibit PKCδ, significantly reduced the hypertrophic effect of DHT and PMA on NRCMs and H9c2 cells. Chromatin immunoprecipitation revealed that AR could bind to Pkcδ promoter. Our results indicate that prenatal exposure to testosterone may induce cardiac hypertrophy in adult female rats through enhanced Pkcδ expression in cardiac myocytes.