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1.
Elife ; 132024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39269275

RESUMEN

Transmembrane channel-like (TMC) proteins are a highly conserved ion channel family consisting of eight members (TMC1-TMC8) in mammals. TMC1/2 are components of the mechanotransduction channel in hair cells, and mutations of TMC1/2 cause deafness in humans and mice. However, the physiological roles of other TMC proteins remain largely unknown. Here, we show that Tmc7 is specifically expressed in the testis and that it is required for acrosome biogenesis during spermatogenesis. Tmc7-/- mice exhibited abnormal sperm head, disorganized mitochondrial sheaths, and reduced number of elongating spermatids, similar to human oligo-astheno-teratozoospermia. We further demonstrate that TMC7 is colocalized with GM130 at the cis-Golgi region in round spermatids. TMC7 deficiency leads to aberrant Golgi morphology and impaired fusion of Golgi-derived vesicles to the developing acrosome. Moreover, upon loss of TMC7 intracellular ion homeostasis is impaired and ROS levels are increased, which in turn causes Golgi and endoplasmic reticulum stress. Taken together, these results suggest that TMC7 is required to maintain pH and ion homeostasis, which is needed for acrosome biogenesis. Our findings unveil a novel role for TMC7 in acrosome biogenesis during spermiogenesis.


Asunto(s)
Acrosoma , Infertilidad Masculina , Ratones Noqueados , Espermatogénesis , Animales , Masculino , Acrosoma/metabolismo , Ratones , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Espermatogénesis/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/deficiencia , Aparato de Golgi/metabolismo , Testículo/metabolismo
2.
Nat Commun ; 15(1): 7747, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39237545

RESUMEN

In this multicenter, non-inferiority, randomized trial, we randomly assigned 992 women undergoing in-vitro fertilization (IVF) with a good prognosis (aged 20-40, ≥3 transferrable cleavage-stage embryos) to strategies of blastocyst-stage (n = 497) or cleavage-stage (n = 495) single embryo transfer. Primary outcome was cumulative live-birth rate after up to three transfers. Secondary outcomes were cumulative live-births after all embryo transfers within 1 year of randomization, pregnancy outcomes, obstetric-perinatal complications, and livebirths outcomes. Live-birth rates were 74.8% in blastocyst-stage group versus 66.3% in cleavage-stage group (relative risk 1.13, 95%CI:1.04-1.22; Pnon-inferiority < 0.001, Psuperiority = 0.003) (1-year cumulative live birth rates of 75.7% versus 68.9%). Blastocyst transfer increased the risk of spontaneous preterm birth (4.6% vs 2.0%; P = 0.02) and neonatal hospitalization >3 days. Among good prognosis women, a strategy of single blastocyst transfer increases cumulative live-birth rates over single cleavage-stage transfer. Blastocyst transfer resulted in higher preterm birth rates. This information should be used to counsel patients on their choice between cleavage-stage and blastocyst-stage transfer (NCT03152643, https://clinicaltrials.gov/study/NCT03152643 ).


Asunto(s)
Blastocisto , Fertilización In Vitro , Nacimiento Vivo , Humanos , Femenino , Embarazo , Fertilización In Vitro/métodos , Adulto , Nacimiento Vivo/epidemiología , Pronóstico , Transferencia de Embrión/métodos , Resultado del Embarazo/epidemiología , Transferencia de un Solo Embrión , Fase de Segmentación del Huevo , Nacimiento Prematuro/epidemiología , Adulto Joven , Índice de Embarazo
3.
F S Sci ; 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39153572

RESUMEN

OBJECTIVE: To evaluate whether intergroup differences in the risk of maternal pregnancy complications after in vitro fertilization (IVF) vary with male factor. DESIGN: A post hoc exploratory secondary analysis of data from a multicenter, randomized, controlled noninferiority trial (NCT03118141). SETTING: Academic fertility centers. PATIENT(S): A total of 1,131 subfertile women with complete recording of their male partner's semen parameters during the trial were enrolled. All participants underwent intracytoplasmic sperm injection followed by frozen embryo transfer (ET) as part of their assisted reproductive technology treatment protocol. INTERVENTION(S): Women were divided into the oligoasthenospermia (n = 405) and normospermia (n = 726) groups according to the quality of male sperm. MAIN OUTCOME MEASURE(S): Pregnancy complications, principally including the incidence of preeclampsia. RESULT(S): Notably, we found that the risk of maternal preeclampsia was significantly higher in the oligoasthenospermia group than in the normospermia group. After adjustments for confounding factors by multivariate logistic regression analysis, the incidence of preeclampsia in the oligoasthenospermia group was still significantly higher than that in the normospermia group (6.55% vs. 3.60%; odds ratio, 0.529; 95% confidence interval, 0.282-0.992). However, there were no significant differences in terms of embryo quality, cumulative live birth rate, other pregnancy complications, or neonatal outcomes between the 2 groups. CONCLUSION(S): Oligoasthenospermia was associated with a higher risk of maternal preeclampsia in subfertile couples undergoing IVF-ET treatment. In clinical practice, it is essential to thoroughly evaluate the sperm quality and quantity of male partners before IVF-ET. Further research is needed to establish the causal relationships between semen quality and adverse pregnancy complications, particularly preeclampsia, and explore potential interventions.

4.
Sci Total Environ ; 951: 175371, 2024 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-39137849

RESUMEN

The widespread use of microplastics and their harmful effects on the environment have emerged as serious concerns. However, the effect of microplastics on the immune system of mammals, particularly their offspring, has received little attention. In this study, polystyrene microplastics (PS-MPs) were orally administered to male mice during lactation. Flow cytometry was used to assess the immune cells in the spleens of both adult male mice and their offspring. The results showed that mice exposed to PS-MPs exhibited an increase in spleen weight and an elevated number of B and regulatory T cells (Tregs), irrespective of dosage. Furthermore, the F1 male offspring of the PS-MPs-exposed group had enlarged spleens; an increased number of B cells, T helper cells (Th cells), and Tregs; and an elevated ratio of T helper cells 17 (Th17 cells) to Tregs and T helper cells 1 (Th1 cells) to T helper cells 2 (Th2 cells). These results suggested a pro-inflammatory state in the spleen. In contrast, in the F1 female offspring exposed to PS-MPs, the changes in splenic immune cells were less pronounced. In the F2 generation of mice with exposed to PS-MPs, minimal alterations were observed in spleen immune cells and morphology. In conclusion, our study demonstrated that exposure to real human doses of PS-MPs during lactation in male mice altered the immune status, which can be passed on to F1 offspring but is not inherited across generations.


Asunto(s)
Lactancia , Microplásticos , Poliestirenos , Animales , Poliestirenos/toxicidad , Microplásticos/toxicidad , Ratones , Femenino , Masculino , Bazo/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología
5.
Nat Commun ; 15(1): 5550, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38956014

RESUMEN

Oocyte in vitro maturation is a technique in assisted reproductive technology. Thousands of genes show abnormally high expression in in vitro maturated metaphase II (MII) oocytes compared to those matured in vivo in bovines, mice, and humans. The mechanisms underlying this phenomenon are poorly understood. Here, we use poly(A) inclusive RNA isoform sequencing (PAIso-seq) for profiling the transcriptome-wide poly(A) tails in both in vivo and in vitro matured mouse and human oocytes. Our results demonstrate that the observed increase in maternal mRNA abundance is caused by impaired deadenylation in in vitro MII oocytes. Moreover, the cytoplasmic polyadenylation of dormant Btg4 and Cnot7 mRNAs, which encode key components of deadenylation machinery, is impaired in in vitro MII oocytes, contributing to reduced translation of these deadenylase machinery components and subsequently impaired global maternal mRNA deadenylation. Our findings highlight impaired maternal mRNA deadenylation as a distinct molecular defect in in vitro MII oocytes.


Asunto(s)
Oocitos , Poliadenilación , Oocitos/metabolismo , Animales , Humanos , Femenino , Ratones , Poli A/metabolismo , Técnicas de Maduración In Vitro de los Oocitos , ARN Mensajero/metabolismo , ARN Mensajero/genética , Transcriptoma , ARN Mensajero Almacenado/metabolismo , ARN Mensajero Almacenado/genética , Metafase , Exorribonucleasas , Proteínas Represoras , Proteínas de Ciclo Celular
6.
Curr Gene Ther ; 24(5): 347-355, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39005061

RESUMEN

Hepatocyte growth factor (HGF) is expressed in multiple systems and mediates a variety of biological activities, such as mitosis, motility, and morphogenesis. A growing number of studies have revealed the expression patterns and functions of HGF in ovarian and testicular physiology from the prenatal to the adult stage. HGF regulates folliculogenesis and steroidogenesis by modulating the functions of theca cells and granulosa cells in the ovary. It also mediates somatic cell proliferation and steroidogenesis, thereby affecting spermatogenesis in males. In addition to its physiological effects on the reproductive system, HGF has shown advantages in preclinical studies over recent years for the treatment of male and female infertility, particularly in women with premature ovarian insufficiency. This review aims to summarize the pleiotropic functions of HGF in the reproductive system and to provide prospects for its clinical application.


Asunto(s)
Factor de Crecimiento de Hepatocito , Humanos , Factor de Crecimiento de Hepatocito/genética , Factor de Crecimiento de Hepatocito/metabolismo , Femenino , Masculino , Reproducción/genética , Animales , Ovario/metabolismo , Espermatogénesis , Testículo/metabolismo , Células de la Granulosa/metabolismo
8.
Sci Total Environ ; 949: 174972, 2024 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-39053555

RESUMEN

Microplastics (MPs) pollution poses a global environmental challenge with significant concerns regarding its potential impact on human health. Toxicological investigations have revealed multi-system impairments caused by MPs in various organisms. However, the specific reproductive hazards in human contexts remain elusive, and understanding the transgenerational reproductive toxicity of MPs remains limited. This study delves into the reproductive toxicity resulting from lactational exposure to polystyrene MPs (PS-MPs) in female mice, extending the inquiry to assess the reproductive effects on their offspring bred by rigorous natural mating. The MPs dosage corresponds to the detected concentration in infant formula prepared using plastic bottles. By systematically evaluating the reproductive phenotypes of F0 female mice from birth to adulthood, we found that female mice exposed to PS-MPs exhibited delayed puberty, disturbed estrous cyclicity, diminished fertility, elevated testosterone, abnormal follicle development, disrupted ovarian steroidogenesis, and ovarian inflammation. Importantly, the observed inheritable reproductive toxicity manifested with gender specificity, showcasing more pronounced abnormalities in male offspring. Specifically, reproductive disorders did not manifest in female offspring; however, a significant decrease in sperm count and viability was observed in PS-MPs-exposed F1 males. Testicular transcriptomics analysis of F1 males significantly enriched pathways associated with reproductive system development and epigenetic modification, such as male germ cell proliferation, DNA methylation, and histone modification. In summary, real-life exposure to PS-MPs impaired the reproductive function of female mice and threateningly disrupted the spermatogenesis of their F1 male offspring, which raises serious concerns about inter- and trans-generational reproductive toxicities of MPs in mammals. These findings underscore the potential threats of MPs to human reproductive health, emphasizing the need for continued vigilance and research in this critical area.


Asunto(s)
Lactancia , Microplásticos , Reproducción , Animales , Femenino , Ratones , Microplásticos/toxicidad , Reproducción/efectos de los fármacos , Masculino , Exposición Materna/efectos adversos
9.
EMBO J ; 43(14): 3044-3071, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38858601

RESUMEN

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells (PGCs) and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss of MCM8 led to R-loop accumulation by reducing the retention of these helicases at R-loops, thus inducing genome instability. Cells expressing premature ovarian insufficiency-causative mutants of MCM8 with decreased interaction with DDX5 displayed increased R-loop levels. These results show MCM8 interacts with R-loop-resolving factors to prevent R-loop-induced DNA damage, which may contribute to the maintenance of genome integrity of PGCs and reproductive reserve establishment. Our findings thus reveal an essential role for MCM8 in PGC development and improve our understanding of reproductive aging caused by genome instability in mitotic germ cells.


Asunto(s)
ARN Helicasas DEAD-box , Inestabilidad Genómica , Proteínas de Mantenimiento de Minicromosoma , Estructuras R-Loop , Animales , Femenino , Humanos , Masculino , Ratones , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Daño del ADN , Células Germinativas/metabolismo , Proteínas de Mantenimiento de Minicromosoma/metabolismo , Proteínas de Mantenimiento de Minicromosoma/genética , Estructuras R-Loop/genética
10.
Adv Sci (Weinh) ; 11(31): e2403866, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38889293

RESUMEN

The progression of spermatogenesis along specific developmental trajectories depends on the coordinated regulation of pre-mRNA alternative splicing (AS) at the post-transcriptional level. However, the fundamental mechanism of AS in spermatogenesis remains to be investigated. Here, it is demonstrated that CWF19L2 plays a pivotal role in spermatogenesis and male fertility. In germline conditional Cwf19l2 knockout mice exhibiting male sterility, impaired spermatogenesis characterized by increased apoptosis and decreased differentiated spermatogonia and spermatocytes is observed. That CWF19L2 interacted with several spliceosome proteins to participate in the proper assembly and stability of the spliceosome is discovered. By integrating RNA-seq and LACE-seq data, it is further confirmed CWF19L2 directly bound and regulated the splicing of genes related to spermatogenesis (Znhit1, Btrc, and Fbxw7) and RNA splicing (Rbfox1, Celf1, and Rbm10). Additionally, CWF19L2 can indirectly amplify its effect on splicing regulation through modulating RBFOX1. Collectively, this research establishes that CWF19L2 orchestrates a splicing factor network to ensure accurate pre-mRNA splicing during the early steps of spermatogenesis.


Asunto(s)
Empalme Alternativo , Proteínas de Ciclo Celular , Infertilidad Masculina , Espermatogénesis , Animales , Masculino , Ratones , Empalme Alternativo/genética , Fertilidad/genética , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Ratones Noqueados , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Espermatogénesis/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo
11.
PLoS Med ; 21(6): e1004388, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38843150

RESUMEN

BACKGROUND: Frozen embryo transfer (FET) has become a widely employed assisted reproductive technology technique. There have historically been concerns regarding the long-term metabolic safety of FET technology in offspring due to pregnancy-induced hypertension and large for gestational age, both of which are well-recognized factors for metabolic dysfunction of children. Therefore, we aimed to compare the metabolic profiles of children born after frozen versus fresh embryo transfer at 2 to 5 years of age. METHODS AND FINDINGS: This was a prospective cohort study. Using data from the "Assisted Reproductive Technology borned KIDs (ARTKID)," a birth cohort of offspring born from assisted reproductive technology at the Institute of Women, Children and Reproductive Health, Shandong University, China. We included 4,246 singletons born after FET (n = 2,181) and fresh embryo transfer (n = 2,065) enrolled between 2008 and 2019 and assessed the glucose and lipid variables until the age of 2 to 5 years. During a mean follow-up of 3.6 years, no significant differences were observed in fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance Index, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels between offspring conceived by fresh and frozen embryo transfer in the crude model and adjusted model (adjusted for parental age, parental body mass index, parental education level, paternal smoking, parity, offspring age and sex). These results remained consistent across subgroup analyses considering offspring age, the stage of embryo transfer, and the mode of fertilization. Results from sensitivity analysis on children matched for age within the cohort remains the same. The main limitation of our study is the young age of the offspring. CONCLUSIONS: In this study, the impact of FET on glucose and lipid profiles during early childhood was comparable to fresh embryo transfer. Long-term studies are needed to evaluate the metabolic health of offspring born after FET.


Asunto(s)
Criopreservación , Transferencia de Embrión , Humanos , Transferencia de Embrión/métodos , Femenino , Preescolar , Masculino , China/epidemiología , Estudios Prospectivos , Metaboloma , Embarazo , Glucemia/metabolismo , Adulto , Estudios de Cohortes , Pueblos del Este de Asia
12.
Reprod Biomed Online ; 49(2): 103736, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38772201

RESUMEN

RESEARCH QUESTION: What is the association between endometrial thickness (EMT) and the birthweight of singleton infants born from frozen-thawed embryo transfer cycles? DESIGN: This retrospective cohort study was conducted from January 2016 to December 2019. Participants were categorized into a natural cycle (NC, n = 8132) group and hormone replacement therapy (HRT, n = 4975) group. Only singleton deliveries were included. The primary outcomes were measures of birthweight and relevant indexes. Multivariable logistic regression and multivariable-adjusted linear regression models that incorporated restricted cubic splines were used. RESULTS: In the HRT group, the risk of delivering a small for gestational age (SGA) infant was increased in women with an EMT <8.0 mm (adjusted odds ratio [aOR] 1.85, 95% confidence interval [CI] 1.17-2.91) compared with women with an EMT of 8.0 to <12.0 mm, and increased with an EMT ≥12.0 mm (aOR 1.85, 95% CI 1.03-3.33). An inverted U-shaped relationship was found between EMT and birthweight in women with HRT. No significant differences were shown in birthweight z-score, or being SGA or large for gestational age, in singletons among the three EMT groups in the natural cycles. CONCLUSIONS: A thinner endometrium seen in women undergoing HRT cycles was associated with a lower birthweight z-score, as well as a higher risk of SGA. However, no significant association was observed between EMT and birthweight z-score or SGA in the NC group. It is noteworthy that a thicker endometrium was not associated with a higher birthweight in frozen-thawed embryo transfer (FET) cycles. Women with a thin endometrium who achieve pregnancy require specialized attention, particularly if they are undergoing FET with HRT cycles.


Asunto(s)
Peso al Nacer , Transferencia de Embrión , Endometrio , Humanos , Femenino , Estudios Retrospectivos , Endometrio/anatomía & histología , Adulto , Embarazo , Transferencia de Embrión/métodos , Recién Nacido , Vitrificación , Criopreservación , Terapia de Reemplazo de Hormonas , Resultado del Embarazo/epidemiología , Recién Nacido Pequeño para la Edad Gestacional
13.
Artículo en Inglés | MEDLINE | ID: mdl-38805186

RESUMEN

CONTEXT: Embryo biopsy, which is necessary for preimplantation genetic testing (PGT), has not been fully investigated regarding its potential influences and safety. Previous studies of children born from biopsied embryos (PGT children) have primarily centered around their growth and neuropsychological development, while there remains limited knowledge concerning their endocrine and metabolic parameters. OBJECTIVE: This study aims to examine the effect of trophectoderm (TE) biopsy on metabolic outcomes for PGT children. METHODS: A total of 1267 children from the Center for Reproductive Medicine, Shandong University, who were conceived through in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) with and without PGT, were analyzed in this study. Three sets of measurements pertaining to growth and metabolism were taken at each predetermined follow-up time point. The linear regression models within a generalized estimating equation were employed to examine the associations between the PGT and each outcome measure and the approach of false discovery rate was used to correct for multiple comparisons. RESULTS: After controlling for confounding factors and correcting for multiple comparisons, no statistically significant difference was identified in any of the measured variables between the PGT children and children conceived by IVF alone (IVF children) and children conceived through IVF using ICSI (ICSI children). The same is true also for age- or sex-based subgroup analyses. CONCLUSION: Between the ages of 1 and 5 years, there are no clinically adverse metabolic outcomes observed in PGT children, and their metabolic profiles are essentially identical to those of IVF children and ICSI children.

14.
Sci China Life Sci ; 67(8): 1620-1634, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38709439

RESUMEN

Polycystic ovary syndrome (PCOS) is a complex disorder. Genome-wide association studies (GWAS) have identified several genes associated with this condition, including DENND1A. DENND1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular transport. However, the specific role of DENND1A in reproductive hormone abnormalities and follicle development disorders in PCOS remain poorly understood. In this study, we investigated DENND1A expression in ovarian granulosa cells (GCs) from PCOS patients and its correlation with hormones. Our results revealed an upregulation of DENND1A expression in GCs from PCOS cases, which was positively correlated with testosterone levels. To further explore the functional implications of DENND1A, we generated a transgenic mouse model overexpressing Dennd1a (TG mice). These TG mice exhibited subfertility, irregular estrous cycles, and increased testosterone production following PMSG stimulation. Additionally, the TG mice displayed diminished responsiveness to FSH, characterized by smaller ovary size, less well-developed follicles, and abnormal expressions of FSH-priming genes. Mechanistically, we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor (FSHR), promoting its internalization and inhibiting recycling. These findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms, thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.


Asunto(s)
Hormona Folículo Estimulante , Células de la Granulosa , Factores de Intercambio de Guanina Nucleótido , Ratones Transgénicos , Síndrome del Ovario Poliquístico , Receptores de HFE , Animales , Femenino , Receptores de HFE/genética , Receptores de HFE/metabolismo , Células de la Granulosa/metabolismo , Hormona Folículo Estimulante/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/genética , Humanos , Ratones , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Testosterona/metabolismo , Transporte de Proteínas
15.
BMC Med ; 22(1): 203, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38764021

RESUMEN

BACKGROUND: To the best of our knowledge, no study has investigated the potential joint effect of large for gestational age (LGA) and assisted reproductive technology (ART) on the long-term health of children. METHODS: This was a prospective cohort study that recruited children whose parents had received ART treatment in the Center for Reproductive Medicine, Shandong Provincial Hospital, affiliated to Shandong University, between January 2006 and December 2017. Linear mixed model was used to compare the main outcomes. The mediation model was used to evaluate the intermediary effect of body mass index (BMI). RESULTS: 4138 (29.5%) children born LGA and 9910 (70.5%) children born appropriate for gestational age (AGA) were included in the present study. The offspring ranged from 0.4 to 9.9 years. LGAs conceived through ART were shown to have higher BMI, blood pressure, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance values, even after controlling for all covariates. The odds of overweight and insulin resistance are also higher in LGA subjects. After adjusting for all covariates, LGAs conceived through ART had BMI and BMI z-scores that were 0.48 kg/m2 and 0.34 units greater than those of AGAs, respectively. The effect of LGA on BMI was identified as early as infancy and remained consistently significant throughout pre-puberty. CONCLUSIONS: Compared to AGA, LGA children conceived from ART were associated with increased cardiovascular-metabolic events, which appeared as early as infancy and with no recovery by pre-puberty.


Asunto(s)
Índice de Masa Corporal , Técnicas Reproductivas Asistidas , Humanos , Estudios Prospectivos , Femenino , Masculino , Niño , Lactante , Preescolar , Edad Gestacional , Resistencia a la Insulina/fisiología , Peso al Nacer/fisiología , Enfermedades Cardiovasculares/epidemiología , Recién Nacido , China/epidemiología
16.
iScience ; 27(4): 109456, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38591005

RESUMEN

Spermiogenesis defines the final phase of male germ cell differentiation. While multiple deubiquitinating enzymes have been linked to spermiogenesis, the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis. We selectively deleted Uaf1 in premeiotic germ cells using the Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. Further, UAF1 interacts and colocalizes with USP1 in the testes. Conditional knockout of Uaf1 in testes results in disturbed protein levels and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. Using tandem mass tag-based proteomics, we identified that conditional knockout of Uaf1 in the testes results in reduced levels of proteins that are essential for spermiogenesis. Thus, we conclude that the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.

17.
JAMA Netw Open ; 7(4): e244438, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38564220

RESUMEN

Importance: The safety of exogenous gonadotropin treatment, based on its effect on embryos and pregnancy outcomes, remains inconclusive. Objective: To evaluate the associations of different doses and durations of gonadotropins with embryonic genetic status and pregnancy outcomes after euploid embryo transfer in couples with infertility. Design, Setting, and Participants: This study was a post hoc analysis of a multicenter randomized clinical trial (RCT) conducted at 14 reproductive centers throughout China from July 2017 to June 2018 that evaluated the cumulative live birth rate with or without preimplantation genetic testing for aneuploidy (PGT-A) among couples with infertility and good prognosis. The PGT-A group from the original RCT was selected for secondary analysis. Patients were divided into 4 groups according to the total dosage of exogenous gonadotropins and treatment duration: group 1 (≤1500 IU and <10 days), group 2 (≤1500 IU and ≥10 days), group 3 (>1500 IU and <10 days), and group 4 (>1 500 IU and ≥10 days). Group 1 served as the control group. Data were analyzed from June through August 2023. Interventions: Blastocyst biopsy and PGT-A. Main outcomes and measures: The primary outcomes were embryonic aneuploidy, embryonic mosaicism, and cumulative live birth rates after euploid embryo transfer. Results: A total of 603 couples (mean [SD] age of prospective mothers, 29.13 [3.61] years) who underwent PGT-A were included, and 1809 embryos were screened using next-generation sequencing. The embryo mosaicism rate was significantly higher in groups 2 (44 of 339 embryos [13.0%]; adjusted odds ratio [aOR], 1.69 [95% CI, 1.09-2.64]), 3 (27 of 186 embryos [14.5%]; aOR, 1.98 [95% CI, 1.15-3.40]), and 4 (82 of 651 embryos [12.6%]; aOR, 1.60 [95% CI, 1.07-2.38]) than in group 1 (56 of 633 embryos [8.8%]). There were no associations between gonadotropin dosage or duration and the embryo aneuploidy rate. The cumulative live birth rate was significantly lower in groups 2 (83 of 113 couples [73.5%]; aOR, 0.49 [95% CI, 0.27-0.88]), 3 (42 of 62 couples [67.7%]; aOR, 0.41 [95% CI, 0.21-0.82]), and 4 (161 of 217 couples [74.2%]; aOR, 0.53 [95% CI, 0.31-0.89]) than in group 1 (180 of 211 couples [85.3%]). Conclusions and relevance: In this study, excessive exogenous gonadotropin administration was associated with increased embryonic mosaicism and decreased cumulative live birth rate after euploid embryo transfer in couples with a good prognosis. These findings suggest that consideration should be given to minimizing exogenous gonadotropin dosage and limiting treatment duration to improve embryo outcomes and increase the live birth rate. Trial Registration: ClinicalTrials.gov Identifier: NCT03118141.


Asunto(s)
Infertilidad , Resultado del Embarazo , Femenino , Embarazo , Humanos , Preescolar , Resultado del Embarazo/epidemiología , Aneuploidia , Transferencia de Embrión , Gonadotropinas/uso terapéutico
18.
Hum Genet ; 143(3): 357-369, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38483614

RESUMEN

Premature ovarian insufficiency (POI) is a common reproductive aging disorder due to a dramatic decline of ovarian function before 40 years of age. Accumulating evidence reveals that genetic defects, particularly those related to DNA damage response, are a crucial contributing factor to POI. We have demonstrated that the functional Fanconi anemia (FA) pathway maintains the rapid proliferation of primordial germ cells to establish a sufficient reproductive reserve by counteracting replication stress, but the clinical implications of this function in human ovarian function remain to be established. Here, we screened the FANCI gene, which encodes a key component for FA pathway activation, in our whole-exome sequencing database of 1030 patients with idiopathic POI, and identified two pairs of novel compound heterozygous variants, c.[97C > T];[1865C > T] and c.[158-2A > G];[c.959A > G], in two POI patients, respectively. The missense variants did not alter FANCI protein expression and nuclear localization, apart from the variant c.158-2A > G causing abnormal splicing and leading to a truncated mutant p.(S54Pfs*5). Furthermore, the four variants all diminished FANCD2 ubiquitination levels and increased DNA damage under replication stress, suggesting that the FANCI variants impaired FA pathway activation and replication stress response. This study first links replication stress response defects with the pathogenesis of human POI, providing a new insight into the essential roles of the FA genes in ovarian function.


Asunto(s)
Proteínas del Grupo de Complementación de la Anemia de Fanconi , Heterocigoto , Insuficiencia Ovárica Primaria , Humanos , Insuficiencia Ovárica Primaria/genética , Femenino , Adulto , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Secuenciación del Exoma , Daño del ADN , Anemia de Fanconi/genética , Mutación Missense
19.
Natl Sci Rev ; 11(3): nwad328, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38449877

RESUMEN

The reprogramming of parental epigenomes in human early embryos remains elusive. To what extent the characteristics of parental epigenomes are conserved between humans and mice is currently unknown. Here, we mapped parental haploid epigenomes using human parthenogenetic and androgenetic embryos. Human embryos have a larger portion of genome with parentally specific epigenetic states than mouse embryos. The allelic patterns of epigenetic states for orthologous regions are not conserved between humans and mice. Nevertheless, it is conserved that maternal DNA methylation and paternal H3K27me3 are associated with the repression of two alleles in humans and mice. In addition, for DNA-methylation-dependent imprinting, we report 19 novel imprinted genes and their associated germline differentially methylated regions. Unlike in mice, H3K27me3-dependent imprinting is not observed in human early embryos. Collectively, allele-specific epigenomic reprogramming is different in humans and mice.

20.
J Transl Med ; 22(1): 145, 2024 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-38347623

RESUMEN

BACKGROUND: Excessive energy intake in modern society has led to an epidemic surge in metabolic diseases, such as obesity and type 2 diabetes, posing profound threats to women's reproductive health. However, the precise impact and underlying pathogenesis of energy excess on female reproduction remain unclear. METHODS: We established an obese and hyperglycemic female mouse model induced by a high-fat and high-sucrose (HFHS) diet, then reproductive phenotypes of these mice were evaluated by examing sexual hormones, estrous cycles, and ovarian morphologies. Transcriptomic and precise metabolomic analyses of the ovaries were performed to compare the molecular and metabolic changes in HFHS mice. Finally, orthogonal partial least squares discriminant analysis was performed to compare the similarities of traits between HFHS mice and women with polycystic ovary syndrome (PCOS). RESULTS: The HFHS mice displayed marked reproductive dysfunctions, including elevated serum testosterone and luteinizing hormone levels, irregular estrous cycles, and impaired folliculogenesis, mimicking the clinical manifestations of women with PCOS. Precise metabolomic overview suggested that HFHS diet disrupted amino acid metabolism in the ovaries of female mice. Additionally, transcriptional profiling revealed pronounced disturbances in ovarian steroid hormone biosynthesis and glucolipid metabolism in HFHS mice. Further multi-omics analyses unveiled prominent aberration in ovarian arginine biosynthesis pathway. Notably, comparisons between HFHS mice and a cohort of PCOS patients identified analogous reproductive and metabolic signatures. CONCLUSIONS: Our results provide direct in vivo evidence for the detrimental effects of overnutrition on female reproduction and offer insights into the metabolic underpinnings of PCOS.


Asunto(s)
Diabetes Mellitus Tipo 2 , Síndrome del Ovario Poliquístico , Femenino , Humanos , Animales , Ratones , Sacarosa/efectos adversos , Diabetes Mellitus Tipo 2/complicaciones , Reproducción , Dieta , Perfilación de la Expresión Génica , Dieta Alta en Grasa/efectos adversos
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