Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency.

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.

Basonuclin 1 deficiency is a cause of primary ovarian insufficiency.

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.

The effects and mechanisms of GM-CSF on endometrial regeneration.

BACKGROUND: Endometrial injury can result in thin endometrium and subfertility. Granulocyte macrophage colony stimulating factor (GM-CSF) contributes to tissue repair, but its role in endometrial regeneration has not been investigated. METHODS: To determine the effect of GM-CSF on endometrial regeneration, we established a mouse model of thin endometrium by uterine perfusion with 20 µL 90% ethanol. Thin endometrium in mice was featured by lowered endometrial thickness, decreased expression of Ki67 in glandular cells, and a reduced number of implantation sites. To explore the mechanism of GM-CSF on endometrial regeneration, endometrium was obtained from patients undergoing hysterectomy or hysteroscopy and endometrial biopsy. Effects of GM-CSF on primary cultured human endometrial glandular and stromal cells were examined by the 5-bromo-2'-deoxyuridine (BrdU) proliferation assay and transwell migration assay, followed by exploration of the potential signaling pathway. RESULTS: GM-CSF intraperitoneal (i.p.) injection significantly increased endometrial thickness, expression of Ki67 in endometrial glandular cells, and the number of implantation sites. GM-CSF significantly promoted proliferation of primary human endometrial glandular cells and migration of stromal cells. GM-CSF activated p-Akt and increased expressions of p70S6K and c-Jun, which were blocked by LY294002. CONCLUSION: We found that GM-CSF could improve endometrial regeneration, possibly through activating PI3K/Akt signaling pathway.

Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue.

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.

Role of anti-Müllerian hormone and testosterone in follicular growth: a cross-sectional study.

BACKGROUND: Anti-Müllerian hormone (AMH) is now considered the best serum biomarker of ovarian reserve, while basal sex hormones are classic markers used for assessing ovarian reserve. The interaction between AMH and sex hormones are complicated and not sufficiently addressed. In this study, we took diminished ovarian reserve (DOR) and polycystic ovarian syndrome (PCOS) as two extremes of ovarian reserve (deficient and excessive respectively) to investigate the role of AMH and sex hormones in follicular growth. METHODS: A retrospective cross-sectional survey was performed. The patients assessed AMH and basal sex hormones in the Second Hospital of Zhejiang University from April 2016 to March 2019 were involved in this study. Serum AMH and sex hormone concentrations were tested with electrochemiluminescence method. Stepwise linear regression and binary logistic regression was used to determine the predictors of AMH level and to explore the involved factors determining DOR and PCOS. RESULTS: In the present study, we found that age and follicle-stimulating hormone (FSH) were main negative correlation factors, and luteinizing hormone (LH) and testosterone (T) were main positive factors of AMH. In DOR group, age, FSH and estradiol (E2) increased and T decreased, while in PCOS group, LH and T increased. Binary logistic regression found that age, weight, FSH, E2, and T were the significant factors which independently predicted the likelihood of DOR, and that age, body mass index (BMI), AMH, LH, and T predicted the likelihood of PCOS. CONCLUSIONS: Our study demonstrated that age, FSH, and T were factors that most closely correlated with AMH level, and T was involved in both DOR and PCOS. Since DOR and PCOS are manifested with insufficient AMH and excessive AMH respectively, it is suggested that total testosterone correlated with AMH closely and plays an important role in follicular growth. More attention should be given to testosterone level during controlled ovarian hyperstimulation (COH) process.

Sperm parameters and anti-Müllerian hormone remain stable with Helicobacter pylori infection: a cross-sectional study.

BACKGROUND AND AIMS: It has been reported that Helicobacter pylori (HP) infection was more prevalent in infertile populations. HP infection could lead to decreased sperm parameters, and treating the HP infection could improve the quality of sperm. However, studies investigating the relationship between infertility and HP infection are still limited, and more evidence is required. Therefore, we performed the present study to investigate the impact of HP infection on sperm quality in males and on ovarian reserve in females. METHODS: A total of 16,522 patients who visited the Second Hospital of Zhejiang University from January 2016 to June 2019 due to abdominal discomfort and underwent a 13/14C-urea breath HP test were included in this retrospective cross-sectional study. Among them, 565 had performed sperm analysis or ovarian reserve tests in the past three months and were involved for further analyses. Sperm parameters were examined with a computer-assisted sperm analysis system, and serum anti-Müllerian hormone (AMH) and sex hormones were tested with an electrochemiluminescence method. RESULTS: Among 363 patients who underwent the sperm test, 136 (37.47%) had HP infection. Among 202 patients who underwent the AMH test, 55 (27.23%) had HP infection. There was no difference in sperm concentration and motility between the HP+ and HP- groups (P > 0.05). Further subgroup analyses stratified into 5-year age groups confirmed that there was no significant difference in sperm parameters (P > 0.05). When pooled with previously published data, no significant difference in sperm concentration or motility was found (P > 0.05). Meanwhile, this study found that the serum AMH level was similar between the HP+ and HP- groups (P > 0.05). Further subgroup analyses confirmed that there was no significant difference in serum AMH level (P > 0.05). CONCLUSIONS: There were no differences in sperm parameters and AMH levels based on history of HP infection among Chinese patients.

Serum and follicular fluid fetuin-B levels are correlated with fertilization rates in conventional IVF cycles.

PURPOSE: To investigate the relationship between serum/follicular fluid fetuin-B levels and fertilization outcomes in conventional IVF cycles. METHODS: A prospective cohort study of conventional IVF treatments including 78 cycles with low fertilization rates (two pronuclei [2PN] rate < 30%; LF group) and 104 cycles performed during the same period with 2PN rate > 70% (high fertilization group, HF). To calculate the required sample size, a two-sample t test power analysis was applied to data from our pilot study, using PASS 11.0 software. Fetuin-B was measured using a commercial sandwich enzyme-linked immunosorbent assay. RESULTS: Serum fetuin-B and follicular fluid fetuin-B were positively correlated (r = 0.703, P < 0.001). Compared to the HF group, the LF group had significantly lower levels of fetuin-B, both in serum (5.81 ± 1.53 vs. 7.19 ± 1.42, P < 0.001) and follicular fluid (5.06 ± 1.29 vs. 6.16 ± 1.52, P < 0.001). The serum fetuin-B level from cycles with polypronuclear (PPN) zygotes was significantly lower when compared to cycles without PPN zygotes (6.82 ± 1.65 vs. 6.10 ± 1.43, P = 0.006). However, serum fetuin-B level was not correlated with preimplantation embryo development or clinical pregnancy. CONCLUSION: Serum fetuin-B level is correlated with fertilization rate in conventional IVF and it may be used as a predictive marker of fertilization in IVF treatment.

Alternative splicing of the androgen receptor in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgen-induced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.

IGFBP1 Involved in the Decreased Birth Weight Due to Fetal High Estrogen Exposure in Mice.

Our previous study indicated that maternal high-estrogen environment in the first trimester is correlated with increased risks of low birth weight (LBW) and adult diseases. The present study aimed to establish an animal model to confirm such an effect in mice, and to further explore the mechanism involved. A mouse model with high estradiol (E2) exposure during early pregnancy was established, and the birth weight, growth after birth, and expression levels of insulin-like growth factor-binding protein 1 (IGFBP1) of pups were examined. Meanwhile, IGFBP1 expression after treatment of E2 was examined in a HepG2 hepatoma cell line. We found that after exposure to a high-E2 environment the weight of the pups decreased significantly, not only before but also after birth. Meanwhile, both mRNA and protein expressions of IGFBP1 were elevated in placenta and liver tissues. Furthermore, the level of IGFBP1 in the HepG2 cell line was elevated by the treatment of E2, whereas this effect was blocked by estrogen receptor antagonist ICI 182780. In summary, maternal high estrogen up-regulates expression of IGFBP1 in placenta and fetal livers, which contributes to LBW and decreases body weight in offspring.

The association between polymorphism of INSR and polycystic ovary syndrome: a meta-analysis.

Polycystic ovary syndrome (PCOS) is the most common gynecological endocrine disorder. The genetic background is believed to play a crucial role in the pathogenesis of PCOS. In recent years, the role of insulin receptor (INSR) polymorphisms in PCOS predisposition has attracted much attention. We performed a meta-analysis to investigate the association between the single nucleotide polymorphisms (SNPs) of INSR and PCOS. Published literature from Pubmed, Embase, and Cochrane CENTRAL was retrieved up until 7 August 2014. A total of 20 case-control studies including 23,845 controls and 17,460 PCOS cases with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.75 were analyzed. Ninety-eight SNPs distributed in 23 exons and the flanking regions of INSR were investigated, among which 17 SNPs were found to be associated with PCOS. Three SNPs detected in more than three studies were selected for further analyses. Twelve studies including 1158 controls and 1264 PCOS cases entered the analysis of rs1799817, but no significant association was found for every genotype (p > 0.05). Further subgroup stratification by ethnicity and weight did not lead to discovery of significant correlation (p > 0.05). For rs2059806, four studies including 442 controls and 524 PCOS cases were qualified for meta-analysis, and no significant association with PCOS was found for any genotype (p > 0.05). Four studies including 12,830 controls and 11,683 PCOS cases investigated the correlation between rs2059807 and PCOS, and five of the six cohorts indicated a significant impact. Our current meta-analysis suggests no significant correlation between rs1799817/rs2059806 SNPs and susceptibility of PCOS, while rs2059807 could be a promising candidate SNP that might be involved in the susceptibility of PCOS.

High-density 3D single molecular analysis based on compressed sensing.

Single molecule fitting-based superresolution microscopy achieves sub-diffraction-limit image resolution but suffers from a need for long acquisition times to gather enough molecules. Several methods have recently been developed that analyze high molecule density images but most are only applicable to two dimensions. In this study, we implemented a high-density superresolution localization algorithm based on compressed sensing and a biplane approach that provides three-dimensional information about molecules, achieving super-resolution imaging at higher molecule densities than those achieved using the conventional single molecule fitting method.

Altered thyroid hormone profile in offspring after exposure to high estradiol environment during the first trimester of pregnancy: a cross-sectional study.

BACKGROUND: The increasing number of babies conceived by in vitro fertilization and embryo transfer (IVF-ET) shifts concern from pregnancy outcomes to long-time health of offspring. Maternal high estradiol (E2) is a major characteristic of IVF-ET and lasts throughout the first trimester of pregnancy. The fetal thyroid develops during this period and may thus be affected by exposure to the supra-physiological E2. The aim of this study is to investigate whether the high E2 maternal environment in the first trimester increases the risk of thyroid dysfunction in children born following IVF-ET. METHODS: A cross-sectional survey design was used to carry out face-to-face interviews with consecutive children attending the hospital. A total of 949 singletons born after fresh embryo transfer (ET) (n=357), frozen ET (n=212), and natural conception (NC) (n=380), aged 3 to 10 years old, were included. All children were thoroughly examined. Meanwhile, another 183 newborns, including 55 fresh ET, 48 frozen ET, and 80 NC were studied. Levels of serum T3, FT3, T4, FT4, and TSH and levels of maternal E2 at different stages of the first trimester were examined. RESULTS: The mean serum E2 levels of women undergoing fresh ET during the first trimester of pregnancy were significantly higher than those of the women undergoing frozen ET or following NC. The thyroid hormone profile, especially the levels of T4, FT4, and TSH, were significantly increased in 3- to 10-year-old children conceived by fresh ET compared to NC. The same tendency was confirmed in newborns. However, levels of T4 and TSH in the frozen ET group were nearer to that of the NC group. Furthermore, levels of T4 and FT4 in fresh ET were positively correlated with maternal serum levels of E2 during early pregnancy. CONCLUSIONS: The maternal high E2 environment in the first trimester is correlated with increased risk of thyroid dysfunction. Frozen ET could reduce risks of thyroid damage in children conceived by IVF. Further studies are needed to confirm these findings and to better determine the underlying molecular mechanisms and clinical significance. TRIAL REGISTRATION: ChicCTR-OCC-14004682 (22-05-2014).

Treatment effects of laparoscopy versus laparotomy on heterotopic pregnancy after in vitro fertilization and embryo transfer.

OBJECTIVE: To compare the treatment effects of laparoscopy versus laparotomy on heterotopic pregnancy (HP) after in vitro fertilization-embryo transfer (IVF-ET). METHODS: The retrospective case-control study enrolled 109 patients diagnosed with HP after IVF-ET treatment in our hospital from January 2009 to March 2020. All patients received surgical treatment by either laparoscopy or laparotomy. Data for general characteristics, diagnostic features, surgical parameters, as well as perinatal and neonatal outcomes were collected. RESULTS: Sixty-two patients received laparoscopy and 47 received laparotomy. Significantly lower percentage of large hemoperitoneum (P = 0.001), shorter surgery duration (P < 0.001), less intraoperative blood loss (P = 0.001), higher rates of general anesthesia (P < 0.001), and lower cesarean section rates for singletons (P = 0.003) were found in the laparoscopy group. The perinatal and neonatal outcomes were comparable between the two groups. When interstitial pregnancy was considered alone, the surgical blood loss was significantly reduced in the laparoscopy group (P = 0.021), but there was no significant difference in hemoperitoneum, surgery duration, or perinatal and neonatal outcomes in singletons. CONCLUSION: Both laparoscopy and laparotomy are effective surgical treatments for HP after IVF-ET. Laparoscopy is minimally invasive but laparotomy can be an alternative in emergency situations.

Active Ingredients of Schisandra chinensis Fruit Oil and their Effect on Propionibacterium acnes-Induced Inflammation in HaCaT Cells.

BACKGROUND: Propionibacterium acnes causes upregulation of inflammatory factors, such as cycloxygenase-2, prostaglandin E2, interleukin-1ß, and tumor necrosis factor-alpha, increased levels of reactive oxygen species (ROS) and inward flow of calcium ions. This causes increased levels of the antimicrobial peptide LL-37 and inflammation of the skin, leading to redness, swelling, itching and other symptoms. Schisandra chinensis fruit oil (SCO) is rich in lignan active ingredients with various antioxidant and anti-inflammatory properties. METHODS: In this study, SCO is obtained by supercritical CO2 fluid extraction. SCO's anti-inflammatory actions were investigated using P. acnes-induced inflammation HaCaT cells model. A method based on reversed-phase high-pressure liquid chromatography with a diode array detector was developed and validated for the simultaneous detection of five lignan components. Levels of inflammatory factors and LL-37 were measured by ELISA kit and western blot respectively. Ca2+ and ROS levels detected by flow cytometry. RESULTS: The experimental results show that the contents of schisanol A, schisanol B, schisanin A, schisanin B, and schisanin C were 33.89 ± 0.24, 14.89 ± 0.45, 8.92 ± 0.02, 29.14 ± 0.67, and 4.74 ± 0.09 mg/g, respectively. Studies have demonstrated that SCO can alleviate skin inflammation by inhibiting the COX-2/PGE2 and NF-κB signalling pathway. In addition, SCO can inhibit ROS production, significantly block inward Ca2+ flow, alleviate cell damage, and modulate the content of the antimicrobial peptide LL-37. CONCLUSIONS: In summary, our study elucidated the anti-inflammatory activity of SCO in a cell model and provided a scientific basis for its application as a raw material in skin care.

Insufficient maintenance DNA methylation is associated with abnormal embryonic development.

BACKGROUND: Early pregnancy loss (EPL) is a frustrating clinical problem, whose mechanisms are not completely understood. DNA methylation, which includes maintenance methylation and de novo methylation directed by DNA methyltransferases (DNMTs), is important for embryo development. Abnormal function of these DNMTs may have serious consequences for embryonic development. METHODS: To evaluate the possible involvement of DNA methylation in human EPL, the expression of DNMT proteins and global methylation of DNA were assessed in villous or decidua from EPL patients. The association of maintenance methylation with embryo implantation and development was also examined. RESULTS: We found that DNMT1 and DNMT3A were both expressed in normal human villous and decidua. DNMT1 expression and DNA global methylation levels were significantly down-regulated in villous of EPL. DNMT3A expression was not significantly changed in the EPL group compared to controls in either villous or decidua. We also found that disturbance of maintenance methylation with a DNMT1 inhibitor may result in a decreased global DNA methylation level and impaired embryonic development in the mouse model, and inhibit in vitro embryo attachment to endometrial cells. CONCLUSIONS: Our results demonstrate that defects in DNA maintenance methylation in the embryo, not in the mother, are associated with abnormal embryonic implantation and development. The findings of the current study provide new insights into the etiology of EPL.

A new model for embryo implantation: coculture of blastocysts and Ishikawa cells.

OBJECTIVE: To explore and develop a new in vitro implantation model that reflects the main process of embryo attachment and invasion. STUDY DESIGN: One of the limitations in human embryo implantation research is lack of an available in vitro model that faithfully replicates human embryo-uterine interactions. In the present study, we examined the attachment and invasiveness of blastocysts from mice in Ishikawa cell (IK), a human endometrial cell, to clarify whether this new model is suitable to study implantation of embryos. We used IK and placed it in contact with blastocysts to initiate coculture experiments using a specifically designed medium. The culture medium was composed of Ham F-12/Dulbecco's modified Eagle medium (1:1), 30% fetal calf serum, 63.5 nmol/L progesterone, 7.14 nmol/L estradiol-17ß, 100 mg/ml of insulin, and 20 ng/ml epidermal growth factor. The culture for 24 h clearly demonstrated that embryos were capable of attachment to the IK and displayed partial invasion. RESULTS: Our results showed that embryos attached to the IK and displayed partial invasion after coculture of blastocysts with IK for 48 h. CONCLUSIONS: The model is capable of demonstrating the procedure of attachment and invasion of embryo into the endometrial cells and has promises to be used in studies related to early embryo implantation in human endometrium.

Pediatric and adult obesity concerns in female health: a Mendelian randomization study.

PURPOSE: Adulthood and childhood obesity are both associated with reproductive diseases and gynecological cancers in females. However, the causal factors associated with these observations have yet to be identified. Mendelian randomization is a process that is independent of inverse bias and confounding and can act as a random control trial in which genetic groups are settled during meiosis, thus representing an effective tool with which to investigate causality. METHODS: We carried out several Mendelian randomization trials based on the combined genetic scores of 75 adult-associated and 15 childhood-associated body mass index (BMI) single nucleotide polymorphisms (SNPs), databases for several gynecological cancers and reproductive diseases from the UK Biobank (with 194,153 participants), using the traditional inverse-variance weighted (IVW) method as the main method. RESULTS: Elevated adult-associated BMI scores (odds ratio [OR] = 1.003; 95% confidence interval [CI]: 1.001-1.004) and childhood-associated BMI scores (OR = 1.003; 95% CI: 1.001-1.004) were related to a higher risk of the polycystic ovarian syndrome (PCOS), as determined by the traditional IVW method. The random IVW method further revealed a nominal negative causal association between childhood-associated BMI and subsequent endometriosis (OR = 0.995; 95% CI: 0.991-0.999). CONCLUSIONS: Consistent with observational consequences, our findings indicated that adulthood obesity may play role in the development of PCOS and that childhood obesity can increase the risk of PCOS but may reduce the incidence of endometriosis in later life. Further research is now needed to validate our findings and identify the precise mechanisms involved.

Effect of lncRNA MALAT1 on the Granulosa Cell Proliferation and Pregnancy Outcome in Patients With PCOS.

Follicle arrest is one of the main characteristics of polycystic ovary syndrome (PCOS), the most common endocrinological disorder in reproductive-aged women. Increasing evidence proves that high anti-Mullerian hormone (AMH) levels may play an important role in follicular development. Long noncoding RNA (lncRNA) with a length of more than 200 nt is widely involved in the directional differentiation, growth, and development of cells, whereas whether lncRNA is involved in AMH's role in follicular development is unknown. In this study, we analyzed lncRNA expression in ovarian granulosa cells (GCs) collected from women with and without PCOS via high-throughput sequencing. The results showed that a total of 79 noncoding transcripts were differently expressed in GCs of PCOS patients, including upregulated lncRNA MALAT1. The upregulation of MALAT1 was further confirmed by RT-qPCR in GCs from a larger cohort of PCOS patients. Furthermore, knockdown MALAT1 can promote the proliferation of KGN cell in vitro. These data suggested a role for MALAT1 in the development of PCOS. Meanwhile, MALAT1 and phosphorylated SMAD 1/5 (Ser463/465) protein were upregulated in KGN cells after exogenous AMH stimulation, which identified AMH perhaps as a regulator for the expression of MALAT1. We also found that MALAT1 can predict clinical pregnancy outcome to a certain extent by ROC curve analysis (area: 0.771, p = 0.007, 95% CI: 0.617-0.925, sensitivity: 57.1%, specificity: 91.7%). Thus, our findings revealed a role of lncRNA MALAT1 in inhibiting granulosa cell proliferation and may be correlated with pregnancy outcome in PCOS.

Intrauterine hyperglycemia impairs memory across two generations.

Studies on humans and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, the molecular mechanisms underpinning the intergenerational effects remain unclear. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes (DEGs) were enriched in neurodevelopment and synaptic plasticity. The reduced representation bisulfite sequencing (RRBS) of sperm in F1 adult males showed that the intrauterine hyperglycemia exposure caused altered methylated modification of F1 sperm, which is a potential epigenetic mechanism for the intergenerational neurocognitive effects of GDM.