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Abstract: So far, the pathogenesis of Parkinson’s disease (PD) remains unclear. Current studies implicate environmental toxins may be potential causes of fetal origin of PD. BPA is a member of the family of estrogenic chemicals existing widely in environment. Significant evidences from animal experimentation have demonstrated that BPA interfere with fetal neurodevelopment. Based on previous reports and our research on EB derived from hESCs, we speculate that maternal exposure to low-dose BPA during gestational period may decrease IGF-1 expression, thus hinder the development of fetal DA neurons, and finally increase the risks of fetal origin of PD. Our hypothesis may shed new light on the pathogenesis of PD and lead to potential preventive treatments. [Copyright &y& Elsevier]

Abstract: Objective: Nonsyndromic cleft lip with or without cleft palate(NSCL/P) is a common birth defect with unclear etiology. Both genetic and environmental factors may contribute to NSCL/P. Many genes have been identified as candidate genes associated with this disease. Interferon regulatory factor 6(IRF6) gene and transforming growth factor-a(TGFA) gene seem to be crucial in the predisposition of NSCL/P. Here we evaluated some single nucleotide polymorphisms(SNPs) loci of TGFA and IRF6 genes in Chinese nuclear families consisting of fathers, mothers and affected offspring with NSCL/P. Methods: Fifty patients of NSCL/P were confirmed by the plastic surgeons. They and their parents were included in the study, all with the informed consents. SNPs loci of TGFA and IRF6 genes were analyzed by microarray technology. Some PCR products were randomly chosen and sequenced to check microarray results. The distribution of gene type and allele frequency between patient group and parents group were compared. Then a Haplotype Relative Risk(HRR) and Transmission Disequilibrium Test(TDT) were performed. Results: The sequences of randomly selected PCR products were all consistent with the microarray results. All loci were in Hardy-Weinberg equilibrium. There were no significant differences in the distribution of genotypes and alleles between patients and their parents. Using HRR and TDT analyses the V274I of IRF6 was associated with NSCL/P, while another SNP locus of IRF6 was not. Strong evidence of linkage disequilibrium was found between the 2 SNP loci of TGFA and disease with the HRR analysis, but not with the TDT analysis. Conclusion: Our study confirms the contribution of IRF6 in the etiology of NSCL/P in populations of Asian ancestry. The association of TGFA with NSCL/P requires further research. [Copyright &y& Elsevier]

Objective: We sought to assess the association between polycystic ovary syndrome (PCOS) and ectopic pregnancy after in vitro fertilization–embryo transfer (ET). Study Design: In this retrospective cohort study, we included 5339 women who had clinical pregnancies after in vitro fertilization treatment (PCOS, 205 women; non-PCOS, 5134 women) at Nanjing Medical University (China) between 2007 and 2011. Fresh and cryo-thawed ET cycles were analyzed respectively. The primary outcome measure was the occurrence of ectopic pregnancy. Multivariate logistic regression analysis was used to adjust for important confounders. Results: In fresh ET cycles of women who were undergoing controlled ovarian hyperstimulation (COH; n = 3303), women with PCOS had 3.06 times higher risk of ectopic pregnancy compared with those without PCOS (7.0% vs 2.4%; adjusted odds ratio [aOR], 3.06; 95% confidence interval [CI], 1.34–6.96). In the stratified analysis, for women without PCOS, the high estradiol group (>4085 pg/mL) had higher ectopic pregnancy rates compared with the low estradiol group (≤4085 pg/mL; 3.4% vs 2.0%; aOR, 1.99; 95% CI, 1.19–3.35); however, for women with PCOS, both high and low estradiol groups had high ectopic pregnancy rates (5.6% vs 7.7%; aOR, 0.92; 95% CI, 0.15–5.67). In cryo-thawed ET cycles without COH (n = 2036), the ectopic rates between women with and without PCOS were similar (2.2% vs 2.0%; aOR, 0.94; 95% CI, 0.22–4.07). Conclusion: PCOS was associated with an increased risk of ectopic pregnancy after COH in fresh ET cycles, but not in cryo-thawed ET cycles. A possible explanation is that, compared with women without PCOS, women with PCOS appear to hold a lower threshold of hyperphysiologic estradiol level that triggers the occurrence of ectopic pregnancy after COH. [Copyright &y& Elsevier]

Abstract: Prenatal exposure to nicotine can be associated with fetal abnormal development and brain damage. This study determined the effect of administration of nicotine with associated in utero hypoxia in maternal rats from early, middle, and late gestation on fetal blood hemoglobin, and expression of cholinergic receptor subtypes in the fetal brain. Our results demonstrated that maternal subcutaneous nicotine from the early gestation increased fetal hemoglobin and hematocrit, associated with reduction of PO2. Although exposure to nicotine during late gestation had no effects on fetal brain weight, nicotine administration from the early gestation significantly decreased fetal brain muscarinic receptor (M1, M2, M3, and M4) mRNA expression, associated with restricted brain growth. Nicotine-altered muscarinic receptor subtype expression in the fetal forebrain and hindbrain showed regional differences. In addition, there were gestational differences for fetal brain muscarinic suppression by prenatal nicotine. Together, the results demonstrate that nicotine-induced in utero hypoxia is associated with poor development of muscarinic receptors in the fetal brain and restricted brain growth, and that either prolonged prenatal exposure to nicotine or critical “window” period for the brain development during pregnancy may play a role in prenatal nicotine-induced fetal muscarinic-receptor deficiency in the fetal brain. [Copyright &y& Elsevier]

Objective: To evaluate the effect of coenzyme Q10 (CoQ10) supplementation on oocyte maturation rates and postmeiotic aneuploidy rates during in vitro maturation (IVM) of human oocytes.Design: Clinical laboratory observation.Setting: Hospital and university laboratories.Patient(s): Forty-five patients aged ≥38 years and 18 patients aged ≤30 years undergoing in vitro fertilization.Intervention(s): The germinal vesicle-stage oocytes and associated cumulus cells were cultured in IVM media for 24-48 hours with or without 50 μmol/L CoQ10. Oocyte maturation rates were determined based on the presence or absence of the first polar body. Postmeiotic aneuploidies were determined using next-generation sequencing analyses of biopsied polar bodies.Main Outcome Measure(s): Oocyte maturation rates, postmeiotic oocyte aneuploidy rates, and chromosome aneuploidy frequencies.Result(s): In women aged 38-46 years, 50 μmol/L CoQ10 significantly increased oocyte maturation rates (82.6% vs. 63.0%; P=.035), reduced oocyte aneuploidy rates (36.8% vs. 65.5%; P=.020), and reduced chromosome aneuploidy frequencies (4.1% vs. 7.0%; P=.012. In women aged ≤30 years, we failed to demonstrate an effect of CoQ10 on oocyte maturation rates or postmeiotic aneuploidies.Conclusion(s): CoQ10 supplementation during IVM increased oocyte maturation rates and reduced postmeiotic aneuploidies for older women. [ABSTRACT FROM AUTHOR]

• For the first time, NR4A1 transcript variants were identified in human granulosa cells (KGN cell line). • Two promoter regions at downstream of NR4A1 TSS were identified which is a vary rare phenomenon in gene transcription regulation. • For the first time, the view of ETS family involving in the pathological changes of PCOS characterized with hyperandrogen was proposed. Hyperandrogenism is one of the clinical and biochemical characteristics of polycystic ovary syndrome (PCOS). Our previous studies confirmed that nuclear receptor subfamily 4 group A member 1 (NR4A1), as a differentially expressed gene in the ovaries of PCOS patients, was upregulated by increased androgen. However, the potential mechanism of NR4A1 upregulation remains unknown. To elucidate the molecular mechanisms involved in NR4A1 regulation, we cloned and characterized the promoter regions of the NR4A1 gene using a series of truncated promoter plasmids in luciferase reporter assays. We identified two unique core promoters of NR4A1 located within the +1055/+1251 and +3183/+3233 regions relative to the transcription start site. TFAP2A downregulated NR4A1 expression, while five ETS transcription factors, ETS1, ELK1, ERG, FLI1 and SPI1, could upregulate NR4A1 promoter activity in HeLa cells. Of these transcription factors, ETS1 and ELK1 were the most effective ones. Moreover, all six transcription factors were confirmed to interact directly with the NR4A1 promoter. In conclusion, this study presents the first description that TFAP2A and ETS family signaling networks are involved in the androgen-mediated transcriptional regulation of NR4A1, which contributes to the understanding of the molecular mechanisms involved in the TFAP2A-NR4A1 and ETS-NR4A1 signaling networks in PCOS. [ABSTRACT FROM AUTHOR]

Abstract Research question Can preimplantation genetic testing (PGT) with next-generation sequencing (NGS) increase the chance of achieving a balanced euploid pregnancy in complex chromosome rearrangement (CCR) carriers? Design Six couples underwent PGT at the Clinical Centre of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University. The CCR carriers in the six couples were: Case A: 46,XY,t(1;4;11)(p31;p16;q22); Case B: 46,XY,t(3;13;5)(p14;q21;p14); Case C: 46,XX,t(6;11;21)(q21;q21;q13); Case D: 46,XX,inv(9)(p12; q13),t(13;15)(q14;q24); Case E: 46,XX,inv(9)(p12;q13),t(7;9)(q22;p22); and Case F: 46,XX,t(2;7)(q21;q36),t(2;4)(p10;q10),t(2;4)(q15;q10). After ovarian stimulation followed by oocyte retrieval and embryo culture, PGT was performed on day 5 or 6 blastocyst biopsies using NGS to identify normal/balanced euploid embryos. Vitrified-warmed single embryo transfers were performed using normal/balanced euploid embryos. Results After seven cycles, 84 oocytes were retrieved. Whole genome sequencing by NGS was performed on 25 trophectoderm biosies. Six (24%) embryos were identified as normal/balanced euploid, four were transferred resulting in four live births. Case A, C, D and E each gave birth to a healthy baby after their first cycle. There was no transferable embryo after two cycles for Case B and one cycle for Case F. The implantation rate per transfer was 4/4 and the live birth rate was 4/4. Conclusion These results strongly support the use of NGS for CCR carriers. [ABSTRACT FROM AUTHOR]

Cumulus cells (CCs) are considered as an important source to predict oocyte quality. Despite numerous candidate genes in CCs have been identified for embryonic developmental competence, the results are inconsistent. The next generation RNA-sequencing was used to investigate the transcriptomic differences in CCs from in vitro matured oocytes did or did not develop to blastocyst stage following in vitro fertilization (IVF). In our study, the corresponding mouse oocytes were traced using a single-cell tracking system, and CCs were pooled into groups based on the embryonic developmental outcomes. In vivo matured oocytes with blastocyst development were set as a reference group. The transcriptomic differences in mouse CCs from in vitro maturated oocytes with or without blastocyst formation were tested by RNA-sequencing. Real-time PCR was used to verify the expression levels of those candidate genes. A total of 103 transcripts were significantly up-regulated, and 97 down-regulated, in the CCs with the oocytes developed to blastocyst stage. The bioinformatics study showed that those genes were involved in tube morphogenesis, cell-cell signaling and cell projection formation. Nine genes were selected from the most significantly changed transcripts after comparison with the reference group: Arrb1, Atp2c1, Cdh5, Cntnap1, Mkln1, Lgr4, Rhobtb1, Smc2 and Six2, as the candidate target genes. They were associated with the regulation of G-protein coupled receptors, Wnt and MAPK signaling, actin filaments and cell adhesion. Real-time PCR verified the up-regulation of all 9 genes, and significantly increased of Rhobtb1, Mkln1, Smc2, Arrb1, Atp2c1, Cdh5 and Lgr4. Based on RNA-sequencing, we found the changes in gene transcription of mouse CCs that were critical for the communication between CCs and oocytes. The results could provide novel insights on non-invasively predicting the oocyte quality and improving developmental competence. [ABSTRACT FROM AUTHOR]

SET (SE translocation, SET), a constitutive inhibitor of protein phosphatase 2A (PP2A), is a multifunctional oncoprotein involved in DNA replication, histone modification, nucleosome assembly, gene transcription and cell proliferation. It is widely expressed in human tissues including the gonadal system and brain. Intensive studies have shown that overexpressed SET plays an important role in the development of Alzheimer's disease (AD), and may also contribute to the malignant transformation of breast and ovarian cancers. Recent studies indicated that through interaction with PP2A, SET may upregulate androgen biosynthesis and contribute to hyperandrogenism in polycystic ovary syndrome (PCOS) patients. This review article summarizes data concerning the SET expression in ovaries from PCOS and normal women, and analyzes the role/regulatory mechanism of SET for androgen biosynthesis in PCOS, as well as the significance of this action in the development of PCOS. The potential value of SET-triggered pathway as a therapeutic target and the application of anti-SET reagents for treating hyperandrogenism in PCOS patients are also discussed. [ABSTRACT FROM AUTHOR]

Aberrant expressions of some miRNAs were reported in the placenta from compromised pregnancies, suggesting that the miRNA profiling of chorionic villi could be related with early recurrent miscarriage (RM). This study was designed to investigate the miRNA expression profile, and to predict their potential target genes and signal pathways. The chorionic villi tissues were collected from 15 early RM cases and 15 controls. We focused on investigating the biological pathways and their potential functions in order to explore what is the likely association and how they are possibly involved in the development of early RM. The chorionic villi tissues were collected from 15 early RM cases and 15 controls. A total of 155 differentially expressed miRNAs over 2-fold changes in expression levels (P < 0.05), including 98 up-regulated and 57 down-regulated expressions. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the target genes of those miRNAs were mainly involved in the pathways of MAPK, B cell receptor, T cell receptor and tumor-associated signaling in the development of early RM. Those target genes of differentially expressed miRNAs, coupled with multiple biological processes and pathways, would be beneficial to understand the etiology and pathophysiological mechanism of early RM. [ABSTRACT FROM AUTHOR]

One characteristic of polycystic ovary syndrome (PCOS) is hyperandrogenism, which may be related to the activity of androgen receptor (AR). This study was designed to investigate the polymorphism of CAG and GGN repeats in the AR gene in women with PCOS. The frequency distributions of CAG and GGN repeat alleles, as well as their X-inactivation patterns, were compared between 76 age-matched normal women (control group) and 80 women with PCOS (PCOS group). The expression of AR mRNA in the ovarian tissues of seven patients with PCOS and five normal women was also tested using real-time quantitative PCR. It was found that PCOS patients had significantly higher frequency of longer GGN biallelic mean (29.8%) and X-weighted biallelic mean (33.3%) than controls (6.1% and 3.2%, respectively, P = 0.002, P = 0.003). The odds ratio of the long GGN repeat length ( n > 16) before and after X-chromosome inactivation (XCI) in the PCOS group was significantly higher than in controls ( P = 0.0001, P = 0.005). AR-GGN repeat mRNA expression was higher in the ovarian tissue of controls compared with PCOS patients ( P = 0.022). In conclusion, the data suggest that the GGN repeat polymorphism in the AR gene is associated with PCOS. [ABSTRACT FROM AUTHOR]

Abstract: Premature ovarian failure (POF) is a syndrome characterized by loss of ovarian function before the age of 40years. Adiponectin, a protein secreted by adipose tissue, exerts beneficial effects on glucose and lipid metabolism. Transcription of adiponectin and its receptor gene is correlated with follicular development. POF, as a type of pathological ovarian aging, is associated with an increase in fat mass and body weight, in which adiponectin may be involved. The present study aimed to investigate the relationship between adiponectin gene polymorphisms and idiopathic POF in Chinese women. We examined DNA samples of the variant SmaI (rs2241766) and BsmI (rs1501299) loci of the adiponectin gene in 120 POF patients and 104 controls. Polymerase chain reaction and restriction fragment length polymorphism were used to assess these genotype variants. Our results showed that the genotype distributions of the SmaI and BsmI polymorphisms did not significantly differ between the patients with idiopathic POF and the controls. Moreover, no significant difference was found between the controls and POF patients in the haplotype analysis. This suggests that the SmaI and BsmI polymorphisms of adiponectin gene might not be responsible for idiopathic POF, at least, in the Chinese population. More researches are required to determine whether these findings can be extrapolated to other populations. [Copyright &y& Elsevier]

Abstract: Although a number of studies have shown neural, hormonal, and behavioral capabilities in the control of body fluid regulation under conditions of dehydration in adults, limited information is available on the development of fetal functional abilities in response to osmotic challenge in rats. This study was performed to investigate the influence of maternal hypertonicity on fetal osmoregulatory capabilities at late gestational time in rats. Maternal and fetal plasma osmolality and blood sodium levels were determined and compared at continuous time points from 0.5 to 9h following maternal injection of hypertonic NaCl. Subcutaneous administration of hypertonic saline evoked a rise in plasma osmolality and sodium concentrations in maternal rats and fetuses associated with an up-regulation in angiotensinogen gene mRNA in the fetal liver and down-regulation of the same gene in the fetal brain. The increased levels of fetal blood osmolality and sodium were less than that in their mothers, and the fetus took less time to balance the enhanced osmolality and sodium concentrations. The results suggest that there may exist additional mechanisms in utero at near-term in protecting fetuses from hypertonic challenge. In addition, molecular results in the present study provide new data on fetal angiotensinogen gene expressed differently in the liver and brain under the same condition of prenatal salt loading, indicating osmotic signals of intracellular dehydration related to an acute increase in angiotensinogen mRNA in the fetal liver, and subsequent decrease in angiotensinogen mRNA levels in the fetal brain. [Copyright &y& Elsevier]