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Original Article Metabolomic Profiling of Human Follicular Fluid from Patients with Repeated Failure of in Vitro Fertilization

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Original Article Metabolomic Profiling of Human Follicular Fluid from Patients with Repeated Failure of in Vitro Fertilization Int J Clin Exp Pathol 2014;7(10):7220-7229 www.ijcep.com /ISSN:1936-2625/IJCEP0001500 Original Article Metabolomic profiling of human follicular fluid from patients with repeated failure of in vitro fertilization using gas chromatography/mass spectrometry Lan Xia, Xiaoming Zhao, Yun Sun, Yan Hong, Yuping Gao, Shuanggang Hu Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reprodutive Medcine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Received July 22, 2014; Accepted August 23, 2014; Epub September 15, 2014; Published October 1, 2014 Abstract: Objective: To establish a gas chromatography/mass spectrometry (GC/MS)-based metabolomics method to compare the metabolites in the follicular fluid (FF) from patients with in vitro fertilization (IVF) and repeated IVF failure (RIF). Methods: A prospective study was employed in Center for Reprodutive Medcine, Renji Hospital, Shanghai, China, between January and October 2010. FF samples were collected from 13 patients with RIF and 15 patients who achieved pregnancy after the first IVF cycle. Results: Partial least squares (PLS) discriminant analysis of the PCA data revealed that the samples were scattered into two different regions. FF from the two groups differed with respect to 20 metabolites. FF from RIF group showed elevated levels of several amino acids (valine, threonine, isoleucine, cysteine, serine, proline, alanine, phenylalanine, lysine, methionine and ornithine), and reduced levels of dicarboxylic acids, cholesterol and some organic acids. Conclusions: The studies corroborated successful determi- nation of the levels of metabolite in the FF. Keywords: In vitro fertilization (IVF), follicular fluid, repeated IVF failure (RIF), metabolomics Introduction or suboptimal embryo culture conditions), endo- metriosis, hydrosalpinges or suboptimal ovari- Despite the advancements in infertility man- an stimulation [3, 4]. Besides, oocyte quality agement that has been achieved using the in has emerged as an important factor that affects vitro fertilization (IVF) method, the success rate the pregnancy outcomes [5]. Basically, FF forms of IVF remains limited to 30-40% [1]. This may the microenvironment of the developing oocyte, due to the report of repeated implnatation and has direct impact on the oocyte quality, failuere (RIF) in many of the couples. RIF, in this sperm-oocyte interaction, sperm-mediated ooc- regard, can be defined as the chances of failure yte activation, implantation and early embryo to achieve a pregnancy following 2-6 IVF cycles development. Human FF is extremely useful for post-inoculation with more than 10 high grade the assessment of the developmental compe- embryos [2]. In current clinical practice, there is tence of female gametes, as it is rich in low- a tendency to transfer only one or two embryos, molecular weight (LMW) metabolites that are and hence, this definition of RIF is no longer responsible for the development and matura- useful. For this reason, it has been suggested tion of viable embryos [6], thus the outcome of more recently that RIF may be considered as pregnancy. Several studies have reported the the failure of three consecutive cycles of IVF, in correlation between components of FF and which reasonably good embryos were trans- implantation rate to identify potential markers ferred [3]. affecting the successful pregnancy. For ins- tance, levels of metabolites (such as glucose, Numerous factors tend to affect the etiology lactate, choline/phosphocholine and lipopro- and success of RIF including reduced endome- teins) in the FF have been reported to capable trial receptivity (due to uterine cavity abnormal- of distinguishing embryos that would develop ities, immunological causes or thrombophilia), into the early cleavage stage [7, 8]. Furthermore, defective embryonic development (due to ge- granulocyte colony-stimulating factor (G-CSF), netic abnormalities, zona pellucida hardening vitamin D and hyaluronan levels in the FF have Human follicular fluid metabolomic study Table 1. Clinical characteristics of the participants in- metabolites, therefore, has been po- cluded in the study tentially more informative than the di- RIF group Control group rect study of gene expression (genom- Parameter (n = 13) (n = 15) ics), mRNAs (transcriptomes) or pro- Age (years) 34.0 ± 3.9 33.3 ± 3.2 teins (proteomes) as the increasing Duration of infertility (years) 7.9 ± 4.3* 3.5 ± 1.5 gene activation with consequent mR- NA and protein synthesis correspond Number of previous cycles received 3.7 ± 1.1* 1.0 ± 0.0 to the altered cellular function, where- Fertilization rate (%) 57.6 64.3 as metabolomes provide idea on the Cleavage rate (%) 98.1 100 actual functional status of a biological Good quality embryo rate (%) 63.5 69.7 system and its cells. Number of embryos transferred 3.1 ± 0.7 2.5 ± 0.6 HCG-day endometrial thickness (mm) 8.0 ± 0.8 8.9 ± 0.9 Metabolomics have been proven to be Data are presented as the mean ± standard deviation or as a percent- a consistent and informative technolo- age. *P < 0.05. RIF, repeated in vitro fertilization failure; HCG, human gy for pattern recognition analysis of chorionic gonadotropin. several biological systems, and pres- ently being applied for studying the shown positive correlations with successful im- human embryos [6, 14, 15] and oocytes [16- plantation, while anti-Mullerian hormone con- 18]. It helps in discriminating the metabolites centrations are found to be negatively correlat- secreted by the oocyte into the surrounding ed with reproductive outcome [9-12]. medium by investigating the FF, or alternatively, the compounds secreted by the oocyte into the Metabolic profiling of FF could prove to be more culture medium in which it is suspended during useful for the assessment of oocyte quality in vitro culture after retrieval (“exometabolo- than a targeted metabolic approach or the stu- mics” or “secretomics”). To date, there are no dy of a selective class of substances. It has literature reports available with the application been observed that more than one metabolite of GC/MS analysis to FF, especially in the con- is involved in determining the oocyte’s develop- text of RIF. mental competence and therefore a panel of biomarkers should be considered for clinical The attempts were made, therefore, to com- diagnostic purposes. Thus it is necessary to pare metabolite profiles in FF samples between identify the reliable metabolic networks in FF patients with RIF and a control group of partici- using comprehensive and powerful technolo- pants employing GC/MS and chemical deriva- gies. This goal can be achieved employing the tization techniques coupled with principal com- metabolomic platforms to identify and quantify ponents analysis (PCA) to identify the metabol- a large array of metabolites simultaneously ic biomarkers in the FF to differentiate between [13]. the patients with RIF and the subjects with suc- cessful pregnancy after the first cycle. Gas chromatography/mass spectrometry (GC/ MS)-based metabolomics are one of the most Materials and methods efficient and reliable platforms available, which can be used for separating and resolving the Chemicals and reagents complex biological mixtures owing to their high efficiency, comprehensive database network 1,-2-chlorophenylalanine (used as an internal and good reproducibility. As an integrated part standard) was obtained from M/s Shanghai of the system biology, metabolomics have nu- Intechem Tech. Co. Ltd., (Shanghai, China); me- merous advantages over the traditional “omics” thanol (pesticide residue grade), bis-(trime- technologies, since metabolites are the end thylsilyl)-trifluoroacetamide (BSTFA) plus 1% tri- products of cellular biological processes and methylchlorosilane (TMCS) and amino acid their levels ultimately reflect the integrated standard solution were purchased from M/s response of a biological system [13]. The low- Sigma-Aldrich (St. Louis, MO, USA). All other molecular weight metabolites can reveal the chemicals and reagents used during the experi- response of the follicles to all the factors influ- mental procedure were purchased from M/s encing its development. The assessment of Ampu Company (Shanghai, China). Triple dis- 7221 Int J Clin Exp Pathol 2014;7(10):7220-7229 Human follicular fluid metabolomic study Figure 1. GC/MS TICs of the FF samples from the RIF (n = 13) and control (n = 15) groups. The upper panel (Group C) shows the TICs of the 15 FF samples of the control group, while the lower panel (Group R) illustrates the TICs of the 13 samples of RIF group. The ordinate shows the relative mass abundance and the abscissa shows the reten- tion time. tilled water produced from the Milli-Q water October 2010. The inclusion criteria for patients purification system (Millipore, Billerica, MA, with RIF selected were age < 38 years followed USA). by at least three IVF embryo transfer failures and the transferal rate of at least 10 high-qual- Enrolment of study participants ity embryos in total. All the male partners had normal semen quality according to World A case-control study was selected and the Health Organization (WHO, 1999) criteria. In entire study was carried out at the Renji Hos- addition, 15 patients who became pregnant in pital, Shanghai Jiaotong University, Shanghai, the first IVF cycle were recruited (over the same China. The study was approved by the Ins- time period) as a control group. All patients had titutional Ethics Committee of Renji Hospital a good hormonal reserve and a good response and written informed consents were taken from to hormonal stimulation (more than eight each participant. Thirteen patients with RIF oocytes/oocyte retrieval). The patients with were recruited between January 2010 and premature ovarian failure and endometriosis 7222 Int J Clin Exp Pathol 2014;7(10):7220-7229 Human follicular fluid metabolomic study Figure 2. Representative GC/MS TICs of FF samples from the RIF and control groups. The upper panel (C1162) shows the TIC of a FF sample from the control group, while the lower panel (R1118) illustrates the TIC of a sample from the RIF group.
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