title: Preconception folic acid use influences the follicle fluid proteome.
abstract: BACKGROUND
  The investigation of the human follicle fluid proteome has gained much interest in the search of new markers as predictors for in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) treatment outcome. Follicular fluid folate, as substrate of one carbon (1-C) metabolism, affects follicular metabolism and oocyte and embryo quality. From this background, we aim to identify a folate-related follicle fluid proteome that associates with IVF/ICSI treatment outcome.
  
  
  METHODS
  In a nested case-control study embedded in a periconception cohort, we performed qualitative and quantitative proteomic analyses using nanoflow LC-MS/MS and TMT labelling in 30 monofollicular fluid samples from women undergoing IVF/ICSI treatment of which 15 used and 15 did not use a folic acid supplement. The protein data are analysed using scaffold proteome Software and differential abundances are expressed as Log2-fold change. Blood samples were obtained before and after treatment for determination of biomarkers of 1-C metabolism and estradiol.
  
  
  RESULTS
  We identified 227 uniquely expressed proteins in follicular fluid. In folic acid supplement users compared to nonusers, we established a lower abundance of C-reactive protein (-2.03; P = < 0.01) and higher abundances of apolipoproteins from high-density lipoprotein (HDL), most notably A-I (+1.28; P = < 0.01) and C-I (+1.11; P = 0.016).
  
  
  CONCLUSIONS
  Preconception folic acid supplement use is associated with suppression of the inflammatory pathway and upregulation of the HDL pathway in human follicular fluid, being a preferential source of cholesterol for steroid hormone synthesis. Studies are needed on the tissue specificity and on the beneficial effects of embryo quality and IVF/ICSI treatment outcome of the proteome of these pathways.
authors.affiliation: Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
authors.forename: John M
authors.initials: JM
authors.lastname: Twigt
authors.affiliation: Proteomics center, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Karel
authors.initials: K
authors.lastname: Bezstarosti
authors.affiliation: Proteomics center, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Lindemans
authors.affiliation: Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Joop S E
authors.initials: JS
authors.lastname: Laven
authors.affiliation: Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.|Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Régine P
authors.initials: RP
authors.lastname: Steegers-Theunissen
mesh_terms: D000328:Adult; D001053:Apolipoproteins / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D050716:Complement C4b-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005307:Fertilization in Vitro; D005492:Folic Acid / Q000627:therapeutic use*; D015571:Follicular Fluid / Q000378:metabolism*; D005786:Gene Expression Regulation; D051228:Geranyltranstransferase / Q000378:metabolism; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000378:metabolism; D007610:Kallikreins / Q000378:metabolism; D006080:Ovarian Follicle; D016742:Preconception Care / Q000379:methods*; D011446:Prospective Studies; D011506:Proteins / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D020554:Sperm Injections, Intracytoplasmic; D015854:Up-Regulation; D014803:Vitamin B Complex / Q000627:therapeutic use*; D000099053:Histidine-Rich Glycoprotein
chemical_list: D001053:Apolipoproteins; D050716:Complement C4b-Binding Protein; C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D011506:Proteins; D020543:Proteome; D017452:Receptors, IgG; D000099053:Histidine-Rich Glycoprotein; D014803:Vitamin B Complex; D002097:C-Reactive Protein; D005492:Folic Acid; D051228:Geranyltranstransferase; D007610:Kallikreins
keywords: Folic acid; follicle fluid; in vitro fertilization and intracytoplasmic sperm injection; proteomics