2047 MICROARRAY ANALYSIS REVEALS MULTIPLE GENES ASSOCIATED WITH MALE INFERTILITY

Abstract

You have accessJournal of UrologyInfertility: Basic Research, Physiology, Pathophysiology1 Apr 20132047 MICROARRAY ANALYSIS REVEALS MULTIPLE GENES ASSOCIATED WITH MALE INFERTILITY Jason Kovac, Josephine Addai, Larry Lipshultz, and Dolores Lamb Jason KovacJason Kovac Houston, TX More articles by this author , Josephine AddaiJosephine Addai Houston, TX More articles by this author , Larry LipshultzLarry Lipshultz Houston, TX More articles by this author , and Dolores LambDolores Lamb Houston, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2466AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The precise mechanisms underlying spermatogenic failure in infertile men are not well understood. Spermatogenesis requires rapid cellular division & DNA repair systems to correct cellular insults or commit the cell to apoptosis. In addition, a well integrated hypothalamic-pituitary-gonadal (HPG) axis is essential for normal testicular function & deregulation of this pathway may contribute to impaired spermatogenesis. Using novel genetic sequencing technologies, we surveyed the genome of infertile men to identify genes involved in abnormal spermatogenesis & perturbation of the HPG axis. METHODS Tissues were obtained from men undergoing testis biopsy for non-obstructive azoospermia (NOA; n=16) & vasectomy controls (n=5). Gene-expression microarray (Agilent Sureprint G3) screened for genetic variations. Microarray data was evaluated with heatmaps, clustering & statistical analysis. Ingenuity Pathway Analysis (IPA) software using False Discovery Rates at 5% highlighted candidate genes & pathways involved. RESULTS Microarray data revealed multiple genes exhibiting altered expression. Comparing infertile men to controls, the largest up-regulated gene-expression was seen in DLX5, SYCE1, KCNK13, LOC643711 & NPTX2. When subdivided based on histopathology, the largest up-regulation as follows: (1) Sertoli Cell Only (SCO): DNTT, NPTX2, KCNK13, DLX5 (2) Maturation Arrest (MA): SRCIN1, NOTUM, DLX5, ZNF259P1 (3) Hypo-spermatogenesis: LOC643711, SYCE1, SEMA6D, KLHDC8A. With respect to DNA repair and apoptosis, genes identified included AREG, CACNA1H, CRYAB, PAX8, SFN, & STAR. IPA identified cancer (43 molecules) & reproductive system disease (39 molecules) to be the most significantly associated diseases/disorders between controls & NOA men. The top molecular networks were cell growth/proliferation (35 molecules) & cell signaling (15 molecules). Significantly up-regulated genes included STAR, HTR2B, GATA4 & CHN2 whereas down-regulated genes were MMP7, KRT14, KRT17 & MAL. The most significantly expressed transcription factors included EZH2, BRCA1, TP73 & CTBP2. CONCLUSIONS This study has identified several genes associated with male infertility & DNA repair. The fact that DLX5 was up-regulated in the SCO & MA subtypes corresponds to previous work noting a relationship between DLX, hormone synthesis & the HPG axis. It is thus tempting to speculate that modulation of steroidogenesis through DLX5 may contribute to male infertility. The stage is now set for future investigations into the molecular signaling mechanisms that regulate infertility. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e840 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jason Kovac Houston, TX More articles by this author Josephine Addai Houston, TX More articles by this author Larry Lipshultz Houston, TX More articles by this author Dolores Lamb Houston, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...