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Alterations in Gene Expression in the Caput Epididymides of Nonobstructive Azoospermic Men¹

INRS-Institut Armand Frappier,³ Université du Québec, Laval, Québec, Canada H7V 1B7 Department of Anatomy and Cell Biology,⁴ McGill University, Montreal, Québec, Canada H3A 2B2 Department of Urology,⁵ Royal Victoria Hospital, McGill University, Montreal, Québec, Canada H3A 1A1

ABSTRACT

Spermatozoal maturation in the epididymis is dependent on proteins secreted by the epithelium and those that create the proper ionic composition and pH of the lumen as well as the blood-epididymal barrier. For the human epididymis, little information exists about the regulation of these proteins in male infertility. Our objectives were to assess gene expression profiles in the caput epididymidis from men with normal spermatogenesis and men with nonobstructive azoospermia. With microarrays, we identified 414 genes in the caput epididymidis that were differentially regulated in infertile men by at least 2-fold compared with the fertile men. They were mostly involved in transcription, intracellular signaling, immunity, and fertility. Although the expression of genes encoding tight junctional proteins was not affected, the localization of CLDN10 and TJP1, but not CLDNs 1, 3, and 8, was altered in infertile patients, suggesting that there are changes in the paracellular functions of the blood-epididymal barrier. Differentially regulated genes included several encoding proteins involved in spermatozoal maturation, water and ion channels, and beta-defensins: CRISP1, SPINLW1, FAM12B, and DEFB129 were upregulated, whereas CFTR, AQP5, KCNK4, KCNK17, SLC6A20, SLC13A3, DEFB126, and DEFB106A were downregulated. Furthermore, the immunolocalization of AQP5, but not of CFTR or CRISP1, varied in infertile and fertile patients. The observation that the expression of genes involved in water and ion transport were repressed in infertile patients suggests that these genes are regulated by the presence of testicular products or spermatozoa in the epididymal lumen or are part of a broader syndrome associated with nonobstructive azoospermia.

beta-defensins, epididymal junctions, epididymis, gene regulation, genomics, infertility, male reproductive tract, male sexual function, water and ion channels

¹Supported by a National Sciences and Engineering Research Council of Canada-Canadian Institutes of Health Research collaborative grant and a Canadian Institutes of Health Research operating grant to D.G.C. and P.T.K.C. E.D. is the recipient of a studentship from the Armand-Frappier Foundation and the FRSQ (Fonds de la Recherche en Santé du Québec). The data discussed in this publication have been deposited in the National Center for Biotechnology Information's Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number GSE9194.

Correspondence: ²Daniel G. Cyr, INRS-Institut Armand Frappier, Université du Québec, 531 boul. des Prairies, Laval, QC, Canada H7V 1B7. FAX: 450 686 5309; e-mail: daniel.cyr{at}iaf.inrs.ca