Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA in normal and pathological adult human epididymis

The pathogenesis of the aberrant development of the male genital tract (epi didymis, vas deferens and seminal vesicles) seen in patients with congenita l bilateral absence of the vas deferens (CBAVD) is still unclear. Since men with CBAVD carry mutations in the cystic fibrosis transmembrane conductanc e regulator gene (CFTR), it is likely that CFTR mRNA of the translated prot ein plays a major role in the pathogenesis of CBAVD. The aim of this study was to compare the pattern of expression of CFTR mRNA in epididymides of me n with CBAVD and other types of obstruction (post-vasectomy and post-inflam matory) with that of normal non-obstructed adult epididymis. Epididymal bio psies were obtained at the time of microsurgical epididymal sperm aspiratio n procedures or during vaso-epididymostomy reanastomosis. A normal epididym is was obtained from an orchiectomy specimen. After standard processing for in situ hybridization, tissue sections were hybridized with CFTR gene-prob e labelled by incorporation of digoxigenin-dUTP. After hybridization the si gnal was detected by an alkaline phosphatase-tagged antidigoxigenin antibod y. CFTR mRNA was clearly identified in the columnar epithelium of the norma l adult epididymis and vas deferens and the signal intensity was greatest i n the most proximal regions of the caput epididymis. Ln contrast, men with genital tract obstructions due to CBAVD or post vasectomy or post-inflammat ory obstructions, had sloughing of the epithelial cells lining the lumen an d as a consequence CFTR mRNA expression was lacking. In one subject (post-v asectomy obstruction), some residual caput epididymal epithelium was preser ved and CFTR mRNA was detected. The abundant CFTR mRNA expression in the pr oximal caput of the epididymis and vas deferens under normal conditions str ongly favours the hypothesis of an early obstructive process in the pathoge nesis of CBAVD. The absent or severely reduced activity of CFTR protein aff ects the ionic exchange and fluid content within the epididymal lumen and t his, in turn, can lead to excessive viscosity of the epididymal fluid, slou ghing of epithelial cells expressing CFTR and further reduction in the amou nt of CFTR activity. As a consequence, variable segments of the epididymis and the vas deferens may be blocked and progressively obliterated. The epid idymal lumen obstruction could also sustain the anatomical defects by not a llowing testosterone to exert a local action on the mesonephric duct.