Function of Epididymis in the Recognition and Elimination of Non-viable Spermatozoa

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Even though the epididymal environment actively promotes sperm survival, the presence of the nonviable sperm population in this region has been observed in many species. Degenerating spermatozoa release enzymes or antigens that could have a detrimental effect on the viability of the neighboring cells. It may be a source of autoantigens that could induce the immune response if they can escape from the blood-epididymis barrier. Anti-sperm antibodies are not uncommon in men; they develop for reasons that are not understood, and they are a source of infertility that is difficult to correct. What are the protective strategies of the epididymis that could prevent these negative impacts on male fertility? We identified a hamster epididymal secretory protein of 64kDa (originally termed HEF64) which assembles into 260 and 280kDa disulfide-linked oligomers. HEF64 is secreted by principal cells of the cauda epididymidis and specifically binds to and then polymerizes into a proteinaceous “death cocoon” coating defective spermatozoa and sperm fragments. The 260/280 kDa oligomers are termed eFGL (for epididymal fibrinogen-like oligomer). Biochemical studies revealed that eFGL is composed of two subunits; the 64kDa polypeptide identified as fibrinogen-like protein-2 and the 33kDa polypeptide identified as fibrinogen-like protein-1. Our morphological studies demonstrated that the eFGL is polymerized into a cocoon-like complex, masking defective luminal spermatozoa and sperm fragments, not the viable sperm population. This research project will define the biochemical basis of this secretory protein (eFGL) recognition and its biological effects on the defective spermatozoa. Our hypothesis is that eFGL represents a novel and unique mechanism to shield the viable sperm population and/or the epididymal epithelium from degenerating spermatozoa contained within the tubule lumen. Completion of the proposed studies will provide new insights into the mechanisms by which the potentially unique epididymal protein functions in the recognition and elimination of defective spermatozoa. Direct demonstration of epididymal protein function would seem critical for development of strategies to help infertile males with normal sperm production but low “sperm quality” of the ejaculate. The aims of this project are: 1. To identify which organelles and potential ligands of defective spermatozoa bind the epididymal eFGL 2. To determine if eFGL binding to specific sperm ligands promotes sperm death and/or death cocoon polymerization.