Semen quality in men exposed to workplace chemicals is one of the priorities of NIOSH's Program Announcement #RFA-OH-00-006. This proposal is aimed at assessing the detrimental effects of workplace chemicals on semen quality in male workers, using a novel, objective, non-invasive semen assay, and at establishing a relevant, non-human primate model for reproductive toxicology. Objective semen quality assays are currently not available and semen screening in workers is based on clinical sperm parameters (motility, count, morphology), assessed by highly subjective morphological evaluation, or at best, by computerized sperm motility analysis. I have shown previously that selective ubiquitination, i.e. the tagging of sperm mitochondrial membranes with universal proteolytic marker peptide, ubiquitin, occurs in testis and after fertilization (Sutovsky et al., 1999, Nature 402:371-372). My new studies show that, due to this initial testicular ubiquitination, all defective sperm and semen contaminants of cellular origin become polyubiquitinated during epididymal passage. The relative levels of ubiquitin in semen can be objectively determined by flow cytometry, ELISA and immunofluorescence using anti-ubiquitin antibodies, and reflect the fertility of men and reproductive performance of animals. Thus, ubiquitin appears to be a universal biomarker of semen abnormalities. This proposal addresses the following questions: 1. Is the detection of sperm-surface ubiquitination the universal approach for assessing semen quality in exposed workers? 2. Is the rhesus monkey the optimal animal model for assessing the effects of workplace chemicals on male fertility and semen quality? If fully developed, this project will allow for rapid, large scale screening of semen samples from exposed workers, and establish the rhesus monkey as a relevant model for human reproductive toxicology. This project will have a positive impact on public health by providing the first truly objective and universal semen quality assay for occupational medicine.
| Tengowski, M W; Sutovsky, P; Hedlund, L W et al. (2005) Reproductive cytotoxicity is predicted by magnetic resonance microscopy and confirmed by ubiquitin-proteasome immunohistochemistry in a theophylline-induced model of rat testicular and epididymal toxicity. Microsc Microanal 11:300-12 |
| Sutovsky, Peter; Hauser, Russ; Sutovsky, Miriam (2004) Increased levels of sperm ubiquitin correlate with semen quality in men from an andrology laboratory clinic population. Hum Reprod 19:628-38 |
| Miranda-Vizuete, Antonio; Tsang, Katie; Yu, Yang et al. (2003) Cloning and developmental analysis of murid spermatid-specific thioredoxin-2 (SPTRX-2), a novel sperm fibrous sheath protein and autoantigen. J Biol Chem 278:44874-85 |
| Thompson, Winston E; Ramalho-Santos, Joao; Sutovsky, Peter (2003) Ubiquitination of prohibitin in mammalian sperm mitochondria: possible roles in the regulation of mitochondrial inheritance and sperm quality control. Biol Reprod 69:254-60 |
