Toxicology

Chronic Cyclophosphamide Exposure Alters the Profile of Rat Sperm Nuclear Matrix Proteins

Abstract
Chronic exposure of male rats to the alkylating agent cyclophosphamide, a well-known male-mediated developmental toxicant, alters gene expression in male germ cells, as well as in early preimplantation embryos sired by cyclophosphamide-exposed males. Sperm DNA is organized by the nuclear matrix into loop domains in a sequence specific manner. In somatic cells, loop domain organization is involved in gene regulation. Various structural and functional components of the nuclear matrix are targets for chemotherapeutic agents. Consequently, we hypothesize that cyclophosphamide treatment alters the expression of sperm nuclear matrix proteins. Adult male rats were treated for 4 weeks with saline or cyclophosphamide (6.0 mg/kg/day) and the nuclear matrix was extracted from cauda epididymal sperm. Proteins were analyzed by two-dimensional gel electrophoresis. Identified proteins within the nuclear matrix proteome were mainly involved in cell structure, transcription, translation, DNA binding, protein processing, signal transduction, metabolism, cell defense or detoxification. Interestingly, cyclophosphamide selectively induced numerous changes in cell defense and detoxification proteins, most notably, in all known forms of the antioxidant enzyme, glutathione peroxidase 4, in addition to an uncharacterized 54 kDa form; an overall increase in glutathione peroxidase 4 immunoreactivity was observed in the nuclear matrix extracts from cyclophosphamide-exposed spermatozoa. An increase in glutathione peroxidase 4 expression suggests a role for this enzyme in maintaining nuclear matrix stability and function. These results lead us to propose that a change in composition of the nuclear matrix in response to drug exposure may be a factor in altered sperm function and embryo development.

Key words: Toxicology • Sperm • Proteomics • Nuclear matrix • Glutathione Peroxidase 4

This article has been cited by other articles:

				C. Paul, D. W. Melton, and P. T.K. Saunders Do heat stress and deficits in DNA repair pathways have a negative impact on male fertility? Mol. Hum. Reprod., January 1, 2008; 14(1): 1 - 8. [Abstract] [Full Text] [PDF]