Hum. Reprod. Advance Access published online on February 15, 2007
Human Reproduction, doi:10.1093/humrep/dem002
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Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa
1 Departments of Pharmacology and Therapeutics 2 Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada
3 To whom correspondence should be addressed at: Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec, Canada H3G 1Y6. E-mail: barbara.hales{at}mcgill.ca
BACKGROUND: The formation of mature sperm involves the expression of numerous proteins during spermiogenesis and the replacement of histones with protamines to package the genome. Exposure to cyclophosphamide (CPA), an anticancer alkylating agent, during spermiogenesis may disrupt chromatin condensation with adverse consequences to the offspring.
METHODS: Adult male rats were given CPA in one of two schedules: (i) subchronic, 4 days—day 1 (100 mg kg–1) and days 2–4 (50 mg kg–1 per day) or (ii) chronic—daily (6.0 mg kg–1 per day). Animals were euthanized on days 14, 21 or 28.
RESULTS: The effects of CPA on epididymal sperm chromatin structure were germ-cell-phase specific; mid-spermiogenic spermatids were most sensitive. The acridine orange DNA denaturation assay showed significant increases in susceptibility to denaturation (P < 0.01). Chromatin packaging assessment revealed 1,4-dithiothreitol-dependent chromomycin A3 DNA binding and less condensed, protamine-deficient sperm; the total thiol (P < 0.001) and protamine contents (P < 0.01), measured using monobromobimane and the HUP1N protamine 1 antibody, respectively, were reduced. The sperm basic proteome was also altered; proteins that were identified are involved in events during spermiogenesis and fertilization.
CONCLUSIONS: Paternal exposure to CPA alters sperm chromatin structure, as well as the composition of sperm head basic proteins. We speculate that these changes underlie effects on fertilization and embryo development.
Key words: chemotherapeutic agents/chromatin packaging/infertility/proteomics/toxicology
Submitted on October 26, 2006; resubmitted on December 15, 2006; accepted on January 2, 2007.
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