title: The Effects of Chemotherapeutic Agents, Bleomycin, Etoposide, and Cisplatin, on Chromatin Remodeling in Male Rat Germ Cells.
abstract: The coadministration of bleomycin, etoposide, and cisplatin (BEP) has increased the survival rate of testicular cancer patients to over 90%. Previous studies have demonstrated that BEP induces germ cell damage during the final stages of spermatogenesis, when major chromatin remodeling occurs. Chromatin remodeling permits histone-protamine exchange, resulting in sperm head chromatin compaction. This process involves different epigenetic modifications of the core histones. The objective of these studies was to investigate the effects of BEP on epigenetic modifications to histones involved in chromatin remodeling. Brown Norway rats were treated with BEP, and their testes were removed to isolate pachytene spermatocytes and round spermatids by unit gravity sedimentation. Western blot analyses were conducted on extracted proteins to detect the expression of key modified histones. In a second cohort testes were prepared for immunohistochemical analysis. The stage-specific expression of each modified histone mark in rat spermatogenesis suggests the involvement of these modifications in chromatin remodeling. BEP treatment significantly increased expression of H3K9m and decreased that of tH2B (or Hist1h2ba) in pachytene spermatocytes, suggesting that nucleosomes were not destabilized to allow for transcription of genes involved in chromatin remodeling. Moreover, BEP treatment altered the expression of H4K8ac in round and elongating spermatids, suggesting that histone eviction was compromised, leading to a looser chromatin structure in mature spermatozoa. Less-compacted sperm chromatin, with alterations to the sperm epigenome, may have an adverse effect on male fertility.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Negar
authors.initials: N
authors.lastname: Bagheri-Sereshki
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Hales
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada Department of Obstetrics and Gynecology, McGill University, Montréal, Québec, Canada bernard.robaire@mcgill.ca.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaire
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001761:Bleomycin / Q000009:adverse effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D002945:Cisplatin / Q000009:adverse effects; D005047:Etoposide / Q000009:adverse effects; D042421:Histone Code; D008297:Male; D011914:Rats, Inbred BN; D013087:Spermatids / Q000187:drug effects*; D013090:Spermatocytes / Q000187:drug effects*; D013091:Spermatogenesis
chemical_list: D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin
keywords: epigenetics; histones; male fertility; spermatogenesis; testicular cancer