title: The effects of chemotherapy with bleomycin, etoposide, and cis-platinum on telomeres in rat male germ cells.
abstract: Co-administration of bleomycin, etoposide, and cis-platinum (BEP) has increased the 5-year survival rate of testis cancer patients to over 90%; however, this treatment induces chemotoxic effects on male germ cells. Treatment of male rats with BEP, using a similar schedule to that used in man, affects reproductive organ weights and sperm count, motility, and DNA integrity, as well as pup survival rates. Telomeres, specialized structures at the termini of chromosomes, play an important role in the maintenance of genetic stability. In previous studies, we demonstrated, using a spermatogonial cell line, that cis-platinum and bleomycin damage telomeres and that cis-platinum also inhibits telomerase activity. Our objective here was to test the hypothesis that in vivo exposure to the BEP regimen used to treat testis cancer targets telomeres in the male germ line. Adult male Brown Norway rats received chronic treatment with a BEP regimen. DNA double strand breaks were increased significantly in zygotene germ cells, as assessed by γ-H2AX immunofluorescence. Interestingly, treatment with this BEP regimen increased γ-H2AX foci in the telomere region of zygotene spermatocytes, but not in other germ cell types, such as pachytene cells, round spermatids, or elongating spermatids. Mean telomere lengths were reduced in zygotene, pachytene, round spermatid, elongating spermatid and cauda epididymal spermatozoa compared with the saline control group. Thus, telomere lengths did not recover during germ cell development. These studies demonstrate that BEP treatment is associated with an effect on telomeres.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Maselli
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
authors.forename: B F
authors.initials: BF
authors.lastname: Hales
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.|Department of Obstetrics and Gynecology, McGill University, Montréal, QC, Canada.|McGill University Health Centre, Montréal, QC, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Robaire
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D053903:DNA Breaks, Double-Stranded; D005047:Etoposide / Q000633:toxicity*; D006657:Histones / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D011914:Rats, Inbred BN; D013093:Spermatogonia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism; D059506:Telomere Shortening / Q000187:drug effects*; D013997:Time Factors
chemical_list: D006657:Histones; D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin
keywords: DNA double strand breaks; alkylating agents; anticancer drugs; fluorescence in situ hybridization; male germ cells; telomerase; telomeres; toxicology; γH2AX