title: The effects of chemotherapy with bleomycin, etoposide, and cis-platinum (BEP) on rat sperm chromatin remodeling, fecundity and testicular gene expression in the progeny.
abstract: During spermiogenesis, histones are replaced first by transition proteins and then by protamines, resulting in a very condensed sperm DNA structure that is absolutely critical for normal sperm function. We have demonstrated previously that, despite a 9-wk recovery period, mature sperm from rats treated for 9 wk with bleomycin, etoposide, and cis-platinum (BEP), the drugs used to treat testicular cancer, have reduced levels of protamine 1 and a concomitant upregulation of specific histones, highlighting a problem in histone eviction. Here, we demonstrate that regulators of histone removal are increased in elongating spermatids following recovery; however, Ac-H4 and gamma H2AX histones remain elevated in elongating spermatids or caudal epididymal spermatozoa 9 wk post-BEP treatment. This indicates that chromatin remodelers and effector proteins that respond to histone removal cues may be a target of BEP treatment. A decrease in the expression of SMARCE1 in elongating spermatids may explain the persistent retention of histones in cauda epididymal sperm 9 wk after the cessation of BEP treatment. Remarkably, proteins implicated in the translational control and posttranslational processing of protamine 1 are also significantly elevated 9 wk post-BEP treatment, suggesting that histone eviction may dictate the DNA availability for protamine binding. Males mated to control females 9 wk after BEP treatment have reduced litter sizes; moreover, the profile of gene expression in the developing testes of their pups is altered. Altering the proportion of histones to protamine in mature spermatozoa has an adverse impact on male fecundity, with modifications to epigenetic marks potentially threatening normal progeny development.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Maselli
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Hales
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaire
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D003433:Crosses, Genetic; D004822:Epididymis / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D044127:Epigenesis, Genetic / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006657:Histones / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008098:Litter Size / Q000187:drug effects; D008297:Male; D018812:Paternal Exposure / Q000009:adverse effects*; D011247:Pregnancy; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; C081018:histone H2B type 1-A; D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin
keywords: F1 transmission; chemotherapeutics; chromatin; histones; male fertility; spermatozoa