Paternal exposure to testis cancer chemotherapeutics alters sperm fertilizing capacity and affects gene expression in the eight-cell stage rat embryo.
Treatment of testicular cancer includes the coadministration of bleomycin, etoposide and cis-platinum (BEP); however, along with its therapeutic benefit, BEP exposure results in extensive reproductive chemotoxic effects, including alterations to sperm chromatin integrity. As an intact paternal genome is essential for successful fertilization and embryogenesis, we assessed the effect of paternal exposure to BEP on sperm fertilization capacity and the resulting consequences on early embryonic gene expression. Adult male Brown Norway rats received a 9-week treatment with BEP or saline and then were sacrificed immediately or subject to a 9-week recovery period. HSP90AA1, HSP90B1 and PDIA3, involved in spermatozoa-egg interactions, were overexpressed in BEP-exposed spermatozoa after the 9-week treatment period; overexpression was also observed in spermatozoa from BEP-treated rats after 9 weeks of recovery. These proteins were localized to the plasma membrane of the sperm head; this localization may facilitate their role in spermatozoa-egg interactions as the highest staining intensities were observed in capacitated spermatozoa. The fertilization potential of spermatozoa was determined by in vitro fertilization with oocytes from unexposed naturally cycling female rats. Interestingly, the fertilization potential of spermatozoa following a 9-week recovery period from BEP treatment was significantly enhanced compared with controls. Moreover, stem cell transcription factors, involved in the regulation of a plethora of early embryonic events, were upregulated by more than twofold in eight-cell stage embryos sired by BEP recovery males compared with controls; this suggests that there are potential deleterious effects on embryo development well after termination of BEP exposure.
Departments of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
J
J
Maselli
B F
BF
Hales
B
B
Robaire
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001761:Bleomycin / Q000009:adverse effects / Q000627:therapeutic use; D002462:Cell Membrane / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D004622:Embryo, Mammalian / Q000187:drug effects*; D005047:Etoposide / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D023421:Models, Animal; D018812:Paternal Exposure; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D055101:Semen Analysis; D013077:Sperm Head / Q000378:metabolism / Q000502:physiology*; D013736:Testicular Neoplasms / Q000188:drug therapy*
D018841:HSP90 Heat-Shock Proteins; C588351:Hsp90aa1 protein, rat; D008562:Membrane Glycoproteins; C053387:endoplasmin; D001761:Bleomycin; D005047:Etoposide; C513196:PDIA3 protein, rat; D019704:Protein Disulfide-Isomerases; D002945:Cisplatin
chemotherapeutics; chromatin packaging; eight-cell stage embryo; in vitro fertilization; spermatozoa