Impact of the chemotherapy cocktail used to treat testicular cancer on the gene expression profile of germ cells from male Brown-Norway rats.
Advances in treatment for testicular cancer that include the coadministration of bleomycin, etoposide, and cisplatin (BEP) have brought the cure rate to higher than 90%%. The goal of this study was to elucidate the impact of BEP treatment on gene expression in male germ cells. Brown-Norway rats were treated for 9 wk with vehicle (0x) or BEP at doses equivalent to 0.3x and 0.6x the human dose. At the end of treatment, spermatogenesis was affected, showing altered histology and a decreased sperm count; spermatozoa had a higher number of DNA breaks. After 9 wk of treatment, round spermatids were isolated, and RNA was extracted and probed on Rat230-2.0 Affymetrix arrays. Of the 31 099 probe sets present on the array, 59%% were expressed in control round spermatids. BEP treatment significantly altered the expression of 221 probe sets, with at least a 1.5-fold change compared with controls; 80% were upregulated. We observed a dose-dependent increase in the expression of oxidative stress response genes and no change in the expression of genes involved in DNA repair. BEP upregulated genes were implicated in pathways related to Jun and Junb protooncogenes. Increased mRNA levels of Jun and Junb were confirmed by quantitative RT-PCR; furthermore, JUN protein was increased in elongating spermatids. Thus, BEP exposure triggers an oxidative stress response in round spermatids and induces many pathways that may lead to the survival of damaged cells and production of abnormal sperm.
Delbès
Geraldine
G
Department of Pharmacology and Therapeutics, McGill University, Montreal Children's Hospital Research Institute, Montréal, Québec, Canada H3G 1Y6.
Chan
Donovan
D
Pakarinen
Pirjo
P
Trasler
Jacquetta M
JM
Hales
Barbara F
BF
Robaire
Bernard
B
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001761:Bleomycin / Q000009:adverse effects / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D016000:Cluster Analysis; D005047:Etoposide / Q000009:adverse effects / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D005854:Germ Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011914:Rats, Inbred BN; D013087:Spermatids / Q000187:drug effects / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014566:Urogenital System / Q000187:drug effects / Q000378:metabolism
D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin