Dexrazoxane exacerbates doxorubicin-induced testicular toxicity.
Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5  mg/kg DXR, 100  mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity.
Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Mattan
M
Levi
Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Moran
M
Tzabari
Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Naphtali
N
Savion
Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Salomon M
SM
Stemmer
Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Ruth
R
Shalgi
Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel Department of Cell and Developmental BiologySackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, IsraelThe Goldschleger Eye Research InstituteSheba Medical Center, Tel Hashomer 52621, IsraelInstitute of OncologyDavidoff Center, Rabin Medical Center, Beilinson Campus, 39 Jabotinski Street, Petah-Tiqva 49100, IsraelSackler Faculty of MedicineTel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel iritbenaharon@gmail.com.
Irit
I
Ben-Aharon
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D064730:Dexrazoxane / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D004822:Epididymis / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D013081:Sperm Motility / Q000187:drug effects; D013093:Spermatogonia / Q000473:pathology; D013733:Testicular Diseases / Q000139:chemically induced* / Q000473:pathology; D013737:Testis / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D064730:Dexrazoxane; D004317:Doxorubicin; D005978:Glutathione