Doxorubicin-induced apoptosis in germinal vesicle (GV) oocytes.
Ovarian failure is a-known side-effect observed in women treated for cancer. Doxorubicin (DXR) was found to be detrimental to MII mouse oocytes. We aimed at characterizing the effect of DXR on germinal vesicle (GV) oocytes that comprise the majority of oocytes within ovaries encountering chemotherapy. Mouse follicles and oocytes were exposed to DXR in vitro. DXR localization and its possible cellular targets were examined by fluorescence confocal microscopy. We demonstrated that DXR crosses the blood-follicle barrier and accumulates in oocytes and granulosa cells. The mechanism of DXR-induced apoptosis involves chromosomal disintegration, activation of the mitochondria followed by activation of PERK and caspase-12 and inactivation of PARP. The follicular GV oocytes were more vulnerable to the toxic effect of DXR than ovulated MII oocytes. We suggest that DXR elicits apoptotic signal within GV oocytes that involves activation of the mitochondria, induction of ER-stress and a possible increase in intracellular calcium.
Bar-Joseph
Hadas
H
Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel.
Ben-Aharon
Irit
I
Rizel
Shulamith
S
Stemmer
Salomon M
SM
Tzabari
Moran
M
Shalgi
Ruth
R
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D053454:Caspase 12 / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009866:Oogenesis; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced; D019892:eIF-2 Kinase / Q000378:metabolism
D000970:Antineoplastic Agents; D053454:Caspase 12; D002843:Chromatin; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D019892:eIF-2 Kinase; C506440:Casp12 protein, mouse