Caspase-2 involvement during ionizing radiation-induced oocyte death in the mouse ovary

Abstract

In mammals, the pool of primordial follicles at birth is determinant for female fertility. Exposure to IR during oogonia proliferation and the diplotene stages of ovarian development induced the virtual disappearance of primordial follicles in the postnatal ovary, while half the follicular reserve remained present after irradiation during the zygotene/pachytene stages. This sensitivity difference was correlated with the level of caspase-2 expression evaluated by immunohistochemistry. At the diplotene stage, Western blot and caspase activity analysis revealed that caspase-2 was activated 2 h after irradiation and a significant increase in the number of oocytes expressing cleaved caspase-9 and -3 occurred 6 h after treatment. Inhibition of caspase-2 activity prevented the cleavage of caspase-9 and partially prevented the loss of oocytes in response to irradiation. Taken together, our results show that caspase-2-dependent activation of the mitochondrial apoptotic pathway is one of the mechanisms involved in the genotoxic stress-induced depletion of the primordial follicle pool.

p63 null mutation protects mouse oocytes from radio-induced apoptosis

“…We recently reported considerable changes in oocyte radiosensitivity during prophase I, with the zygotene stage being resistant to high doses of IR, the pachytene stage also showing some degree of radioresistance and the diplotene stage being highly radiosensitive (Hanoux et al 2006). The expression of p63 therefore seems to be correlated with oocyte radiosensitivity to genotoxic stress.…”

“…Overall, these data indicate that p63 plays a unique and upstream role in the commitment of the oocyte to the cell death pathway following genotoxic stress. Several other factors, such as sphingosine 1-phosphate and caspase-2, have been shown to regulate or to be involved in this stress-induced death, but none has been shown both to abolish oocyte apoptosis entirely and to be activated in response to genotoxic stress (Morita et al 2000, Hanoux et al 2006.…”

“…Oocytes from primordial follicles are extremely sensitive to radiation, with the pool of primordial follicles in young adult female mouse ovaries almost completely destroyed within 2 weeks of a single exposure to 0.1 Gy of ionising radiation (IR; Morita et al 2000). We recently reported that caspase-2 plays a key role in the radiation-induced death of oocytes (Hanoux et al 2006). However, caspase-2 alone cannot prevent oocyte apoptosis, and other pathways must therefore be activated during this process.…”

“…Foci of phosphorylated histone H 2 AX (gH2AX) have been observed in irradiated diplotene oocytes. These foci appear shortly before the sequential activation of caspases-9 and -3 (Hanoux et al 2006).…”

“…We recently reported that this sensitivity changes considerably during ovarian development. Indeed, mouse oocytes in the early stages of prophase I of meiosis (leptotene, zygotene and pachytene) are more resistant to high doses of IR than their oogonial precursors or later diplotene/diakinesis-stage oocytes (Hanoux et al 2006). Foci of phosphorylated histone H 2 AX (gH2AX) have been observed in irradiated diplotene oocytes.…”