Differential effects of ionizing radiation and platinum-derivative chemotherapy on apoptotic pathways in testicular germ cells

The purpose here was to identify whether ionizing radiation and oxaliplatin triggered testicular germ cells apoptosis through different executionary pathways.Adult male mice are treated with oxaliplatin (0.5 mg/kg, Ox) 4 h before being locally irradiated (0.5 Gy, IR, considered as time 0 h).The number of apoptotic germ cells was significantly higher for IR (p0.008), Ox (p0.0001) and Ox + IR (p0.0001) groups compared to the untreated mice group. Similarly, the different treatments induced an increase of p53 expression. Downstream p53, IR and Ox used different pathways. Indeed, IR increased effector caspase-3 expression in terms of mRNA (p0.002), pro-enzyme p0.0001) and active (3.7-fold, p0.003) protein levels but not the inhibitors of apoptosis proteins (IAP) including cIAP1, cIAP2 and XIAP. In contrast, while oxaliplatin treatment had no apparent effect on caspase-3 expression, it significantly decreased the cIAP1 (p0.005), cIAP2 (p0.008) and XIAP (p0.02) proteins levels. Finally, the combination of both treatments decreased IAP expression but did not modify caspase-3 levels while it increased the AIF (apoptosis-inducing factor) protein levels (5.5-fold, p0.003). No modification of AIF levels was observed with OX or IR alone.Together, these results indicate that the platinum analogue oxaliplatin and the ionizing radiations trigger apoptosis in the testicular germ cells, probably through different pathways.