Dose-dependent effects of silver nanoparticles on cell death modes in mouse blastocysts induced via endoplasmic reticulum stress and mitochondrial apoptosis

In view of the rapidly expanding medical and commercial applications of silver nanoparticles (AgNPs), their potential health risks and environmental effects are a significant growing concern. Earlier research by our group uncovered the embryotoxic potential of AgNPs, showing detrimental impacts of these nanoparticles on both pre- and post-implantation embryonic development. In the current study, we showed that low (50-100 μM) and high (200-400 μM) dose ranges of AgNPs trigger distinct cell death programs affecting mouse embryo development and further explored the underlying mechanisms. Treatment with low concentrations of AgNPs (50-100 μM) triggered ROS generation, in turn, inducing mitochondria-dependent apoptosis, and ultimately, harmful effects on embryo implantation, post-implantation development, and fetal development. Notably, high concentrations of AgNPs (200-400 μM) evoked more high-level ROS generation and endoplasmic reticulum (ER) stress-mediated necrosis. Interestingly, pre-incubation with Trolox, a strong antioxidant, reduced ROS generation in the group treated with 200-400 μM AgNPs to the level induced by 50-100 μM AgNPs, resulting in switching of the cell death mode from necrosis to apoptosis and a significant improvement in the impairment of embryonic development. Our findings additionally indicate that activation of PAK2 is a crucial step in AgNP-triggered apoptosis and sequent detrimental effects on embryonic development. Based on the collective results, we propose that the levels of ROS generated by AgNP treatment of embryos serve as a critical regulator of cell death type, leading to differential degrees of damage to embryo implantation, post-implantation development and fetal development through triggering apoptosis, necrosis or other cell death signaling cascades.