Copper Oxide Nanoparticles\nImpair Mouse Preimplantation\nEmbryonic Development through Disruption of Mitophagy-Mediated Metabolism

Copper oxide nanoparticles (CuONPs) have been widely\napplied, posing\npotential risks to human health. Although the toxicity of CuONPs on\nthe liver and spleen has been reported, their effects on reproductive\nhealth remain unexplored. In this study, we investigate the effects\nof CuONPs on embryonic development and their potential mechanisms.\nOur results demonstrate that CuONPs exposure impairs mouse preimplantation\nembryonic development, particularly affecting the morula-to-blastocyst\ntransition. Additionally, CuONPs were found to reduce the pluripotency\nof the inner cell mass (ICM) and mouse embryonic stem cells (mESCs).\nMechanistically, CuONPs block autophagic flux and impair mitophagy,\nleading to the accumulation of damaged mitochondria. This mitochondrial\ndysfunction leads to reduced tricarboxylic acid (TCA) cycle activity\nand decreased α-ketoglutarate (α-KG) production. Insufficient\nα-KG induces the failure of DNA demethylation, reducing corresponding\nchromatin accessibility and consequently inhibiting ICM-specific genes\nexpressions. Similar reduced development and inhibitions of pluripotency\ngene expression were observed in CuONPs-treated human blastocysts.\nMoreover, in women undergoing assisted reproductive technology (ART),\na negative correlation was found between urinary Cu ion concentrations\nand clinical outcomes. Collectively, our study elucidates the mitophagy-mediated\nmetabolic mechanisms of CuONPs embryotoxicity, improving our understanding\nof the potential reproductive toxicity associated with it.