Copper Nanoparticles Show Obvious in vitro and in vivo Reproductive Toxicity via ERK Mediated Signaling Pathway in Female Mice

摘要

Copper nanoparticles (Cu-NPs) and other inorganic nanomaterials have caused increasing concern owing to be widely used. Early studies have reported that they can result in injuries to the kidney, liver and spleen of mice; cause embryonic damage; and inhibit the reproductive capacity of red worms. However, few studies have reported the toxicity of Cu-NPs on the reproductive systems of mammals. In the present work, we explored the cytotoxicity of Cu-NPs in human extravillous trophoblast cells and in the reproductive organs of mice. Cu-NPs induced ovarian and placental pathophysiology and dysfunction in mice. These nanoparticles also induced apoptosis and suppressed the proliferation of human extravillous trophoblast cells and caused cell cycle arrest at the G2/M phase in a time-and dose-dependent manner. Cu-NPs can significantly damage the mitochondrial membrane potential (MMP), which suggests that Cu-NPs can activate the mitochondria-mediated apoptosis signaling pathway. We also observed that Cu-NPs significantly inhibit the expression of BRAF, ERK, and MITF expression, all of which are important genes in the ERK signaling pathway. Our research demonstrated that Cu-NPs exert obvious reproductive toxicity in mice by disrupting the balance of sex hormones and exert cytotoxicity on human extravillous trophoblast cells, and ERK signaling and the mitochondrial apoptosis pathway made great contribution to the toxicity of Cu-NPs on female mice.