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

Irisin is an exercise-induced myokine/adipokine in mice and humans that plays an important role in ‘browning’ of white adipose tissue and has shown great potential as a treatment for some metabolic diseases, such as obesity, insulin resistance, and inflammation. The circulating irisin level is reported to be associated with exercise, obesity, diet, diseases, and exposure to different pharmacological agents. Several studies have attempted to characterize the role of irisin in PCOS and other reproductive diseases, but contradictory results have been reported. Our previous study showed that irisin may serve further functions in folliculogenesis and fertility. In this review, we present the current knowledge on the physiology of irisin and its role in gonadal axis. Firstly, we describe irisin circulating levels and speculate on the potential mechanisms involved in irisin secretion and regulation. Then, we focus on the irisin levels in PCOS, and explore the relationships between, BMI, insulin resistance, and hyperandrogenism. Finally, we present the results from animal interventional studies and in vitro experiments to investigate the relationship between irisin and gonadal axis, indicating its novel effects on reproduction and fertility.