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氧化铜纳米颗粒通过破坏线粒体自噬介导的代谢来损害小鼠植入前胚胎发育。

Copper Oxide Nanoparticles Impair Mouse Preimplantation Embryonic Development through Disruption of Mitophagy-Mediated Metabolism.

机构信息

Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing 400013, China.

Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing 400013, China.

出版信息

ACS Nano. 2024 Nov 12;18(45):31244-31260. doi: 10.1021/acsnano.4c09734. Epub 2024 Nov 2.

DOI:10.1021/acsnano.4c09734
PMID:39487804
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11562798/
Abstract

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.

摘要

氧化铜纳米颗粒（CuONPs）已经被广泛应用，这对人类健康构成了潜在风险。尽管已经报道了 CuONPs 对肝脏和脾脏的毒性，但它们对生殖健康的影响仍未被探索。在这项研究中，我们研究了 CuONPs 对胚胎发育的影响及其潜在机制。我们的结果表明，CuONPs 暴露会损害小鼠的着床前胚胎发育，特别是影响桑葚胚到囊胚的过渡。此外，CuONPs 被发现降低了内细胞团（ICM）和小鼠胚胎干细胞（mESCs）的多能性。从机制上讲，CuONPs 阻断自噬流并损害线粒体自噬，导致受损线粒体的积累。这种线粒体功能障碍导致三羧酸（TCA）循环活性降低和α-酮戊二酸（α-KG）生成减少。不足的α-KG 导致 DNA 去甲基化失败，降低相应的染色质可及性，从而抑制 ICM 特异性基因表达。在接受辅助生殖技术（ART）的女性中，CuONPs 处理的人类囊胚也观察到类似的发育减少和多能性基因表达抑制。此外，在接受辅助生殖技术（ART）的女性中，尿铜离子浓度与临床结局之间存在负相关。总的来说，我们的研究阐明了 CuONPs 胚胎毒性的线粒体自噬介导的代谢机制，提高了我们对其潜在生殖毒性的认识。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/a5baf510fb57/nn4c09734_0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/05143cf2cc65/nn4c09734_0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/2e5cfc21fea0/nn4c09734_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/2cdaf2b26d0d/nn4c09734_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/2e31a1e91536/nn4c09734_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/616c579f0fc2/nn4c09734_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/d1353e547181/nn4c09734_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01ce/11562798/a5baf510fb57/nn4c09734_0009.jpg

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