Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Food Chem Toxicol. 2024 Apr;186:114576. doi: 10.1016/j.fct.2024.114576. Epub 2024 Mar 6.
Cinnabar is the naturally occurring mercuric sulfide (HgS) and concerns about its safety have been grown. However, the molecular mechanism of HgS-related neurotoxicity remains unclear. S-phase kinase-associated protein 1 (Skp1), identified as the target protein of HgS, plays a crucial role in the development of neurological diseases. This study aims to investigate the neurotoxic effects and molecular mechanism of HgS based on Skp1 using the Caenorhabditis elegans (C. elegans) model. We prepared the HgS nanoparticles and conducted a comparative analysis of neurobehavioral differences in both wild-type C. elegans (N2) and a transgenic strain of C. elegans (VC1241) with a knockout of the SKP1 homologous gene after exposure to HgS nanoparticles. Our results showed that HgS nanoparticles could suppress locomotion, defecation, egg-laying, and associative learning behaviors in N2 C. elegans, while no significant alterations were observed in the VC1241 C. elegans. Furthermore, we conducted a 4D label-free proteomics analysis and screened 504 key proteins significantly affected by HgS nanoparticles through Skp1. These proteins play pivotal roles in various pathways, including SNARE interactions in vesicular transport, TGF-beta signaling pathway, calcium signaling pathway, FoxO signaling pathway, etc. In summary, HgS nanoparticles at high doses suppress the neurobehavioral functions of C. elegans through a Skp1-dependent mechanism.
辰砂是一种天然的硫化汞（HgS），人们对其安全性的担忧与日俱增。然而，HgS 相关神经毒性的分子机制仍不清楚。S 期激酶相关蛋白 1（Skp1）被确定为 HgS 的靶蛋白，在神经疾病的发展中起着至关重要的作用。本研究旨在基于 Skp1 利用秀丽隐杆线虫（C. elegans）模型研究 HgS 的神经毒性作用及其分子机制。我们制备了 HgS 纳米颗粒，并对暴露于 HgS 纳米颗粒后的野生型秀丽隐杆线虫（N2）和 Skp1 同源基因敲除的秀丽隐杆线虫（VC1241）的神经行为差异进行了比较分析。结果表明，HgS 纳米颗粒可抑制 N2 秀丽隐杆线虫的运动、排便、产卵和联想学习行为，而 VC1241 秀丽隐杆线虫则无明显变化。此外，我们进行了 4D 无标记蛋白质组学分析，通过 Skp1 筛选出 504 个受 HgS 纳米颗粒显著影响的关键蛋白。这些蛋白在各种途径中发挥关键作用，包括囊泡运输中的 SNARE 相互作用、TGF-β信号通路、钙信号通路、FoxO 信号通路等。综上所述，高剂量的 HgS 纳米颗粒通过 Skp1 依赖性机制抑制秀丽隐杆线虫的神经行为功能。
