Mercuric sulfide nanoparticles suppress the neurobehavioral functions of Caenorhabditis elegans through a Skp1-dependent mechanism.

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.