New Evidence for the Mechanisms of Nanoplastics Amplifying Cadmium Cytotoxicity: Trojan Horse Effect, Inflammatory Response, and Calcium Imbalance
Xiangxiang Li, Shaoyang Hu, Zelian Yu, Falin He, Xingchen Zhao, Rutao Liu
Abstract
Nanoplastics (NPs) are emerging pollutants worldwide. Particularly worrisome is that although studies have reported that NPs can amplify the biotoxicity of environmental pollutants, the specific mechanism remains unclear. Here, we found that NPs, even without significant toxicity (cell survival: 99.11%), amplified the hepatocyte toxicity of Cd 2+ . Mechanistically, higher Cd 2+ uptake (Δ = 23.80%) combined with crucial intracellular desorption behavior of Cd 2+ loaded in NPs (desorption rate: 82.70%) were identified as prerequisites for NPs amplifying Cd 2+ cytotoxicity. As for toxigenic pathways, the inflammatory response and calcium (Ca) signaling pathway were identified as the primary molecular events leading to the amplification of Cd 2+ cytotoxicity. Further phenotypic monitoring revealed that NPs synergized with Cd 2+ to induce more severe pyroptosis and apoptosis by activating the inflammatory caspase-1-dependent and Ca 2+ -mitochondrial-caspase-3 pathways to a greater extent, respectively. This study reveals and proves for the first time the “Trojan horse” effects of NPs, thus elucidating the actual mechanisms by which NPs act as toxicity amplifiers of pollutants, providing significant insights into accurate risk assessment of NPs in composite pollution.