Intestinal Cu(II)/(I) Redox State Transformation Causes Cu(I) Overflow and Toxicity of the Gut and Liver in Zebrafish

Copper (Cu) has long been a concern for human health. While previous studies have explored the toxic effects of Cu, no study is available on the relationship between the Cu redox state transformation and biotoxicity in higher organisms. In this study, we explored the gut and liver toxicity caused by the overflow of Cu­(I) at low doses of Cu exposure. Here, we first elucidated the digestive and metabolic systems as the main toxic target sites by a systematic epidemiological analysis. Then, ICP-MS analysis verified that the gut and liver were the top two Cu-high-accumulated organs in zebrafish exposed to 10 and 100 μg/L waterborne Cu for 72 h. In-situ Cu­(I) and Cu­(II) imaging techniques demonstrated that exogenous Cu­(II) was converted to Cu­(I) in the zebrafish gut. Furthermore, transcriptomic sequencing revealed that the high overflow of Cu­(I) induced gut toxicity by cell cycle arrest in the G phase. However, the substantial accumulation of Cu­(I) disrupted the metabolism of energy source nutrients and energy supply, leading to hepatic toxicity. This study provides new insights into the toxic mechanism based on Cu redox state and emphasizes the health risks associated with Cu exposure in the digestive and metabolic systems.