Research
| Title： | Integrative multi-omics and molecular modeling reveal mechanisms of 6PPD-induced hepatic oxidative stress and energy metabolism disruption in zebrafish |
|---|---|
| First author： | Rao, Chenyang; Zuo, Yanxia; Gao, Tianyu; Xiang, Dongfang; Chu, Fuhao; Xiang, Xiaowei; Dene, Xingkang; Tang, Wei; Bao, Shaopan; Fang, Tao |
| Journal： | JOURNAL OF ENVIRONMENTAL MANAGEMENT |
| Years： | 2025 |
| DOI： | 10.1016/j.jenvman.2025.127611 |
| Abstract： | N-(1,3-dimethylbuty1)-N'-phenyl-p-phenylenediamine (6PPD), a widely used tire rubber antioxidant has emerged as a concerning environmental contaminant. While its toxicity to aquatic organisms is well established, the molecular mechanisms remain unclear. This work systematically investigated the molecular mechanisms of 6PPD-induced hepatotoxicity in zebrafish through an integrated approach combining histological analysis, multiomics profiling, biochemical assays, and computational modeling. Hematoxylin and eosin (H&E) staining revealed significant liver damage after 28 d of exposure. Transcriptomic and proteomic profiling of the high-concentration group (200 mu g/L) demonstrated disruptions in Phase I/11 detoxification, redox homeostasis, and energy metabolism, notably involving the mitochondrial electron transport chain and TCA cycle. Biochemical assays further confirmed increased malondialdehyde (MDA) levels and impaired antioxidant capacity. Additionally, molecular docking and dynamics simulations revealed strong binding affinities between 6PPD and key hepatic proteins (CYP2K6, CAT and GSTM2), suggesting potential direct interference with metabolic and antioxidant defense pathways. Based on these findings, we hypothesize a positive feedback mechanism whereby excessive reactive oxygen species (ROS) generation exacerbates metabolic dysfunction. This hypothesis is supported by gene expression changes, elevated MDA levels, and abnormal lipid accumulation observed via Oil Red O staining. Overall, our results provide mechanistic insight into 6PPD-induced liver injury, highlighting the interplay between oxidative stress and disrupted energy metabolism. |
