Emodin-8--β-D-glucopyranoside (Em8G) is an active ingredient of traditional Chinese medicine et Rhizoma and Thunb.. And it caused hepatotoxicity, while the underlying mechanism was not clear yet. We aimed to explore the detrimental effects of Em8G on the zebrafish liver through the metabolome and transcriptome integrated analysis. In this study, zebrafish larvae were used in acute toxicity tests to reveal the hepatotoxicity of Em8G. Adult zebrafish were then used to evaluate the gender differences in hepatotoxicity induced by Em8G. Integration of transcriptomic and metabolomic analysis was used further to explore the molecular mechanisms underlying gender differences in hepatotoxicity. Our results showed that under non-lethal concentration exposure conditions, hepatotoxicity was observed in Em8G-treated zebrafish larvae, including changes in liver transmittance, liver area, hepatocyte apoptosis and hepatocyte vacuolation. Male adult zebrafish displayed a higher Em8G-induced hepatotoxicity than female zebrafish, as demonstrated by the higher mortality and histopathological alterations. The results of transcriptomics combined with metabolomics showed that Em8G mainly affected carbohydrate metabolism (such as TCA cycle) in male zebrafish and amino acid metabolism (such as arginine and proline metabolism) in females, suggesting that the difference of energy metabolism disorder may be the potential mechanism of male and female liver toxicity induced by Em8G. This study provided the direct evidence for the hepatotoxicity of Em8G to zebrafish models , and brought a new insight into the molecular mechanisms of Em8G hepatotoxicity, which can guide the rational application of this phytotoxin. In addition, our findings revealed gender differences in the hepatotoxicity of Em8G to zebrafish, which is related to energy metabolism and provided a methodological reference for evaluating hepatotoxic drugs with gender differences.

中文翻译：

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代谢组学和转录组学整合揭示大黄素-8-O-β-D-吡喃葡萄糖苷诱导的斑马鱼肝毒性和性别差异

大黄素-8-β-D-吡喃葡萄糖苷（Em8G）是中药根茎类药物的活性成分，可引起肝毒性，但其机制尚不清楚。我们的目的是通过代谢组和转录组综合分析来探讨 Em8G 对斑马鱼肝脏的有害影响。在本研究中，使用斑马鱼幼虫进行急性毒性试验，以揭示 Em8G 的肝毒性。然后使用成年斑马鱼评估 Em8G 诱导的肝毒性的性别差异。转录组学和代谢组学分析的整合被进一步用于探索肝毒性性别差异的分子机制。我们的结果表明，在非致死浓度暴露条件下，Em8G处理的斑马鱼幼虫观察到肝毒性，包括肝脏透光率、肝脏面积、肝细胞凋亡和肝细胞空泡化的变化。雄性成年斑马鱼表现出比雌性斑马鱼更高的 Em8G 诱导的肝毒性，这通过更高的死亡率和组织病理学改变来证明。转录组学结合代谢组学结果表明，Em8G主要影响雄性斑马鱼的碳水化合物代谢（如TCA循环）和雌性斑马鱼的氨基酸代谢（如精氨酸和脯氨酸代谢），提示能量代谢紊乱的差异可能是潜在的原因。 Em8G 诱导男性和女性肝毒性的机制。该研究为Em8G对斑马鱼模型的肝毒性提供了直接证据，为Em8G肝毒性的分子机制提供了新的见解，可以指导该植物毒素的合理应用。此外，我们的研究结果揭示了Em8G对斑马鱼的肝毒性存在性别差异，这与能量代谢有关，为评估具有性别差异的肝毒性药物提供了方法学参考。