The pervasive environmental presence of N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its transformation product, 6PPD-quinone (6PPDQ), has raised concerns about their potential toxicity, yet their interactions with the gut microbiota at environmentally relevant concentrations remain poorly understood. Here, we investigated the effects of 6PPD and 6PPDQ on the gut-liver axis in zebrafish (Danio rerio). Zebrafish larvae exposed to 0.01, 1, and 100 μg/L of 6PPD or 6PPDQ for five days exhibited intestinal and hepatic developmental toxicity, including hepatic lipid accumulation and hepatomegaly. Adult zebrafish exposed for 21 days displayed compromised intestinal barrier integrity, gut dysbiosis, and lipidomic disturbances in the liver. Statistical analysis using the multi-response permutation procedure confirmed significant shifts in gut microbial community structure. Dysbiosis was characterized by reduced beneficial bacteria and an increase in pathogenic taxa, accompanied by elevated circulating lipopolysaccharide (LPS) and upregulated hepatic expression of lbp (LPS-binding receptor). Hepatic lipid accumulation resulted from increased triglyceride (TG) and total cholesterol synthesis, with lipidomics revealing distinct disruptions: 6PPD impaired phosphatidylinositol phosphate synthesis, while 6PPDQ affected TG homeostasis. Correlation analysis linked gut microbial shifts to hepatic lipid dysregulation. These findings suggest that 6PPD and 6PPDQ exposure disrupts gut-liver axis homeostasis, potentially driving non-alcoholic fatty liver disease development. This study underscores the need to integrate gut-liver-microbiota endpoints into environmental risk assessments for aquatic organisms.

中文翻译：

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斑马鱼 6PPD 和 6PPDQ 诱导的肠肝轴破坏和非酒精性脂肪肝疾病进展的多组学见解 （Danio rerio）

N-（1,3-二甲基丁基）-N'-苯基对苯二胺 （6PPD） 及其转化产物 6PPD-醌 （6PPDQ） 在环境中普遍存在，这引起了人们对其潜在毒性的担忧，但人们对它们在环境相关浓度下与肠道微生物群的相互作用仍然知之甚少。在这里，我们研究了 6PPD 和 6PPDQ 对斑马鱼 （Danio rerio） 肠肝轴的影响。斑马鱼幼虫暴露于 0.01、1 和 100 μg/L 的 6PPD 或 6PPDQ 5 天后表现出肠道和肝脏发育毒性，包括肝脂质积累和肝肿大。暴露 21 天的成年斑马鱼表现出肠道屏障完整性受损、肠道菌群失调和肝脏脂质组紊乱。使用多反应排列程序的统计分析证实了肠道微生物群落结构的显着变化。菌群失调的特征是有益菌减少和病原菌群增加，伴有循环脂多糖 （LPS） 升高和 lbp （LPS 结合受体） 肝脏表达上调。肝脏脂质积累是由甘油三酯 （TG） 和总胆固醇合成增加引起的，脂质组学揭示了明显的破坏： 6PPD 损害了磷脂酰肌醇磷酸酯的合成，而 6PPDQ 影响了 TG 稳态。相关性分析将肠道微生物转移与肝脏脂质失调联系起来。这些发现表明，6PPD 和 6PPDQ 暴露会破坏肠-肝轴稳态，可能推动非酒精性脂肪肝疾病的发展。本研究强调了将肠道-肝脏-微生物群终点整合到水生生物环境风险评估中的必要性。