BACKGROUND Environmental pollutants, including polychlorinated biphenyls (PCBs) have been implicated in the pathogenesis of liver disease. Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in a rodent model of alcohol-associated liver disease (ALD). OBJECTIVE To better understand how PCB126 promoted ALD in our previous model, the current study adopts multiple omics approaches to elucidate potential mechanistic hypotheses. METHODS Briefly, male C57BL/6J mice were exposed to 0.2mg/kg polychlorinated biphenyl (PCB) 126 or corn oil vehicle prior to ethanol (EtOH) or control diet feeding in the chronic-binge alcohol feeding model. Liver tissues were collected and prepared for mRNA sequencing, phosphoproteomics, and inductively coupled plasma mass spectrometry for metals quantification. RESULTS Principal component analysis showed that PCB126 uniquely modified the transcriptome in EtOH-fed mice. EtOH feeding alone resulted in >4,000 differentially expressed genes (DEGs), and PCB126 exposure resulted in more DEGs in the EtOH-fed group (907 DEGs) in comparison with the pair-fed group (503 DEGs). Top 20 significant gene ontology (GO) biological processes included "peptidyl tyrosine modifications," whereas top 25 significantly decreasing GO molecular functions included "metal/ion/zinc binding." Quantitative, label-free phosphoproteomics and western blot analysis revealed no major significant PCB126 effects on total phosphorylated tyrosine residues in EtOH-fed mice. Quantified hepatic essential metal levels were primarily significantly lower in EtOH-fed mice. PCB126-exposed mice had significantly lower magnesium, cobalt, and zinc levels in EtOH-fed mice. DISCUSSION Previous work has demonstrated that PCB126 is a modifying factor in metabolic dysfunction-associated steatotic liver disease (MASLD), and our current work suggests that pollutants also modify ALD. PCB126 may, in part, be contributing to the malnutrition aspect of ALD, where metal deficiency is known to contribute and worsen prognosis. https://doi.org/10.1289/EHP14132.

中文翻译：

---

PCB126 对小鼠慢性酗酒模型影响的多组学分析。


背景技术包括多氯联苯(PCB)在内的环境污染物与肝病的发病机制有关。我们的小组最近证明，PCB126 在酒精相关性肝病 (ALD) 啮齿动物模型中促进脂肪变性、肝肿大并调节中间代谢。目的 为了更好地了解 PCB126 在我们之前的模型中如何促进 ALD，当前的研究采用多种组学方法来阐明潜在的机制假设。方法 简而言之，在慢性酗酒模型中，雄性 C57BL/6J 小鼠在乙醇 (EtOH) 或对照饮食喂养之前先接触 0.2mg/kg 多氯联苯 (PCB) 126 或玉米油载体。收集并制备肝组织用于 mRNA 测序、磷酸化蛋白质组学和电感耦合等离子体质谱法以进行金属定量。结果主成分分析表明 PCB126 独特地改变了 EtOH 喂养小鼠的转录组。单独饲喂 EtOH 会导致 >4,000 个差异表达基因 (DEG)，而与配对饲喂组 (503 DEG) 相比，暴露于 PCB126 会导致 EtOH 饲喂组 (907 DEG) 产生更多 DEG。前 20 名重要的基因本体 (GO) 生物过程包括“肽基酪氨酸修饰”，而前 25 名显着降低的 GO 分子功能包括“金属/离子/锌结合”。定量、无标记磷酸化蛋白质组学和蛋白质印迹分析显示，PCB126 对 EtOH 喂养小鼠的总磷酸化酪氨酸残基没有显着影响。定量的肝脏必需金属水平主要在乙醇喂养的小鼠中显着降低。与 EtOH 喂养的小鼠相比，暴露于 PCB126 的小鼠的镁、钴和锌水平显着降低。 讨论 先前的工作已证明 PCB126 是代谢功能障碍相关脂肪肝病 (MASLD) 的调节因子，而我们目前的工作表明污染物也会调节 ALD。 PCB126 可能在一定程度上导致 ALD 的营养不良，其中金属缺乏已知会导致预后恶化。 https://doi.org/10.1289/EHP14132。