Multiomics analysis of the impact of polychlorinated biphenyls on environmental liver disease in a mouse model,Environmental Toxicology and Pharmacology

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Multiomics analysis of the impact of polychlorinated biphenyls on environmental liver disease in a mouse model
Environmental Toxicology and Pharmacology ( IF 4.2 ) Pub Date : 2022-07-06 , DOI: 10.1016/j.etap.2022.103928
Belinda J Petri ₁ , Kellianne M Piell ₁ , Banrida Wahlang ₂ , Kimberly Z Head ₃ , Kalina Andreeva ₄ , Eric C Rouchka ₅ , Jianmin Pan ₆ , Shesh N Rai ₇ , Matthew C Cave ₈ , Carolyn M Klinge ₉

Affiliation

Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA.
University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA.
University of Louisville Hepatobiology and Toxicology Center, USA.
KY INBRE Bioinformatics Core, University of Louisville, USA.
Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA; KY INBRE Bioinformatics Core, University of Louisville, USA.
Biostatistics and Bioinformatics Facility, Brown Cancer Center, USA.
University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; Biostatistics and Bioinformatics Facility, Brown Cancer Center, USA.
Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA.
Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA.

Exposure to high fat diet (HFD) and persistent organic pollutants including polychlorinated biphenyls (PCBs) is associated with liver injury in human populations and non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. Previously, exposure of HFD-fed male mice to the non-dioxin-like (NDL) PCB mixture Aroclor1260, dioxin-like (DL) PCB126, or Aroclor1260 + PCB126 co-exposure caused toxicant-associated steatohepatitis (TASH) and differentially altered the liver proteome. Here unbiased mRNA and miRNA sequencing (mRNA- and miRNA- seq) was used to identify biological pathways altered in these liver samples. Fewer transcripts and miRs were up- or down- regulated by PCB126 or Aroclor1260 compared to the combination, suggesting that crosstalk between the receptors activated by these PCBs amplifies changes in the transcriptome. Pathway enrichment analysis identified “positive regulation of Wnt/β-catenin signaling” and “role of miRNAs in cell migration, survival, and angiogenesis” for differentially expressed mRNAs and miRNAs, respectively. We evaluated the five miRNAs increased in human plasma with PCB exposure and suspected TASH and found that miR-192–5p was increased with PCB exposure in mouse liver. Although we observed little overlap between differentially expressed mRNA transcripts and proteins, biological pathway-relevant PCB-induced miRNA-mRNA and miRNA-protein inverse relationships were identified that may explain protein changes. These results provide novel insights into miRNA and mRNA transcriptome changes playing direct and indirect roles in the functional protein pathways in PCB-related hepatic lipid accumulation, inflammation, and fibrosis in a mouse model of TASH and its relevance to human liver disease in exposed populations.

中文翻译：

多氯联苯对小鼠模型环境性肝病影响的多组学分析

暴露于高脂肪饮食 (HFD) 和持久性有机污染物（包括多氯联苯 (PCB)）与人类肝损伤以及动物模型中的非酒精性脂肪性肝病 (NAFLD) 和脂肪性肝炎 (NASH) 相关。以前，将 HFD 喂养的雄性小鼠暴露于非二恶英样 (NDL) PCB 混合物 Aroclor1260、二恶英样 (DL) PCB126 或 Aroclor1260 + PCB126 的共同暴露导致毒物相关脂肪性肝炎 (TASH) 并不同程度地改变了肝脏蛋白质组。此处使用无偏 mRNA 和 miRNA 测序（mRNA-和 miRNA-seq）来鉴定这些肝脏样本中改变的生物途径。与组合相比，PCB126 或 Aroclor1260 上调或下调的转录本和 miR 更少，表明由这些 PCB 激活的受体之间的串扰放大了转录组的变化。通路富集分析分别鉴定了差异表达的 mRNA 和 miRNA 的“Wnt/β-连环蛋白信号传导的正调控”和“miRNA 在细胞迁移、存活和血管生成中的作用”。我们评估了暴露于 PCB 和疑似 TASH 的人血浆中增加的五种 miRNA，发现小鼠肝脏中 miR-192-5p 随 PCB 暴露而增加。尽管我们观察到差异表达的 mRNA 转录本和蛋白质之间几乎没有重叠，但发现了与生物通路相关的 PCB 诱导的 miRNA-mRNA 和 miRNA-蛋白质反向关系，这可能解释了蛋白质的变化。

更新日期：2022-07-10

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