Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey,Environmental Health Perspectives

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Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey
Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2022-1-6 , DOI: 10.1289/ehp9467
Matthew C Cave _{1,

2,

3,

4,

5,

6,

7,

8,

9} , Christina M Pinkston _{4,

10,

11} , Shesh N Rai _{4,

5,

6,

9,

10,

11} , Banrida Wahlang _{1,

5} , Marian Pavuk ₁₂ , Kimberly Z Head _{1,

4} , Gleta K Carswell ₁₃ , Gail M Nelson ₁₃ , Carolyn M Klinge ₃ , Douglas A Bell ₁₄ , Linda S Birnbaum ₁₄ , Brian N Chorley ₁₃

Affiliation

Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, Louisville, Kentucky, USA.
Department of Pharmacology & Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky, USA.
Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky, USA.
Superfund Research Center, University of Louisville, Louisville, Kentucky, USA.
Center for Integrative Environmental Health Sciences, University of Louisville, Louisville, Kentucky, USA.
Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky, USA.
Liver Transplant Program at UofL Health-Jewish Hospital Trager Transplant Center, Louisville, Kentucky, USA.
University of Louisville Alcohol Research Center, Louisville, Kentucky, USA.
Department of Bioinformatics and Biostatistics, University of Louisville School of Public Health and Information Sciences, Louisville, Kentucky, USA.
Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
United States Environmental Protection Agency, Research Triangle Park, North Carolina, USA.
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.

Abstract

Background:

Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress.

Objectives:

We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort.

Methods:

Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed.

Results:

The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor $α$ were well integrated within the top identified networks.

Discussion:

These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467

中文翻译：

安尼斯顿社区健康调查中的循环 MicroRNA、多氯联苯和环境性肝病

摘要

背景：

多氯联苯 (PCB) 暴露与人类群体中的肝损伤以及模型系统中的脂肪性肝炎和肝坏死相关。MicroRNA (miR) 维持细胞稳态并可能调节对环境压力的反应。

目标：

我们在一个居住队列中测试了特定 miR 与肝病和 PCB 暴露相关的假设。

方法：

在横断面安尼斯顿社区健康调查中，对 734 名 PCB 暴露参与者的存档血清中测量了 68 个目标肝毒性 miR。坏死性和其他肝病类别由血清角蛋白 18 (K18) 生物标志物定义。确定了暴露生物标志物（35 种邻位取代的 PCB 同系物）和疾病生物标志物（高表达的 miR 或先前测量的细胞因子）之间的关联，并进行了 Ingenuity Pathway Analysis。

结果：

坏死性肝病类别与 4 个上调 miR（miR-99a-5p、miR-122-5p、miR-192-5p 和 miR-320a）和 5 个下调 miR（let-7d-5p、 miR-17-5p、miR-24-3p、miR-197-3p 和 miR-221-3p)。22 个 miR 与其他肝病类别或 K18 测量值相关。11 个 miR 与 24 种 PCB 相关，最常见的是具有抗雌激素活性的同源物。大多数与暴露相关的 miR 与至少一种血清肝细胞死亡、促炎细胞因子或胰岛素抵抗生物标记物相关，或与两者相关。在每个生物标志物类别中，肝脏特异性 miR-122-5p 的关联性最强。已确定的肝毒性途径包括炎症/肝炎、增生/过度增殖、肝硬化和肝细胞癌。肿瘤蛋白p53和肿瘤坏死因子 $α$ 已很好地集成到顶级识别网络中。