Project 1 - Toxicity and Liver Carcinogenicity of 1,4-Dioxane: Single Chemical and Mixtures Studies

项目 1 - 1,4-二恶烷的毒性和肝脏致癌性：单一化学品和混合物研究

基本信息

批准号：
10361886
负责人：
Ying Chen
金额：
$ 31.28万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10361886
关键词：
Animals Biological Biological Markers Biological Models CYP2E1 gene Carcinogens Cells Chemicals Chronic DNA Damage Data Analyses Development Dioxanes Dose Ethylene Dichlorides Event Exposure to Fostering GCLC gene GCLM gene Gamma-H2AX Genetic Glutathione Goals Health Hepatocarcinogenesis Hepatocyte Hepatotoxicity Homeostasis Human In Vitro International Agency for Research on Cancer Lipid Peroxidation Liver Long Island Malignant Neoplasms Malignant neoplasm of liver Molecular Molecular Target Mouse Strains Mus NQO1 gene Oncogenes Organ Oxidation-Reduction Pathway interactions Pattern Persons Phase Phenotype Plasma Predisposition Process Proteins Rattus Reactive Oxygen Species Research Resources Risk Role Safety Site Source Subgroup Superfund Time Toxic effect Transgenic Organisms Translational Research Trichloroethylene Uncertainty Urine Water Pollutants Xenobiotics Zebrafish adverse outcome base carcinogenicity cohesion cytotoxicity drinking water exposed human population genotoxicity high throughput screening in vitro Assay in vivo liver cancer model metabolomics mouse model multiple omics novel oxidation programs promoter response screening sound stem transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY 1,4-Dioxane (1,4-DX) is an emerging drinking water contaminant. The potential for 1,4-DX exposure is elevated for people living near Superfund or other types of 1,4-DX release sites. The International Agency for Research on Cancer has classified 1,4-DX as a group 2B carcinogen with the primary organ target being the liver in animal studies. Despite this concern, safety standards for 1,4-DX in drinking water have been slow to develop and vary widely, with the variability being related to the uncertainty associated with its liver carcinogenic potential. Mechanistic studies are urgently needed to (i) understand how 1,4-DX may contribute to liver carcinogenesis by itself or in combination with other co-occurring drinking water contaminants [such as trichloroethylene (TCE) and 1,1-dichloroethane (1,1-DCA)], (ii) determine the exposure concentration range over which these effects occur, and (iii) identify potentially more vulnerable subgroups. Our preliminary studies in mice have revealed molecular targets and pathways potentially involved in 1,4-DX carcinogenicity and set the stage for the proposed studies. These preliminary studies utilized various 1,4-DX concentrations (50, 500 and 5,000 ppm) in drinking water for periods of up to 3 month. These studies revealed mild liver cytotoxicity that is consistent with previous studies. The highest 1,4-DX dose induced assorted molecular changes in the liver including: (i) persistent induction of NRF2 and its target proteins involved in anti-oxidative response (i.e., GCLC, GCLM, HMOX1 and NQO1), (ii) time-dependent induction of CYP2E1 (key oxidative pathway capable of activating endogenous and xenobiotic compounds and a generator of reactive oxygen species), (iii) centrilobular accumulation of the lipid peroxidation by-product 4-HNE, and (iv) elevations in the DNA damage marker γH2AX. Importantly, these 1,4-DX-elicited molecular changes were amplified in a mouse model of systemic glutathione (GSH) deficiency. This project will build upon these intriguing findings and investigate our novel hypothesis predicting that long-term exposure to 1,4-DX causes liver tumorigenesis by disrupting redox homeostasis, thereby potentiating genetic instability. This proposed 1,4-DX mode of action would be of high relevance in assessing carcinogenic effects of co-occurring contaminants that may utilize or modulate overlapping molecular pathways. We propose to (1) delineate the contribution of key redox pathways to 1,4-DX liver carcinogenicity in vivo using transgenic redox mouse models, (2) identify the biological network motifs that predict 1,4-DX-induced liver carcinogenesis and the dose response pattern for perturbation of these networks in vivo, and (3) elucidate the capacity of co-occurring contaminants (TCE and 1,1-DCA) to modify 1,4-DX carcinogenicity in human hepatocyte cells and zebrafish model systems.

项目概要 1,4-二恶烷 (1,4-DX) 是一种新兴的饮用水污染物 1,4-DX 暴露的可能性是。居住在超级基金或其他类型 1,4-DX 释放地点附近的人们的水平升高。癌症研究已将 1,4-DX 列为 2B 类致癌物，主要靶器官是尽管存在这种担忧，饮用水中 1,4-DX 的安全标准却进展缓慢。发展和变化很大，其变异性与其肝脏相关的不确定性有关迫切需要进行机制研究以 (i) 了解 1,4-DX 的作用机制。其本身或与其他同时发生的饮用水污染物[例如三氯乙烯（TCE）和1,1-二氯乙烷（1,1-DCA）]，（ii）确定暴露浓度范围这些影响发生的范围，以及 (iii) 确定潜在的更脆弱的亚群体。在小鼠中的研究揭示了可能涉及 1,4-DX 致癌性的分子靶标和途径，并确定了这些初步研究使用了不同的 1,4-DX 浓度（50、500）。和 5,000 ppm），在饮用水中持续长达 3 个月，这些研究表明存在轻微的肝细胞毒性。这与之前的研究一致。最高的 1,4-DX 剂量诱导了各种分子变化。肝脏，包括：（i）持续诱导 NRF2 及其参与抗氧化反应的靶蛋白（即， GCLC、GCLM、HMOX1 和 NQO1)，(ii) CYP2E1（关键氧化途径能够激活内源性和外源性化合物以及活性氧发生器），（iii）小叶中心脂质过氧化副产物 4-HNE 的积累，以及 (iv) DNA 损伤的升高重要的是，这些 1,4-DX 引发的分子变化在小鼠模型中得到了放大。该项目将基于这些有趣的发现并调查我们的系统性谷胱甘肽（GSH）缺乏症。新假说预测长期暴露于 1,4-DX 通过破坏氧化还原而导致肝脏肿瘤发生体内平衡，从而增强遗传不稳定性。所提出的 1,4-DX 作用模式将具有高度的稳定性。评估可能利用或调节的共存污染物的致癌作用的相关性我们建议 (1) 描述关键氧化还原途径对 1,4-DX 的贡献。使用转基因氧化还原小鼠模型进行体内肝癌致癌性，（2）识别生物网络基序预测 1,4-DX 诱导的肝癌发生以及这些网络扰动的剂量反应模式 (3) 阐明共存污染物（TCE 和 1,1-DCA）修饰 1,4-DX 的能力人类肝细胞和斑马鱼模型系统的致癌性。