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

• 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
• 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

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.

项目摘要 1，4-二氧六环（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Superfund或其他类型的1，4-DX释放地点附近的人可以提高。国际防盲组织international association for 癌症研究已将1，4-DX归类为2B组致癌物，主要靶器官为 动物研究中的肝脏。尽管存在这种担忧，但饮用水中1，4-DX的安全标准一直进展缓慢， 发展和变化很大，与变异性有关的不确定性与其肝脏 致癌潜力迫切需要进行机制研究，以（i）了解1，4-DX如何发挥作用 本身或与其他共同发生的饮用水污染物[如 三氯乙烯（TCE）和1，1-二氯乙烷（1，1-DCA）]，（ii）确定接触浓度范围 在这些影响发生，（iii）确定潜在的更脆弱的亚组。我们的初步研究 在小鼠中发现了可能涉及1，4-DX致癌性的分子靶点和途径， 为拟议的研究提供了舞台。这些初步研究使用了不同的1，4-DX浓度（50，500 和5，000 ppm），持续时间长达3个月。这些研究显示轻度肝细胞毒性 这与以前的研究一致。最高剂量的1，4-DX诱导了各种分子的变化， 肝脏包括：（i）持续诱导NRF 2及其参与抗氧化反应的靶蛋白（即， GCLC、GCLM、HMOX 1和NQO 1），（ii）CYP 2 E1（能够 激活内源性和异生物质化合物以及活性氧物质的发生器），（iii） 脂质过氧化副产物4-HNE的小叶中心蓄积，以及（iv）DNA损伤的升高 标记γ H2 AX。重要的是，这些1，4-DX引起的分子变化在小鼠模型中被放大， 系统性谷胱甘肽（GSH）缺乏症。这个项目将建立在这些有趣的发现和调查我们的 预测长期暴露于1，4-DX通过破坏氧化还原导致肝脏肿瘤发生的新假说 体内平衡，从而增强遗传不稳定性。这种提出的1，4-DX作用模式将具有高的 在评估可能利用或调节 重叠的分子途径。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在体内研究肝脏致癌性，（2）鉴定生物网络基序， 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 阐明共存污染物（TCE和1，1-DCA）对1，4-DX的改性能力 在人类肝细胞和斑马鱼模型系统中的致癌性。