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-DX（1,4-DX）是一种新兴的饮用水污染物。 1,4-DX暴露的潜力是 居住在超级基金附近或其他类型的1,4-DX发布地点的人们提升。国际机构 癌症的研究已将1,4-DX归类为2B组致癌，主要器官靶标是 生活在动物研究中。尽管担心了这一问题，但饮用水中1,4-DX的安全标准却很慢。 发展和变化很大，变异性与与肝脏相关的不确定性有关 致癌潜力。迫切需要（i）了解1,4-DX如何贡献的机械研究 单独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，（iii）识别潜在的脆弱亚组。我们的初步研究 在小鼠中，揭示了可能参与1,4-DX致癌性并设置的分子靶标和途径 拟议研究的阶段。这些初步研究利用了各种1,4-DX浓度（50，500 和5,000 ppm）在饮用水中长达3个月。这些研究揭示了轻度的肝细胞毒性 这与以前的研究一致。最高的1,4-DX剂量引起的分子变化 肝脏包括：（i）持续诱导NRF2及其与抗氧化反应有关的靶蛋白（即 GCLC，GCLM，HMOX1和NQO1），（ii）CYP2E1的时间依赖性诱导（关键氧化途径 激活内源性和异种生物化合物以及活性氧的发生器），（iii） 脂质过氧化副产物4-HNE和（iv）DNA损伤的抬高的中心腔积累 标记γH2AX。重要的是，在小鼠模型中，这1,4-DX引起的分子变化是 全身性谷胱甘肽（GSH）缺陷。该项目将基于这些有趣的发现，并调查我们的 新的假设预测，长期暴露于1,4-DX会通过破坏氧化还原引起肝肿瘤发生 稳态，从而潜在的遗传不稳定。提出的1,4-DX的作用方式将很高 在评估可能利用或调制的共发生污染物的致癌作用方面的相关性 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肝癌，（2）识别生物网络基序 预测这些网络扰动的1,4-DX诱导的肝癌和剂量反应模式 体内，（3）阐明了同时发生污染物（TCE和1,1-DCA）修改1,4-DX的能力 人肝细胞和斑马鱼模型系统中的致癌性。