Ultra-Low Dose Carcinogen Testing with the Trout Model

使用鳟鱼模型进行超低剂量致癌物测试

基本信息

批准号：
7777642
负责人：
David E Williams
金额：
$ 10.87万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777642
关键词：
2-Acetylaminofluorene Accounting Address Aflatoxin B1 Aflatoxins Animal Model Animals Apoptosis Biological Markers Bladder Carcinogen exposure Carcinogenicity Tests Carcinogens Cell Proliferation Cessation of life Coupled Custom DNA Adduction Data Disease Dose Environmental Carcinogens Exhibits Female Food Supply Gene Expression Gene Targeting Housing Human Inbred BALB C Mice Incidence International Agency for Research on Cancer Linear Models Literature Liver Liver neoplasms Malignant Neoplasms Measurement Measures Metabolism Methods Modeling Molecular Mus Oncogene Activation Oncorhynchus mykiss Oregon Organ Pathology Primary carcinoma of the liver cells Process Protocols documentation Pyrenes Research Personnel Risk Assessment Rodent Rodent Model Salmo trutta Sampling Solid Neoplasm Study models Testing Time Universities animal data cancer chemoprevention cancer risk carcinogenesis carcinogenicity cost dosimetry exposed human population programs response tumor

项目摘要

DESCRIPTION (provided by applicant): Extrapolation of dose-response carcinogen data from animals to establish "safe" levels for human exposures (1 in a million) is challenging as it requires modeling of dose-response over at least 4 orders of magnitude. In many cases, the conservative approach is assumed linearity. The largest tumor study in a rodent model used 24,192 mice to detect 1 cancer in 100. The trout tumor model has proven valuable in identification of carcinogens and their mechanism of action. Trout are very sensitive to the hepatocarcinogenicity of aflatoxin B1 (AFB1), the only IARC human carcinogen where exposure is through the food supply. Hepatocellular carcinoma (HCC) is responsible for over 600,000 deaths a year worldwide and accounts for 10-15% of all deaths in certain regions. HCC is the most rapidly increasing solid tumor in the U.S. For AFB1, the target organ, metabolism, DNA adduction and gene targets are similar in trout and human and, in this example, the trout model is superior to mouse. The trout model can utilize large numbers of animals to evaluate cancer across a wide range of doses. This approach is possible due to a number of advantages of this model including low spontaneous tumor incidence and low per diem costs. We have recently completed the largest cancer study in any animal model, utilizing 42,000 trout to assess carcinogenicity of dibenzo[a,l]pyrene (DBP) at ultra-low doses. The target was an order of magnitude lower than the mouse ED01 study, to one cancer in 1000. Our data established a dose of DBP that resulted in 1 cancer in 5,000 trout and the dose-response was non-linear. We now propose to utilize this ultra-low dose model to test the hypothesis that the non-linearity of cancer incidence at ultra-low dose also applies to AFB1. Tumor incidence data will be coupled with measurements of molecular dosimetry, cell proliferation, apoptosis and gene expression utilizing a custom microarray in order to test the second hypothesis, that in contrast to tumor incidence, these biomarkers of carcinogenicity exhibit linearity across the entire tumor dose-response range.

描述（由申请人提供）：从动物中推断剂量反应致癌数据以建立人类暴露的“安全”水平（100万分之一）很具有挑战性，因为它需要在至少4个数量级上对剂量反应进行建模。在许多情况下，保守方法是线性的。在啮齿动物模型中，最大的肿瘤研究使用了24,192只小鼠在100中检测1个癌症。鳟鱼肿瘤模型已被证明在鉴定致癌物及其作用机理方面具有价值。鳟鱼对黄曲霉毒素B1（AFB1）的肝癌非常敏感，这是唯一通过食物供应暴露的IARC人类致癌物。肝细胞癌（HCC）每年在全球造成60万多人死亡，占某些地区所有死亡人数的10-15％。 HCC是美国AFB1的最快增加的实体瘤，靶器官，代谢，DNA内收和基因靶标在鳟鱼和人类中相似，在此示例中，鳟鱼模型优于小鼠。鳟鱼模型可以利用大量动物来评估各种剂量的癌症。由于该模型的许多优势，包括低自发性肿瘤的发生率和较低的DIEM成本，因此这种方法是可能的。我们最近在任何动物模型中都完成了最大的癌症研究，利用42,000鳟鱼评估二本佐[a，l] pyrene（dbp）以超低剂量的致癌性。该靶标比小鼠ED01研究低的数量级，在1000次癌症中。我们的数据建立了一定剂量的DBP，导致5,000个鳟鱼中1个癌症，剂量反应是非线性的。现在，我们建议利用这种超低剂量模型来检验以下假设：超低剂量时癌症发病率的非线性也适用于AFB1。肿瘤的发生率数据将与分子剂量法，细胞增殖，凋亡和基因表达的测量相结合，利用自定义微阵列来检验第二个假设，而这些假设与肿瘤发生的相反，这些癌变的生物标志物在整个肿瘤剂量剂量范围内表现出线性。