Interactions between tobacco smoke constituents in rodent tumor models

描述（由申请人提供）：烟草烟雾是一种复杂的化学物质混合物，其中许多是有毒和致癌的。这些化学物质如何相互作用，导致烟草烟雾和产品对人类健康的影响，目前还不清楚。为了降低烟草制品和烟雾的毒性和致癌性，重要的是要确定要减少的许多烟草成分中的哪一种。如果相互作用放大了已知人类致癌物残留水平的影响，则降低一种化学品的水平可能不会降低烟草产品的总体致癌特性。鉴于混合物的复杂性和缺乏关于混合物的单个组分如何共同作用以引发癌症的信息，我们将探索两种可能具有协同致瘤作用的化学物质组合之间的相互作用。本项目的目标是在已建立的啮齿动物肿瘤模型中表征已知人类致癌物（NNK、NNN或BaP）与烟草烟雾挥发性组分（乙醛、丙烯醛和甲醛）之间的潜在相互作用，具体目标如下：目标1。确定乙醛是否可以影响大鼠食管肿瘤模型中NNN的致癌特性。目标二。确定吸入的醛（甲醛、乙醛、丙烯醛）是否可以调节A/J小鼠肺肿瘤模型中NNK的致癌特性。目标3：在A/J小鼠肺肿瘤模型中，确定吸入的醛类（甲醛、乙醛、丙烯醛）是否可以调节BaP的致癌特性。在每个目标中，我们将探索每种醛与NNN，NNK或BaP组合对肿瘤发生率，肿瘤多样性和肿瘤大小的影响，以确定是否需要减少致癌物和醛以减少危害，或者减少一组成分是否足够。将测量尿液代谢物和DNA加合物生物标志物，以确定这些生物标志物的水平是否受到联合暴露的影响。这些研究将提供关于挥发性化合物影响已确定的烟草致癌物的致瘤活性的能力的重要缺失信息

DESCRIPTION (provided by applicant): Tobacco smoke is a complex mixture of chemicals, many of which are toxic and carcinogenic. How these chemicals interact to cause the human health effects of tobacco smoke and products is not well-understood. To decrease the toxicity and carcinogenicity of tobacco products and smoke, it is important to identify which of the many tobacco constituents to target for reduction. Lowering the levels of one type of chemical may not reduce the overall carcinogenic properties of the tobacco product if interactions amplify the effects of residual levels of the known human carcinogens. Given the complexity of the mixtures and the lack of information regarding how individual components of the mixtures act together to trigger cancer, we will explore the interactions between combinations of two chemicals that are likely to have synergistic tumorigenic effects. The goal of this project is to characterize the potential interactions between known human carcinogens (NNK, NNN, or BaP) and volatile components of tobacco smoke (acetaldehyde, acrolein, and formaldehyde) in established rodent tumor models as outlined in the following specific aims: Aim 1. Determine if acetaldehyde can influence the carcinogenic properties of NNN in a rat esophageal tumor model. Aim 2. Determine if inhaled aldehydes (formaldehyde, acetaldehyde, acrolein) can modulate the carcinogenic properties of NNK in the A/J mouse lung tumor model. Aim 3. Determine if inhaled aldehydes (formaldehyde, acetaldehyde, acrolein) can modulate the carcinogenic properties of BaP in the A/J mouse lung tumor model. In each aim, we will explore the influence of each aldehyde in combination with NNN, NNK, or BaP on tumor incidence, tumor multiplicity and tumor size to determine if reduction of both carcinogen and aldehyde is necessary to reduce harm, or if reductions in one group of constituents would suffice. Urinary metabolite and DNA adduct biomarkers will be measured to determine if the levels of these biomarkers are influenced by the co-exposure. These studies will provide important missing information about the ability of volatile compounds to influence the tumorigenic activity of established tobacco carcinogens