Interactions between tobacco smoke constituents in rodent tumor models

描述(申请人提供)：烟草烟雾是一种复杂的化学混合物，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还不是很清楚。为了减少烟草产品和烟雾的毒性和致癌性，重要的是要确定许多烟草成分中的哪些是减少的目标。如果相互作用放大了已知人类致癌物残留水平的影响，那么降低一种化学物质的水平可能不会降低烟草产品的总体致癌性能。鉴于混合物的复杂性，以及缺乏关于混合物的各个成分如何共同作用引发癌症的信息，我们将探索两种化学物质的组合之间的相互作用，这些化合物可能具有协同致癌作用。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的人类致癌物(NNK、NNN或BaP)与烟草烟雾挥发性成分(乙醛、丙烯醛和甲醛)之间的潜在相互作用，具体目的如下：目的1.确定乙醛是否可以影响NNN在大鼠食道肿瘤模型中的致癌特性。目的2.研究吸入醛(甲醛、乙醛、丙烯醛)对NNK在A/J小鼠肺癌模型中的致癌作用。目的3.确定吸入醛(甲醛、乙醛、丙烯醛)是否能调节BaP在A/J小鼠肺癌模型中的致癌作用。在每个目标中，我们将探索每种醛与NNN、NNK或BaP联合使用对肿瘤发生率、肿瘤多样性和肿瘤大小的影响，以确定是否有必要同时减少致癌物和醛以减少危害，或者减少一组成分是否就足够了。尿代谢物和DNA加合物生物标记物将被测量，以确定这些生物标记物的水平是否受到共同暴露的影响。这些研究将提供有关挥发性化合物影响已确定的烟草致癌物质致癌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