Kinetotoxic Mechanisms of Environmental Carcinogens

描述(申请人提供)：发展了几种不同的体外和体外来源的啮齿动物细胞系，概括了体内成体组织干细胞的特殊不对称细胞动力学。此前，这些模型细胞已被用来研究和定义控制成体干细胞动力学的遗传和分子机制。在这项拟议的研究中，模型细胞将被用来研究环境因素是否通过扰乱成人干细胞的动力学来实现这一点。环境因素已知会诱发人类癌症，但没有可检测到的突变活性。具体地说，将检验一些非诱变致癌物通过诱导干细胞增殖率来发挥作用的假设。破坏不对称干细胞动力学是人类致癌过程中必不可少的一步。环境污染物的“运动毒性”效应导致成体干细胞增殖增加，在与细胞增殖改变相关的其他慢性过程的病因学上也可能是重要的(例如，过早衰老)。模型细胞已经被用来鉴定3种有机化合物，它们将暴露的细胞从不对称细胞动力学转变为指数细胞动力学。拟议研究的主要重点将是使用这些细胞系来评估公认的非诱变环境致癌物的运动毒性。将对急性高剂量和慢性低剂量暴露进行调查。除了评估非致突变化合物外，还将检查几种众所周知的致突变致癌物，因为它们可能同时表现出运动毒性。被发现引起细胞动力学变化的化学物质将被评估对以前被认为是不对称细胞动力学调节器的细胞基因的分子效应。在初步研究中，IARC第1类人类致癌物苯显示出运动毒性的证据。苯作为一种有效的、非诱变的人类致癌物，有很好的记录历史。它将作为运动毒剂的原型，开发一种系统的方法来揭示运动毒药的机制。在体外，具有不对称细胞动力学的人类细胞系将被派生出来，以提供可能与人类成年干细胞生理学更相关的运动毒性分析。这项拟议的研究旨在为经过充分研究的环境污染物的致癌机制提供新的见解，这些污染物的作用模式仍然是一个谜。这些见解将推动制定更好的战略，以限制与环境致癌物接触有关的发病率。

DESCRIPTION (provided by applicant): Several different in vitro and ex vivo-derived rodent cell lines were developed that recapitulate the specialized asymmetric cell kinetics of adult somatic tissue stem cells in vivo. Previously, these model cells have been used to investigate and define genetic and molecular mechanisms that control adult stem cell kinetics. In the proposed research, the model cells will be used to investigate whether environmental agents, that are known to induce human cancers but with no detectable mutagenic activity, do so by disrupting adult stem cell kinetics. Specifically, the hypothesis that some non-mutagenic carcinogens function by inducing increased rates of stem cell proliferation will be examined. Disruption of asymmetric stem cell kinetics is an essential step in human carcinogenesis. "Kinetotoxic" effects by environmental contaminants, that lead to increased adult stem cell proliferation, may also be important in the etiology of other chronic processes associated with altered cell proliferation (e.g., premature aging). The model cells have already been used to identify 3 organic compounds that switch exposed cells from asymmetric cell kinetics to exponential cell kinetics. The main focus of the proposed research will be to use these cell lines to evaluate well established non-mutagenic environmental carcinogens for kinetotoxicity. Both acute high-dose and chronic low-dose exposures will be investigated. In addition to evaluating non-mutagenic compounds, several well-known mutagenic carcinogens will be examined, as they may exhibit concurrent kinetotoxicity. Chemicals found to induce changes in cell kinetics will be evaluated for molecular effects on cellular genes previously identified as regulators of asymmetric cell kinetics. In preliminary studies, the IARC Group 1 human carcinogen benzene exhibits evidence for kinetotoxicity. Benzene has a well-documented history as a potent non-mutagenic human carcinogen. It will serve as the prototype kinetotoxic agent for developing a systematic approach to revealing kinetotoxic mechanisms. In vitro human cell lines with asymmetric cell kinetics will be derived to provide kinetotoxicity assays that may have greater relevance to human adult stem cell physiology. The proposed research has the goal of providing new insights to the carcinogenic mechanisms of well studied environmental contaminants whose mode of action remains a mystery. Such insights will advance efforts to develop better strategies to limit morbidity associated with exposure to environmental carcinogens.