Kinetotoxic Mechanisms of Environmental Carcinogens

描述（由申请人提供）：开发了几种不同的体外和离体衍生的啮齿动物细胞系，其概括了体内成体体组织干细胞的专门不对称细胞动力学。以前，这些模型细胞已被用于研究和定义控制成体干细胞动力学的遗传和分子机制。在拟议的研究中，模型细胞将被用于研究环境因子是否会通过破坏成体干细胞动力学来诱导人类癌症，但没有可检测到的诱变活性。具体而言，一些非致突变致癌物通过诱导干细胞增殖率增加而发挥作用的假设将被检验。不对称干细胞动力学的破坏是人类致癌的重要步骤。导致成体干细胞增殖增加的环境污染物的“运动毒性”效应在与改变的细胞增殖相关的其他慢性过程（例如，过早老化）。该模型细胞已被用于识别3种有机化合物，这些化合物将暴露的细胞从不对称细胞动力学转换为指数细胞动力学。拟议研究的主要重点将是使用这些细胞系来评价已确立的非致突变环境致癌物的运动毒性。将对急性高剂量和慢性低剂量照射进行调查。除了评价非致突变化合物外，还将检查几种已知的致突变致癌物，因为它们可能表现出并发的运动毒性。将评价发现诱导细胞动力学变化的化学品对先前确定为不对称细胞动力学调节因子的细胞基因的分子效应。在初步研究中，IARC第1组人类致癌物苯显示出运动毒性的证据。苯作为一种强有力的非致突变人类致癌物，有充分的历史记录。它将作为原型的运动毒性剂开发一个系统的方法来揭示运动毒性机制。将衍生具有不对称细胞动力学的体外人细胞系，以提供可能与人成体干细胞生理学具有更大相关性的动力学毒性试验。这项研究的目的是为研究充分的环境污染物的致癌机制提供新的见解，这些污染物的作用方式仍然是一个谜。这些见解将推动制定更好的战略，以限制与暴露于环境致癌物相关的发病率。

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.