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，这些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。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通过破坏成体干细胞动力学来诱导人类癌症，这些环境因子已知会诱导人类癌症，但没有可检测到的致突变活性。具体地说，一些非诱变致癌物通过诱导干细胞增殖率增加而起作用的假设将被检验。不对称干细胞动力学的破坏是人类癌变的重要步骤。环境污染物的“动质毒性”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（如早衰）的病因学中也很重要。模型细胞已经被用来鉴定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已建立的非致突变环境致癌物的着丝毒性。将调查急性高剂量和慢性低剂量暴露。除了评估非致突变性化合物外，还将研究几种众所周知的致突变性致癌物，因为它们可能同时表现出着丝毒性。被发现的诱导细胞动力学变化的化学物质将被评估对细胞基因的分子效应，之前被确定为不对称细胞动力学的调节因子。在初步研究中，IARC第1组人类致癌物苯显示出动性毒性的证据。苯作为一种强效的非致突变性人类致癌物有充分的文献记载。它将作为原型动蛋白毒性剂，用于开发揭示动蛋白毒性机制的系统方法。具有不对称细胞动力学的体外人类细胞系将被衍生出来，以提供可能与人类成体干细胞生理学更相关的动蛋白毒性测定。拟议的研究的目标是提供新的见解，充分研究的环境污染物的致癌机制，其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有关的发病率的努力。

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.