Influences of environmental agents on Alu/Alu recombination

Alu元件之间的不平等重组事件导致了与癌症和出生缺陷相关的人类基因组不稳定性的很大一部分。有50多个独立的Alu/Alu重组事件导致不同的人类疾病。以前的研究表明，各种诱变化合物有助于提高随机重复序列之间的重组率。这些分析表明，复合环境污染物通常对小突变和复合有不同的影响。我们假设诱变剂也将有助于分散的Alu元素之间更多的重组，尽管不同诱变剂的刺激在这两种不同类型的重组中可能不同。因此，我们设计了一种报告的系统，该系统将被引入组织培养细胞和转基因小鼠，以允许直接测量Alu/Alu重组率。我们相信，这项检测将比以往的检测更能代表人类基因组中发生的典型重组事件。Alu/Alu重组试验将被用来测试在暴露于广泛的诱变剂时重组率的增加。将特别注意芳基碳氢化合物，因为它们代表着如此普遍和稳定的污染物类别。特别是苯并[a]芘与。将进行各种卤代芳香烃的测试，以确定较易代谢的碳氢化合物与非可代谢碳氢化合物之间的重组潜力是否存在差异。此外，还将进行研究，以确定芳烃受体在任何重组刺激中的作用。

Unequal recombination events between Alu elements contribute to a significant portion of human genome instabilities associated with cancer and birth defects. There are over 50 independent examples of Alu/Alu recombination events causing different human diseases. Previous studies have shown that various mutagenic compounds contribute to increased recombination rates between randomly repeated sequences. These assays have demonstrated that recombination environmental pollutants often have different influences on small mutations versus recombination. We hypothesize that mutagens will also contribute to the more recombination between dispersed Alu elements, although the stimulation by different mutagens may not be identical between these two different types of recombinant. Thus, we have designed a reported system that will be introduced into tissue culture cells and transgenic mice to allow the direct measurement of Alu/Alu recombination rates. We believe that this assay will be more representative of typical recombination events occurring in the human genome than previous assays. The Alu/Alu recombination assay will be utilized to test for increases in recombination rate upon exposure to a broad range of mutagens. Particular attention will be paid to the aryl hydrocarbons because they represent such a ubiquitous and stable class of pollutants. In particular, studies of benzo[a]pyrene versus. various halogenated aromatic hydrocarbons will be carried out to determine whether there are differences in recombination potential between the more metabolizable hydrocarbons versus no-.metabolizable ones. In addition, studies to determine the role of the aryl hydrocarbon receptor in any recombination stimulation will be carried out.