Toxicogenomics of metal response in genetically-variable Drosophilapopulations

项目总结 环境毒素对人类健康构成相当大的风险，其中最令人担忧的是有毒物质。 金属。由于广泛的工业使用和历史上广泛地并入普通产品(例如， )，饮用水、食品和土壤中普遍存在金属污染。即使是极低 接触某些金属的水平可能会对人类健康造成有害后果。这是特别的 对于儿童来说是这样的，因为接触金属与认知功能和神经功能较差有关 有问题。鉴于与金属毒性相关的主要健康风险，了解遗传， 表观遗传，和潜在的有毒金属反应的分子途径。 很明显，不同的人对一种特定的有毒物质的反应方式有相当大的差异 化合物，无论是环境金属毒素，如铅，还是药物化合物，如 化疗药物。对一些人来说，特定剂量可能具有极大的破坏性，而对另一些人来说，同样的剂量 剂量的影响要小得多。了解对有毒金属的差异反应的本质 挑战，找到导致金属毒性易感性变异的基因，将使我们能够获得更多 准确预测与暴露相关的风险，更好地了解与金属相关的症状 毒性，更具体地治疗接触过的人。 探索人类直接对金属毒性反应的遗传变异面临的主要挑战是 金属的极端毒性，排除了伦理人体研究，以及缺乏对任何 以人口为基础的研究。模型实验室系统提供了相当大的优势，例如 果蝇(果蝇)；暴露水平可以精确控制，组织特异性基因测量 表达可以收集，候选毒性基因可以使用复杂的 基因工具包。关键是，人类和苍蝇之间存在广泛的保守性，包括许多基因。 参与大脑发育和神经功能，以及许多已知的金属反应和解毒 基因。因此，对苍蝇的研究可以为人类种群的毒性变化提供基本的见解。 在这项提案中，我们将利用一个非常大的、遗传特征良好的近亲交配果蝇小组 台词。我们将整合来自强大、高效的毒性筛查的数据，以及来自一系列复杂的 基因组学研究产生全基因组范围的基因表达测量和调控区域图。作为一名 结果，我们将确定导致四个关键环境和环境的毒性变化的机制和基因 工业金属毒素；铅、汞、镉和锰。

PROJECT SUMMARY Environmental toxins present considerable risk to human health, and among the most concerning are toxic metals. Due to broad industrial use and historically widespread incorporation into common products (e.g., paints), there is widespread metal contamination of drinking water, food items, and soil. Even extremely low levels of exposure to certain metals can have deleterious consequences for human health. This is especially true for children since metal exposure has been associated with poorer cognitive function and neurological problems. Given the major health risks associated with metal toxicity it is critical to understand the genetic, epigenetic, and molecular pathways underlying the response to toxic metals. It is clear there is considerable variation among individuals in how they respond to a given toxic compound, whether it is an environmental metal toxin such as lead, or a pharmaceutical compound such as a chemotherapeutic. For some individuals a particular dose can be highly damaging, while for others that same dose has a much more minor effect. Understanding the nature of differential response to a toxic metal challenge, and finding genes that contribute to variation in susceptibility to metal toxicity, will enable us to more accurately predict the risks associated with exposure, better understand the symptoms associated with metal toxicity, and more specifically treat exposed individuals. A principal challenge with exploring genetic variation for metal toxicity response directly in humans is the extreme toxicity of the metals, precluding ethical human studies, and the lack of control of toxin dose in any population-based study. Considerable advantages are offered by model laboratory systems such as Drosophila (fruitflies); Exposure levels can be precisely controlled, tissue-specific measures of gene expression can be gathered, and candidate toxicity genes can be functionally validated using a sophisticated genetic toolkit. Critically, there is broad conservation between humans and flies, including many genes involved in brain development and neuronal function, and many known metal response and detoxification genes. Thus, studies in flies can provide fundamental insight into toxicity variation in human populations. In this proposal we will exploit a very large, genetically well-characterized panel of Drosophila inbred lines. We will integrate data from powerful, efficient toxicity screens, and from a series of sophisticated genomics studies that generate genomewide gene expression measures and maps of regulatory regions. As a result, we will identify mechanisms and genes contributing to variation in toxicity to four key environmental and industrial metal toxins; lead, mercury, cadmium, and manganese.