Toxicogenomics of metal response in genetically-variable Drosophilapopulations

遗传变异果蝇种群中金属反应的毒理学

• 批准号: 10088445
• 负责人: Stuart John Macdonald
• 金额: $ 20.45万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088445
• 关键词: ATAC-seq; Alleles; Animals; Biological; Biological Assay; Biological Models; Biological Process; Brain; Cadmium; Cell physiology; Child; Chromatin; Complex; Data; Data Set; Development; Diet; Dissection; Dose; Drosophila genus; Drug Metabolic Detoxication; Elements; Environment; Enzymes; Epigenetic Process; Ethics; Exposure to; Food; Gene Expression; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Head; Health; Human; Inbreeding; Individual; Industrialization; Laboratories; Lead; Mammals; Manganese; Maps; Measures; Mercury; Metal exposure; Metals; Methylmercury Compounds; Minor; Modeling; Molecular; Nature; Neurologic; Neurons; Nucleic Acid Regulatory Sequences; Paint; Parkinson Disease; Pathway interactions; Pharmacologic Substance; Phenotype; Physiological; Poison; Population; Population Study; Predisposition; Quantitative Trait Loci; Recombinants; Recording of previous events; Resolution; Resources; Risk; Role; Series; Soil; Syndrome; System; Testing; Tissues; Toxic Environmental Substances; Toxic effect; Toxicogenomics; Toxin; Transposase; Uncertainty; Variant; Work; associated symptom; base; brain tissue; cognitive development; cognitive function; contaminated drinking water; dietary; experimental study; exposed human population; feeding; fly; genetic approach; genome-wide; insight; lead exposure; metal poisoning; neurotoxicity; phenotypic data; response; toxic metal; trait; transcriptome sequencing

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.

项目摘要 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.由于广泛的工业用途和历史上广泛地并入普通产品（例如， 油漆），饮用水、食品和土壤普遍受到金属污染。甚至极低 暴露于某些金属的水平可对人类健康产生有害后果。这是特别 儿童也是如此，因为金属接触与认知功能和神经功能较差有关。 问题考虑到与金属毒性相关的主要健康风险， 表观遗传和对有毒金属反应的分子途径。 很明显，个体对特定有毒物质的反应存在相当大的差异。 化合物，无论其是环境金属毒素如铅，还是药物化合物如 化疗。对某些人来说，特定的剂量可能具有高度的破坏性，而对其他人来说， 剂量的影响要小得多。理解对有毒金属的不同反应的性质 挑战，并找到基因，有助于变异的易感性，金属毒性，将使我们能够更多地 准确预测与接触相关的风险，更好地了解与金属相关的症状， 毒性，更具体地治疗暴露个体。 直接在人类中探索金属毒性反应的遗传变异的主要挑战是 金属的极端毒性，阻碍了符合伦理的人类研究，并且缺乏对任何毒素剂量的控制 基于人口的研究。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，基因的组织特异性措施 表达可以收集，候选毒性基因可以使用复杂的 基因工具箱至关重要的是，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，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中的毒性变化提供基本的见解。 在这个建议中，我们将利用一个非常大的，遗传特征良好的小组果蝇近交 线我们将整合来自强大，高效的毒性筛选的数据，以及来自一系列复杂的 基因组学研究，产生全基因组基因表达的措施和调控区的地图。作为 结果，我们将确定机制和基因的毒性变化，以四个关键的环境和 工业金属毒素;铅、汞、镉和锰。