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.