Humans vary in their genetic susceptibility to the toxic effects of chemicals found at Superfund sites.Cancers and other forms of toxicity may arise from adverse gene-environment interactions. Geneticsusceptibility to the toxic effects of a chemical is likely to be related to the cellular targets of the chemicaland its metabolites. However, we still have a limited understanding of cellular targets for many of thepriority chemicals on the Superfund list. We will take advantage of the conservation of basic metabolicpathways and fundamental cellular processes between the yeast S. cerevisiae and humans to identifycandidate human susceptibility genes. Here, we propose a new approach to discover these targets in yeastand human cells using parallel deletion analysis (PDA) and RNA interference (RNAi), respectively. Deletionstrains for almost every yeast gene enable new approaches to determine in parallel (PDA) the relativeimportance of each yeast gene for susceptibility (sensitivity) to a chemical toxicant. We propose to identifycandidate susceptibility genes for selected priority Superfund chemicals that require metabolic activationincluding benzene, polycyclic aromatic hydrocarbons (PAHs), halogenated aliphatic hydrocarbons, and forselected metals such as arsenic and cadmium, which do not. We will select and prioritize likely humancandidate genes by computational analysis of the yeast data sets. The candidate human susceptibilitygenes will be silenced in appropriate human cell lines using RNAi so that their roles in sensitivity tocytotoxicity, genotoxicity and epigenetic effects of the Superfund chemical and/or its metabolites can beevaluated. We suggest that this approach will identify genes that confer human susceptibility to Superfundchemicals and their metabolites and will enable future work to examine associations between variants inthese genes and adverse outcomes. In addition, this work will likely provide important insights in thecellular processes leading to toxicity for priority Superfund chemicals.
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