Project 2: Genetic Susceptibility to Superfund Chemicals. Humans vary in their susceptibility to the adverse effects of toxic chemicals found at Superfund sites, and a genetic component is strongly suspected. The overall goal of this project is to identify genetic factors which contribute to human susceptibility to toxicity as a result of exposure to chemicals present at Superfund sites. The application of whole genome association studies, which assess the association of single nucleotide polymorphisms with phenotypic effects of exposure on an unbiased genome-wide scale, is often precluded by the limited size ofthe exposed study populations. Very large numbers of individuals are required to observe true associations because of the need for multiple test correction. The candidate gene approach can be informative for smaller study populations but requires prior knowledge ofthe genes involved in the human response to toxicants for selection of candidate genes. As limited information is available on genes involved in the human response to many of the Superfund chemicals, we developed a functional screening approach that takes advantage of the conservation of fundamental cellular processes and metabolism between yeast (S. cerevisiae) and human, to help us identify candidate genes involved in human susceptibility to Superfund chemicals. In this approach, genes are selected in a yeast parallel deletion (PDA) assay by their ability to alter resistance to toxicant exposures. The roles ofthe selected genes are then further assessed in human and other mammalian cells in vitro. In the last project period, we successfully identified a list of genes most likely to play key roles in human susceptibility to several metals, arsenicals and metabolites of benzene and trichloroethylene, through this functional screening approach. We also obtained preliminary data on the potential functions of several genes in human cells, and will, in the next project period, expand these functional studies in human cells in vitro and in whole animal studies in vivo. In addition, we will extend our yeast functional screening assay to several persistent bio-accumulative halogenated toxicants of emerging concern at Superfund sites. Further, we will apply a novel and complementary human haploid cell screening approach to identify additional candidate human susceptibility genes. Together, these studies will provide a comprehensive high-throughput approach to identify important genes and cellular processes involved in toxicant susceptibility.

Public Health Relevance

Humans vary in their susceptibility to toxicants found at Superfund sites. Genetic variation likely accounts for a significant proportion of these individual differences. An increased understanding ofthe genetic variability of toxicant response will enable more accurate chemical exposure risk assessment, more targeted, and potentially more cost effective, harm mitigation and/or remediation strategies for contaminated sites.

National Institute of Health (NIH)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Special Emphasis Panel (ZES1)
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University of California Berkeley
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Zhang, L; Samad, A; Pombo-de-Oliveira, M S et al. (2015) Global characteristics of childhood acute promyelocytic leukemia. Blood Rev 29:101-25
Gaytán, Brandon D; Vulpe, Chris D (2014) Functional toxicology: tools to advance the future of toxicity testing. Front Genet 5:110
McHale, Cliona M; Smith, Martyn T; Zhang, Luoping (2014) Application of toxicogenomic profiling to evaluate effects of benzene and formaldehyde: from yeast to human. Ann N Y Acad Sci 1310:74-83
Ward, Mary H; Colt, Joanne S; Deziel, Nicole C et al. (2014) Residential levels of polybrominated diphenyl ethers and risk of childhood acute lymphoblastic leukemia in California. Environ Health Perspect 122:1110-6
Xiao, Jianqiao; Lee, Seung-Tae; Xiao, Yuanyuan et al. (2014) PTPRG inhibition by DNA methylation and cooperation with RAS gene activation in childhood acute lymphoblastic leukemia. Int J Cancer 135:1101-9
Morris, Patrick J; Medina-Cleghorn, Daniel; Heslin, Ann et al. (2014) Organophosphorus flame retardants inhibit specific liver carboxylesterases and cause serum hypertriglyceridemia. ACS Chem Biol 9:1097-103
Men, Yujie; Seth, Erica C; Yi, Shan et al. (2014) Sustainable growth of Dehalococcoides mccartyi 195 by corrinoid salvaging and remodeling in defined lactate-fermenting consortia. Appl Environ Microbiol 80:2133-41
Mehinto, Alvine C; Prucha, Melinda S; Colli-Dula, Reyna C et al. (2014) Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides). Aquat Toxicol 152:186-94
Koster van Groos, Paul G; Esser, Bradley K; Williams, Ross W et al. (2014) Isotope effect of mercury diffusion in air. Environ Sci Technol 48:227-33
Thomas, Reuben; Hubbard, Alan E; McHale, Cliona M et al. (2014) Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure. PLoS One 9:e91828

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