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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES004705-25
Application #
8382047
Study Section
Special Emphasis Panel (ZES1-SET-V)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
25
Fiscal Year
2012
Total Cost
$312,919
Indirect Cost
$104,107
Name
University of California Berkeley
Department
Type
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Shen, Hua; McHale, Cliona M; Haider, Syed I et al. (2016) Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells. Toxicol Sci 151:10-22
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