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.
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.
|Wiemels, Joseph L; Walsh, Kyle M; de Smith, Adam J et al. (2018) GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21. Nat Commun 9:286|
|Prasse, Carsten; Ford, Breanna; Nomura, Daniel K et al. (2018) Unexpected transformation of dissolved phenols to toxic dicarbonyls by hydroxyl radicals and UV light. Proc Natl Acad Sci U S A 115:2311-2316|
|Smith, Allan H; Marshall, Guillermo; Roh, Taehyun et al. (2018) Lung, Bladder, and Kidney Cancer Mortality 40?Years After Arsenic Exposure Reduction. J Natl Cancer Inst 110:241-249|
|Castriota, Felicia; Acevedo, Johanna; Ferreccio, Catterina et al. (2018) Obesity and increased susceptibility to arsenic-related type 2 diabetes in Northern Chile. Environ Res 167:248-254|
|Rothman, Nathaniel; Zhang, Luoping; Smith, Martyn T et al. (2018) Formaldehyde, Hematotoxicity, and Chromosomal Changes-Response. Cancer Epidemiol Biomarkers Prev 27:120-121|
|Yik-Sham Chung, Clive; Timblin, Greg A; Saijo, Kaoru et al. (2018) Versatile Histochemical Approach to Detection of Hydrogen Peroxide in Cells and Tissues Based on Puromycin Staining. J Am Chem Soc 140:6109-6121|
|Rappaport, Stephen M (2018) Redefining environmental exposure for disease etiology. NPJ Syst Biol Appl 4:30|
|Tachachartvanich, Phum; Sangsuwan, Rapeepat; Ruiz, Heather S et al. (2018) Assessment of the Endocrine-Disrupting Effects of Trichloroethylene and Its Metabolites Using in Vitro and in Silico Approaches. Environ Sci Technol 52:1542-1550|
|Guyton, Kathryn Z; Rieswijk, Linda; Wang, Amy et al. (2018) Key Characteristics Approach to Carcinogenic Hazard Identification. Chem Res Toxicol :|
|Roh, Taehyun; Steinmaus, Craig; Marshall, Guillermo et al. (2018) Age at Exposure to Arsenic in Water and Mortality 30-40 Years After Exposure Cessation. Am J Epidemiol 187:2297-2305|
Showing the most recent 10 out of 629 publications