Toxicant Susceptibility
One reason that individuals vary in how susceptible they are to toxic effects of chemicals is because they differ in genes that are affected by the chemicals. Cancers and other disease can arise from such interactions between environmental agents and genes. How agents affect the cell is likely to influence which genes that are affected. At present, understanding of how many chemicals affect cells is limited.
As part of Project 2 of the UC Berkeley Superfund Research Program, we use yeast (Saccharomyces cerevisiae) to investigate the targets for toxic chemicals in eukaryotic cells. We use parallel deletion analysis or a “barcoding” approach to simultaneously determine the relative importance of individual genes in susceptibility to toxicant exposure. We are focusing on toxic metals (e.g. copper, cadmium, iron), metalloids (e.g. arsenical compounds) and aromatic hydrocarbons (benzene and its metabolites), as well as pesticides and emergent contaminants (including flame retardants). This method will identify candidates for genes that contribute to susceptibility to environmental agents.
The human homologs or functional orthologs of these yeast genes will then be tested in human cells lines for a possible role in toxicant susceptibility. We hope to identify genes that contribute to human susceptibility to chemicals and their metabolites.
Relevant Recent Publications
Genome-wide functional profiling reveals genes required for tolerance to benzene metabolites in yeast.
PLoS One. 2011;6(8):e24205. Epub 2011 Aug 30.
- Ela WP, Sedlak DL, Barlaz MA, Henry HF, Muir DC, Swackhamer DL, Weber EJ, Arnold RG, Ferguson PL, Field JA, Furlong ET, Giesy JP, Halden RU, Henry T, Hites RA, Hornbuckle KC, Howard PH, Luthy RG, Meyer AK, Sáez AE, Vom Saal FS, Vulpe CD, Wiesner MR.
Toward identifying the next generation of superfund and hazardous waste site contaminants.
Environ Health Perspect. 2011 Jan;119(1):6-10.
- Ren X, Aleshin M, Jo WJ, Dills R, Kalman DA, Vulpe CD, Smith MT, Zhang L.
Involvement of N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) in arsenic biomethylation and its role in arsenic-induced toxicity.
Environ Health Perspect. 2011 Jun;119(6):771-7.
- North M, Vulpe CD.
Functional Toxicogenomics: Mechanism-Centered Toxicology.
Int. J. Mol. Sci. 2010 Nov;11(12):4796-4813.
- Zhang L, McHale CM, Rothman N, Li G, Ji Z, Vermeulen R, Hubbard AE, Ren X, Shen M, Rappaport SM, North M, Skibola CF, Yin S, Vulpe C, Chanock SJ, Smith MT, Lan Q.
Systems biology of human benzene exposure.
Chem Biol Interact. 2010 Mar 19;184(1-2):86-93.
- Jo WJ, Ren X, Chu F, Aleshin M, Wintz H, Burlingame A, Smith MT, Vulpe CD, Zhang L.
Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure.
Toxicol Appl Pharmacol. 2009 Oct;111(2):424-36.
- Jo WJ, Loguinov A, Wintz H, Chang M, Smith AH, Kalman D, Zhang L, Smith MT, Vulpe CD.
Comparative functional genomic analysis identifies distinct and overlapping sets of genes required for resistance to monomethylarsonous acid (MMAIII) and arsenite (AsIII) in yeast.
Toxicol Sci. 2009 Oct;111(2):424-36.
- Jo WJ, Loguinov A, Chang M, Wintz H, Nislow C, Arkin AP, Giaever G, Vulpe CD.
Identification of genes involved in the toxic response of Saccharomyces cerevisiae against iron and copper overload by parallel analysis of deletion mutants.
Toxicol Sci. 2008 Jan;101(1):140-51. Erratum in: Toxicol Sci. 2008 Mar;102(1):205.
