Project 2: Functional profiling of susceptibility genes
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. Genetic susceptibility to the toxic effects of a chemical is likely to be related to the cellular targets of the chemical and its metabolites. However, we still have a limited understanding of cellular targets for many of the priority chemicals on the Superfund list. Project investigators are taking advantage of the conservation of basic metabolic pathways and fundamental cellular processes between the yeast S. cerevisiae and humans to identify candidate human susceptibility genes. They are using a new approach to discover these targets in yeast and human cells using parallel deletion analysis (PDA) and RNA interference (RNAi), respectively. Deletion strains for almost every yeast gene enable new approaches to determine in parallel (PDA) the relative importance of each yeast gene for susceptibility (sensitivity) to a chemical toxicant. They are endeavoring to identify candidate susceptibility genes for selected priority Superfund chemicals that require metabolic activation including benzene, polycyclic aromatic hydrocarbons (PAHs), halogenated aliphatic hydrocarbons, and for selected metals such as arsenic and cadmium, which do not. Project investigators select and prioritize likely human candidate genes by computational analysis of the yeast data sets. The candidate human susceptibility genes are silenced in appropriate human cell lines using RNAi so that their roles in sensitivity to cytotoxicity, genotoxicity and epigenetic effects of the Superfund chemical and/or its metabolites can be evaluated. The investigators believe that this approach will identify genes that confer human susceptibility to Superfund chemicals and their metabolites and will enable future work to examine associations between variants in these genes and adverse outcomes. In addition, this work will likely provide important insights in the cellular processes leading to toxicity for priority Superfund chemicals.
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People clearly differ in their susceptibility to the toxic effects of Superfund chemicals and a genetic (familial) component is strongly suspected.
The aim of Project 2 is to identify genes that confer susceptibility to Superfund chemicals, through the use of a simple yeast model system that allows rapid identification of these genes. Further studies are then done to confirm the genes in both human cells in a Petri dish and eventually in human populations. The investigators are studying Superfund-related chemicals including benzene, arsenic, trichloroethylene (TCE), and flame retardants. An increased understanding of the genetic variability in response to these toxicants will enable more accurate risk assessments for sites contaminated with these compounds.
Important discoveries so far
To date, the investigators have been able to examine thousands of genes in yeast cells for their importance in an individual’s vulnerability to toxic chemicals at Superfund sites, including various metals, arsenic compounds, and benzene and its metabolites. They have discovered several key genes (including NF1, SRXN1, PRDX1) associated with the response to oxidative stress following exposures to benzene and its metabolites. Benzene is an established cause of leukemia and other blood disorders, and oxidative DNA damage may be a potential mechanism to cause the disease.
They also found that yeast deletion mutants lacking the gene MTQ2 were highly resistant to arsenic exposure. The human equivalent of yeast MTQ2 is N-6 adenine-specific DNA methyltransferase 1 (N6AMT1). Enhanced expression of N6AMT1 in human bladder cells significantly increased their resistance to the toxicity of arsenic and its metabolites and N6AMT1 was shown to methylate arsenic to a non-toxic metabolite. The newly discovered protein N6AMT1 could play a role in susceptibility to arsenic toxicity and carcinogenicity.
Highlight for last year
The most important thing we discovered over the last year was that a recently discovered protein called N6AMT1 can metabolize arsenic compounds and lower toxicity. This is a novel finding. A paper on this is in press in Environmental Health Perspectives.
What we plan to do next
The investigators will extend the studies with the yeast method to several persistent bio-accumulative halogenated toxicants of emerging concern at Superfund sites. Further, they will apply a novel and complementary human 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 susceptibility to Superfund chemicals.
- Gaytan BD, Loguinov A, Lantz SR, Lerot JM, Denslow N, Vulpe CD (2013) Functional profiling discovers that the dieldrin organochlorinated pesticide affects leucine availability in yeast. Toxicol Sci. Jan 28. [Epub ahead of print]. PMID: 23358190. (PMC Journal – In Process). (PDF available soon).
- Ren X, Ji Z, Yuh J, Tang M, Bersonda J, Smith MT, Zhang L (2013) The impact of FANCD2 deficiency on formaldehyde-induced toxicity in human lymphoblastoid cell lines. Arch Toxicol. Jan;87(1):189-196. PMID: 22872141. NIHMS399462. [PDF]
- Gaytán B, Loguinov A, Lantz S, Lerot JM, Denslow N, Vulpe C (2013) Functional profiling discovers that the dieldrin organochlorinated pesticide affects leucine availability in yeast. Toxicol. Sci. [Epub ahead of print: January 28, 2013]. doi: 10.1093/toxsci/kft018. PMID: 23358190. (PMC Journal – In Process). [PDF]
- Zhang L, Bassig BA, Mora JL, Vermeulen R, Ge Y, Curry JD, Hu W, Shen M, Qiu C, Ji Z, Reiss B, McHale CM, Liu S, Guo W, Purdue MP, Yue F, Li L, Smith MT, Huang H, Tang X, Rothman N, Lan Q (2013) Alterations in serum immunoglobulin levels in workers occupationally exposed to trichloroethylene. Carcinogenesis. Jan16. [Epub ahead of print]. PMID: 23276795. (PMC Journal- In Progress). [PDF]
- Zhang L, Lan Q, Ji Z, Li G, Shen M, Vermeulen R, Guo W, Hubbard A, McHale CM, Rappaport SM, Hayes RB, Linet B, Yin S, Fraumeni JF, Rothman N, Smith MT (2012). Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers. Leukemia. Dec;26(12):2494-2498. PMCID: PMC3472034. [PDF]
- O’Connor ST, Lan J, North M, Loguinov A, Zhang L, Smith MT, Gu A, Vulpe C (2012) Genome-wide functional and stress response profiling reveals toxic mechanism and genes required for tolerance to benzo[a]pyrene in S. cerevisiae. Front in Toxicogenomics. Dec;doi: 10.3389/fgene.2012.00316. (PMC Journal – In Process). [PDF]
- Vermeulen R, Zhang L, Spirenburg A, Tang X, Bonventre JV, Reiss B, Shen M, Smith MT, Qui C, Ge Y, Ji Z, Xiong J, He J, Hao Z, Liu S, Xie Y, Yue F, Guo W, Purdue M, Beane-Freeman LE, Sabbisetti V, Li L, Huang H, Rothman N, Lan Q (2012) Kidney toxicity in Chinese factory workers exposed to trichloroethylene. Carcinogenesis. Aug;33(8):1538-41. PMID: 22730190. [PDF]
- Phuong J, Kim S, Thomas R, Zhang L (2012) Predicted toxicity of the biofuel candidate 2,5-dimethylfuran in environmental and biological systems. Environ Mol Mutagen. Jul;53(6):478-87. PMID: 22730190. (PMC Journal – In Process). [PDF]
- Thomas R, Phuong J, McHale CM, Zhang L (2012) Using bioinformatic approaches to identify pathways targeted by human leukemogens. Int J Environ Res Public Health. Jul;9(7):2479-503. PMCID: PMC3407916. [PDF]
- Ji Z, Weldon RH, Marchetti F, Chen H, Li G, Xing C, Kurtovich E, Young S, Schmid TE, Waidyanatha S, Rappaport SM, Zhang L, Eskenazi B (2012) Comparison of aneuploidies of chromosomes 21, X, and Y in the blood lymphocytes and sperm cells among workers exposed to benzene. Environ Mol Mutagen. Apr;53(3):218-26. PMID: 22351378. (PMC Journal – In Process). [PDF]
- Marchetti F, Eskenazi B, Weldon RH, Li G, Zhang L, Rappaport SM, Schmid TE, Xing C, Kurtovich E, Wyrobek AJ (2012) Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environ Health Perspect. Feb;120(2):229-34. PMCID: PMC3279447. [PDF]
- Ji Z and Zhang L (2012) Chromosomics: Detection of numerical and structural alterations in all 24 human chromosomes simultaneously using a novel OctoChrome FISH assay. J Vis Exp. Feb;(60). Pii:3619. PMID: 22331009. (PMC Journal – In Process). [PDF]
- Godderis L, Thomas R, Hubbard AE, Tabish AM, Hoet P, Zhang L, Smith MT, Veulemans H, McHale CM (2012) Effect of Chemical Mutagens and Carcinogens on Gene Expression Profiles in Human TK6 Cells. PLoS One. 7(6):e39205. PMCID: PMC3377624. [PDF]
- Hosgood HD, Zhang L, Tang X, Vermeulen R, Shen M, Smith MT, Blair A, Qui C, Ge Y, Ji Z, Xiong J, He J, Reiss B, Liu S, Xie Y, Guo W, Galvan N, Li L, Hao Z, Rothman N, Huang H, Lan Q (2011) Decreased numbers of CD4+ naive and effector memory T cells, and CD8+ naïve T cells, are associated with trichloroethylene exposure. Front Oncol. 1:53. PMCID: PMC3355872. [PDF]
- North M, Tandon VJ, Thomas R, Loguinov A, Gerlovina I, Hubbard AE, Zhang L, Smith MT, Vulpe CD (2011) Genome-Wide Functional Profiling Reveals Genes Required for Tolerance to Benzene Metabolites in Yeast. PLoS ONE. 6(8): e24205. doi:10.1371/journal.pone.0024205. [PDF]
- Smith MT, Zhang L, McHale CM, Skibola CF, Rappaport SM (2011) Benzene, the exposome and future investigations of leukemia etiology. Chem Biol Interact. Jun 30;192(1-2):155-9. PMID: 21333640. [PDF]
- Shen M, Zhang L, Lee KM, Vermeulen R, Hosgood HD, Li G, Yin S, Rothman N, Chanock S, Smith MT, Lan Q (2011) Polymorphisms in genes involved in innate immunity and susceptibility to benzene-induced hematotoxicity. Exp mol Med. Jun 30;43(6):374-8. PMCID: PMC3128916. [PDF]
- Ren X, Aleshin M, Jo WJ, Dills R, Kalman DA, Vulpe CD, Smith MT, Zhang L (2011) Involvement of N-6 Adenine-Specific DNA Methyltransferase 1 (N6AMT1) in Arsenic Biomethylation and Its Role in Arsenic-Induced Toxicity. Environ Health Perspect. Jun;119(6):771-7. PMCID: PMC3114810. [PDF]
- McHale CM, Zhang L, Lan Q, Vermeulen R, Li G, Hubbard AE, Porter KE, Thomas R, Portier CJ, Shen M, Rappaport SM, Yin S, Smith MT, Rothman N (2011) Global Gene Expression Profiling of a Population Exposed to a Range of Benzene Levels. Environ Health Perspect. May;119(5):628-34. PMCID: PMC3094412. [PDF]
- Zhang L, Lan Q, Guo W, Hubbard AE, Li G, Rappaport SM, McHale CM, Shen M, Ji Z, Vermeulen R, Yin S, Rothman N, Smith MT (2011) Chromosome-Wide Aneuploidy Study (CWAS) in Workers Exposed to an Established Leukemogen, Benzene. Carcinogenesis. Apr;32(4):605-12. PMCID: PMC3066415. [PDF]
- Ren X, Lim S, Ji Z, Yuh J, Peng V, Smith MT, Zhang L (2011) Comparison of Proliferation and Genomic Instability Responses to WRN Silencing in Hematopoietic HL60 and TK6 Cells. PLoS One. Jan 18;6(1):e14546. PMCID: PMC3022623. [PDF]
- North M, Vulpe, CD (2010) Functional toxicogenomics: Mechanism-centered Toxicology. Int J Mol Sci. Nov 22;11(12):4796-813. [PDF]
- Ji Z, Zhang L, Peng V, Ren X, McHale CM, Smith MT (2010) A comparison of the cytogenetic alterations and global DNA hypomethylation induced by the benzene metabolite, hydroquinone, with those induced by melphalan and etoposide. Leukemia. May;24(5):986-91. PMID: 20339439. [PDF]
- Lan Q, Zhang L, Tang X, Shen M, Smith MT, Qiu C, Ge Y, Ji Z, Xiong J, He J, Reiss B, Hao Z, Liu S, Xie Y, Guo W, Purdue M, Galvan N, Xin KX, Hu W, Freeman LE, Blair A, Li L, Rothman N, Vermeulen R, Huang H (2010) Occupational exposure to trichloroethylene is associated with a decline in lymphocyte subsets and soluble CD27 and CD30 markers. Carcinogenesis. Sep;31(9):1592-6. PMCID: PMC2930801. [PDF]
- Shuga J, Zeng Y, Novak R, Mathies R, Hainaut P, Smith MT (2010) Selected technologies for measuring acquired genetic damage in humans. Environmental and Molecular Mutagenesis. Oct;51(8-9):851-70. PMID: 20872848. [PDF]
- North M, Vulpe CD. Functional Toxicogenomics: Mechanism-Centered Toxicology. Submitted to Int. J. Mol. Sci. 2010.
- Zhang L, Freeman LE, Nakamura J, Hecht SS, Vandenberg JJ, Smith MT, Sonawane BR (2010) Formaldehyde and leukemia: Epidemiology, potential mechanisms, and implications for risk assessment. Environ Mol Mutagen. Apr; 51(3):181-91. PMID: 19790261. PMCID: PMC2839060. [PDF]
- 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 (2010) Systems biology of human benzene exposure. Chem Biol Interact. Mar; 184(1-2)86-93. PMID: 20026094. [PDF]
- Vlaanderen J, Moore LE, Smith MT, Lan Q, Zhang L, Skibola CF, Rothman N, Vermeulen R (2010) Application of OMICS technologies in occupational and environmental health research; current status and projections. Occup Environ Med. Feb; 67(2):136-43. PMID: 19933307. [PDF]
- Tang X, Bai Y, Duong A, Smith MT, Li L, Zhang L (2009) Formaldehyde in China: production, consumption, exposure levels, and health effects. Environ Int. Nov; 35(8):1210-24. PMID: 19589601. [PDF]
- Jo WJ, Ren X, Chu F, Aleshin M, Wintz H, Burlingame A, Smith MT, Vulpe CD, Zhang L (2009) Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure. Toxicol Appl Pharmacol. Dec 15; 241(3):294-302. PMID: 19732783. PMCID: PMC2784148. [PDF]
- Hosgood HD, 3rd, Zhang L, Shen M, Berndt SI, Vermeulen R, Li G, Yin S, Yeager M, Yuenger J, Rothman N, Chanock S, Smith M, Lan Q (2009) Association between genetic variants in VEGF, ERCC3 and occupational benzene haematotoxicity. Occup Environ Med. Dec; 66(12):848-53. PMID: 19773279. [PDF]
- Jo WJ, Loguinov A, Wintz H, Chang M, Smith AH, Kalman D, Zhang L, Smith MT, Vulpe CD (2009) 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. Oct; 111(2):424-36. PMID: 19635755. PMCID: PMC2742584. [PDF]
- Ji Z, Zhang L, Guo W, McHale CM, Smith MT (2009) The benzene metabolite, hydroquinone and etoposide both induce endoreduplication in human lymphoblastoid TK6 cells. Mutagenesis. Jul; 24(4):367-72. PMID: 19491217. PMCID: PMC2701990. [PDF]
- Guyton KZ, Kyle AD, Aubrecht J, Cogliano VJ, Eastmond DA, Jackson M, Keshava N, Sandy MS, Sonawane B, Zhang L, Waters MD, Smith MT (2009) Improving prediction of chemical carcinogenicity by considering multiple mechanisms and applying toxicogenomic approaches. Mutat Res. Mar-Jun; 681(2-3):230-40. PMID: 19010444. [PDF]
- Zhang L, Steinmaus C, Eastmond DA, Xin XK, Smith MT (2009) Formaldehyde exposure and leukemia: a new meta-analysis and potential mechanisms. Mutat Res. Mar-Jun; 681(2-3):150-68. PMID: 18674636. [PDF]
- Ren X, Lim S, Smith MT, Zhang L (2009) Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone. Toxicol Sci. Feb; 107(2):367-75. PMID: 19064679. PMCID: PMC2639759. [PDF]
- Lan Q, Zhang L, Shen M, Jo WJ, Vermeulen R, Li G, Vulpe C, Lim S, Ren X, Rappaport SM, Berndt SI, Yeager M, Yuenger J, Hayes RB, Linet M, Yin S, Chanock S, Smith MT, Rothman N (2009) Large-scale evaluation of candidate genes identifies associations between DNA repair and genomic maintenance and development of benzene hematotoxicity. Carcinogenesis. Jan; 30(1):50-8. PMID: 18978339. PMCID:PMC2639030. [PDF]
- Jo WJ, Kim JH, Oh E, Jaramillo D, Holman P, Loguinov AV, Arkin AP, Nislow C, Giaever G, Vulpe CD (2009) Novel insights into iron metabolism by integrating deletome and transcriptome analysis in an iron deficiency model of the yeast Saccharomyces cerevisiae. BMC Genomics. 10:130. PMID: 19321002. PMCID: PMC2669097. [PDF]
- Galvan N, Lim S, Zmugg S, Smith MT, Zhang L (2008). Depletion of WRN enhances DNA damage in HeLa cells exposed to the benzene metabolite, hydroquinone. Mutat Res. 2008 Jan; 649(1-2): 54-61. PMID 17875398. [PDF]
- Kim S, Lan Q, Waidyanatha S, Chanock S, Johnson BA, Vermeulen R, Smith MT, Zhang L, Li G, Shen M, Yin S, Rothman N, Rappaport SM (2007) Genetic polymorphisms and benzene metabolism in humans exposed to a wide range of air concentrations. Pharmacogenet Genomics. Oct; 17(10):789-801. PMID: 17885617. [PDF]
- Shen M, Lan Q, Zhang L, Chanock S, Li G, Vermeulen R, Rappaport SM, Guo W, Hayes RB, Linet M, Yin S, Yeager M, Welch R, Forrest MS, Rothman N, Smith MT (2006) Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity. Carcinogenesis. Oct; 27(10):2083-9. PMID: 16728435. [PDF]
- Lan Q, Zhang L, Shen M, Smith MT, Li G, Vermeulen R, Rappaport SM, Forrest MS, Hayes RB, Linet M, Dosemeci M, Alter BP, Weinberg RS, Yin S, Yeager M, Welch R, Waidyanatha S, Kim S, Chanock S, Rothman N (2005) Polymorphisms in cytokine and cellular adhesion molecule genes and susceptibility to hematotoxicity among workers exposed to benzene. Cancer Res. Oct 15; 65(20):9574-81. PMID: 16230423. [PDF]