Project 2: Genetic Susceptibility to Superfund Chemicals

Summary

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 of the 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 of the 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 of the 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.

This is relevant because 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 of the 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.

Project Leadership

Martyn T. Smith, PhD

Professor of Toxicology

Environmental Health Sciences,
School of Public Health
University of California, Berkeley

Luoping Zhang, PhD

Associate Adjunct Professor

Environmental Health Sciences,
School of Public Health
University of California, Berkeley

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News Archive

Selected Publications

2015

Shen H, McHale CM, Smith MT, Zhang L (2015) Functional Genomic Screening Approaches in Mechanistic Toxicology and Potential Future Applications of CRISPR-Cas9. Mutat Res Rev. Arp-Jun;728(3):118-138. PMCID: PMC4456615. [PDF]

Ji Z, McHale CM, Bersonda J, Tang J, Smith MT, Zhang L (2015) Induction of centrosome amplification by formaldehyde, but not hydroquinone, in human lymphoblastoid TK6 cells. EMM. Jul;56(6):535-44. PMID: 25821186. DOI: 10.1002/em.21947. [PDF]

Carlos-Wallace FM, Zhang L, Smith MT, Rader G, Steinmaus C (2016) Parental, In Utero, and Early-Life Exposure to Benzene and the Risk of Childhood Leukemia: A Meta-Analysis. Am J Epidemiol. Jan 1;183(1):1-14. PMCID: PMC4751231. [PDF]

Bassig BA, Zhang L, Vermeulen R, Tang X, Li G, Hu W, Guo W, Purdue MP, Yin S, Rappaport SM, Shen M, Ji Z, Qiu C, Ge Y, Hosgood HD, Reiss B, Wu B, Xie Y, Li L, Yue F, Freeman LE, Blair A, Hayes RB, Huang H, Smith MT, Rothman N, Lan Q (2016) Comparison of hematological alterations and markers of B-cell activation in workers exposed to benzene, formaldehyde and trichloroethylene. Carcinogenesis. Jul;37(7):692-700. PMCID: PMC4936387. [PDF]

2014

McHale CM, Smith MT, Zhang L (2014) Application of toxicogenomic profiling to evaluate effects of benzene and formaldehyde: from yeast to human. Ann N Y Acad Sci. 1310:74-83. PMCID: PMC3978411. [PDF]

North M, Shuga J, Fromowitz M, Loguinov A, Shannon K, Zhang L, Smith MT and Vulpe CD (2014) Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke. BMC Cancer. Jan 5;14(1):6. PMCID: PMC3898384. [PDF]

Zhang L, McHale CM, Greene N, Snyder RD, Rich IN, Aardema MJ, Roy S, Pfuhler S, Venkatactahalam S (2014) Emerging approaches in predictive toxicology. Environ Mol Mutagen. Dec;55(9):679-88. PMCID: PMC4749138. [PDF]

Gaytan BD, Vulpe CD (2014) Functional toxicology: tools to advance the future of toxicity testing. Front genet. May 5;5:110. PMCID: PMC4017141. [PDF]

Ji Z, Li X, Fromowitz M, Mutter-Rottmayer E, Tung J, Smith MT, Zhang L (2014) Formaldehyde induces micronuclei in mouse erythropoietic cells and suppresses the expansion of human erythroid progenitor cells. Toxicology Letters. Jan 13;224(2):233-239. PMCID: PMC3891867. [PDF]

Bassig BA, Zhang L, Cawthon RM, Smith MT, Yin S, Li G, et al. (2014) Alterations in leukocyte telomere length in workers occupationally exposed to benzene. Environ Mol Mutagen. 55(8):673-8. PMCID: PMC4360990. [PDF]

2013

Gaytán BD, Loguinov AV, Lantz SR, Lerot JM, Denslow ND, Vulpe CD (2013) Functional genomics discovers that the dieldrin organochlorinated pesticide affects leucine availability in yeast. Toxicol. Sci. 132:347-58. PMID: 23358190.

Gaytan BD, Loguinov AV, De La Rosa VY, Lerot JM, Vulpe CD (2013) Functional genomics indicates yeast requires Golgi/ER transport, chromatin remodeling, and DNA repair for low dose DMSO tolerance. Front genet. Aug 13;4:154. PMCID: PMC3741465. [PDF]

Gaytan BD, Loguinov AV, Penate X, Lerot JM, Chavez S, Denslow ND, Vulpe CD (2013) A genome-wide screen identifies yeast genes required for tolerance to technical toxaphene, an organochlorinated pesticide mixture. PLoS One. Nov 18;8(11):e81253. PMCID: PMC3832591. [PDF]

Shuga J, Zeng Y, Novak R, Lan Q, Tang X, Rothman N, Vermeulen R, Li L, Hubbard A, Zhang L, Mathies RA, Smith MT (2013) Single molecule quantitation and sequencing of rare translocations using microfluidic nested digital PCR. Nucleic Acids Res. Sep;41(16):e159. PMCID: PMC3763562

McHale CM, Zhang L, Thomas R, Smith MT (2013) Analysis of the transcriptome in molecular epidemiology studies. Environ Mol Mutagen. Aug;(54(7):500-17. PMID: 23907930. (PMCID Journal in Process).

Metayer C, Zhang L, Wiemels JL, Bartley K, Schiffman J, Ma X, Aldrich MC, Chang JS, Selvin S, Fu CH, Ducore J, Smith MT, Buffler PA (2013) Tobacco Smoke Exposure and the Risk of Childhood Acute Lymphoblastic and Myeloid Leukemias by Cytogenetic

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 Tox, jan;87(1):189-196. PMCID: PMC4312773. [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]

2012

Zhang L, Lan Q, Ji Z, Li G, Shen M, Vermeulen R, et al. (2012) Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers. Leukemia. 26(12):2494-8. 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]

2011

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]

2010

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]

2009

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]

2008

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]

2007

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]

2006

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]

2005

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]