Core C: Toxicogenomics Laboratory
Summary
The overall goal of the Berkeley Superfund Basic Research Program (SBRP) is to apply functional genomics, proteomics, transcriptomics, and nanotechnology to better detect arsenic, mercury, benzene, polycyclic aromatic hydrocarbons, trichloroethylene, and other Superfund priority chemicals in the environment; evaluate their effects on human health, especially the health of susceptible populations such as children; and remediate their presence and reduce their toxicity. The individual research projects use functional genomics, proteomics, and transcriptomics in their studies. Their success largely depends on the effective handling and management of biological samples, as well as access to and expertise in the latest “-omic” technologies. Thus, detailed collection and storage protocols have been designed and core facilities are being provided for the cytogenetic, genotyping, gene expression and proteomic analyses to be undertaken in the research projects. Specific Core activities include: 1) processing, maintaining and storeing biological samples and cell lines; 2) providing facilities and methodologies for cytogenetic analysis; 3) providing facilities for gene expression profiling using Affymetrix, Illumina, and custom array technologies; 4) providing facilities for proteomic analyses using various mass spectrometric technologies; and, 5) providing facilities and methodologies for the analysis of genetic polymorphisms by Taqman-based and bead array technologies using the ABI 7900 Sequence Detection System and Illumina Bead Station platforms.
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Core Update
Christine Skibola and Chris Vulpe, co-leaders of the Toxicogenomics laboratory facilities, have continued to provide significant support in cytogenetic, cell culture, proteomic and genetic analyses to meet the goals of multiple projects. Specifically, in their work with Drs. Buffler and Smith, they processed 45 childhood leukemia bone marrow samples and 40 peripheral blood samples, and performed cytogenetic analyses by fluorescent in situ hybridization on an additional 25 cases.
As part of their work with project investigators Alan Smith and Craig Steinmaus, they studied the role of genetics in arsenic metabolism by examining the percent of ingested arsenic excreted in the urine as monomethylarsonic/monomethylarsonous acid (%MMA) and as dimethylarsinic/dimethylarsinous acid (%DMA). They investigated polymorphisms in methylenetetrahydrofolate reductase, cystathionine-β-synthase (CBS), methionine synthase, thymidylate synthase, dihydrofolate reductase and serine hydroxymethyltransferase 1, genes that encode enzymes involved in folate metabolism. Two additional polymorphisms in glutathione-S-transferase-1 (GST01) also were chosen due to the modest influence of GST01 SNPs on urinary %MMA in previous reports. In a case-control study population exposed to either high or low arsenic levels from Cordoba Province, Argentina, they found statistically significant increases in %MMA associated with variant genotypes for CBS rs234709 and rs4920037 polymorphisms. Taking the mean level of %MMA, these gene variants accounted for a 26% increase in MMA levels in this population. These gene variants also accounted for a modest negative association with %DMA. MMA is considered to be the ultimate toxic arsenic metabolite (manuscript submitted). The researchers also went on to show potential gene-environment interaction with CBS SNPs, %MMA and risk of lung cancer (manuscript in preparation). These findings are the first to suggest that CBS SNPs may influence arsenic metabolism in humans and susceptibility to arsenic-induced disease.
The discovery of gene variants that influence arsenic metabolism may help to elucidate the mechanisms of arsenic-induced disease which are currently unknown. The Core plans to further study the influence of additional CBS gene variants on the potential toxic effects of MMA3 in humans and the role of other folate-metabolizing genes in arsenic toxicity.
Publications
- Scelo, Ghislaine, Catherine Metayer, L. Zhang, Joseph L. Wiemels, Melinda C. Aldrich, Steve Selvin, Stacy Month, M.T. Smith, and Patricia A. Buffler. 2009. Household exposure to paint and petroleum solvents, chromosomal translocations, and the risk of childhood leukemia. Environmental Health Perspectives. 117(1):133-9. doi:10.1289/ehp.11927 (http://dx.doi.org/10.1289/ehp.11927)
- Hegedus, Christine M., Chistine F. Skibola, Marcella Warner, Danica R. Skibola, David Alexander, S. Lim, Nygerma L. Dangleben, L. Zhang, M. Clark, Ruth M. Pfeiffer, C. Steinmaus, Allan H. Smith, Martyn T. Smith, and Lee E. Moore. 2008. Decreased urinary Beta Defensin-1 expression as a biomarker of response to arsenic. Toxicological Sciences. (http://www3.oup.co.uk/toxsci/) 106:74-82. doi:10.1093/toxsci/kfn104 (http://dx.doi.org/10.1093/toxsci/kfn104)
- Wiemels, Joseph L., Jerry Hofmann, M. Kang, Rebecca Selzer, Roland Green, Mi Zhou, Sheng Zhong, Luoping Zhang, Martyn T. Smith, Carmen J. Marsit, Mignon L. Loh, Patricia A. Buffler, and Ru-Fang Yeh. 2008. Chromosome 12p Deletions in TEL-AML1 Childhood Acute Lymphoblastic Leukemia Are Associated with Retrotransposon Elements and Occur Postnatally. Cancer Research. (http://cancerres.aacrjournals.org/) 68:9935-9944. doi:10.1158/0008-5472.CAN-08-2139 (http://dx.doi.org/10.1158/0008-5472.CAN-08-21 39)