Global Responses to Aflatoxin B1 & Alkylating Agents

Summary

Principal Investigator: Leona Samson
Abstract: DESCRIPTION (provided by applicant) In response to RFA:ES-01-002, this is an application to become a member of the NIEHS-sponsored Toxicogenomics Research Consortium. The have proposed a highly integrated plan to explore the transcriptional responses of a variety of organisms, including humans, to a broad range of toxic agents found in the environment. Transcriptional profiling is expected to reveal a truly global view of how cells, tissues and animals attempt to recover, not always successfully from environmental insults. The investigators hope to learn what features of environmentally induced transcriptional responses are predictive of success or failure, and in addition to learn what features correlate with specific outcomes of toxic exposures, for instance, cell death, apoptosis, mutagenesis and carcinogenesis. The model environmental agents to be studied are Aflatoxin B1 and its metabolites, plus a range of SNI and SN2 alkylating agents. Together these agents are representative of toxic agents found in the external environment, food supply, the endogenous cellular environment, and the cancer chemotherapy clinic. The model organisms and cell systems whose transcriptional responsiveness will be scrutinized include E. coli, S. cerevisiae, cultured rodent and human cell lines, engineered rat and mouse liver tissues, rats and mice. The investigators have integrated an in vitro tissue engineering Project into this application with the goal of developing an alternative to using animals to test for toxicity and carcinogenicity. It seems to the investigators that appropriate transcriptional responsiveness in this system represents a rigorous test of its similarity to in vivo tissues. Two platforms for mRNA profiling will be employed, namely, Affymetrix GeneChip DNA oligonucleotide microarrays, and cDNA arrays fabricated in the MIT BioMicro Center. The Microarraying and Bioinformatics Core will have its center of gravity in the MIT BioMicro Center, and this Core will serve as the focal point for three Research Projects and the Toxicology Research Core Project (TRCP). The TRCP activities will be closely aligned with the activities of the other 4 or 5 members of the Toxicogenomics Research Consortium. Together the overarching goals will be to establishing good working practices in transcriptional profiling as it relates to the area of toxicogenomics, and to contribute to the development of an extensive relational database as a repository for high quality data emerging from the field of toxicogenomics. The investigators anticipate that this research will uncover a myriad of hitherto unknown ways in which cells respond to environmental agents.
Funding Period: 2001-09-30 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. pmc A rapid survival assay to measure drug-induced cytotoxicity and cell cycle effects
    Chandni Valiathan
    Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, USA
    DNA Repair (Amst) 11:92-8. 2012
  2. pmc The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner
    Glen E Kisby
    Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 6:e20911. 2011
  3. pmc Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Mol Biosyst 6:1195-206. 2010
  4. pmc A multipathway phosphoproteomic signaling network model of idiosyncratic drug- and inflammatory cytokine-induced toxicity in human hepatocytes
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
    Conf Proc IEEE Eng Med Biol Soc 2009:5452-5. 2009
  5. pmc Liver tissue engineering in the evaluation of drug safety
    Ajit Dash
    Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Expert Opin Drug Metab Toxicol 5:1159-74. 2009
  6. pmc Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Toxicol Appl Pharmacol 237:317-30. 2009
  7. pmc Genomic predictors of interindividual differences in response to DNA damaging agents
    Rebecca C Fry
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Genes Dev 22:2621-6. 2008
  8. ncbi An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Hepatology 48:276-88. 2008
  9. pmc Transcriptional networks in S. cerevisiae linked to an accumulation of base excision repair intermediates
    Ivan Rusyn
    Center for Environmental Health Sciences and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
    PLoS ONE 2:e1252. 2007
  10. pmc Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothers
    Rebecca C Fry
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
    PLoS Genet 3:e207. 2007

Scientific Experts

  • Rebecca C Fry
  • Leona Samson
  • Mathuros Ruchirawat
  • Glen E Kisby
  • Benjamin D Cosgrove
  • Chandni Valiathan
  • Ivan Rusyn
  • Richard P Beyer
  • John M Essigmann
  • James C Delaney
  • Ajit Dash
  • Linda G Griffith
  • Albert J Hwa
  • Terrance J Kavanagh
  • Jonathan H Freedman
  • Brenda K Weis
  • Rickie D Fannin
  • William K Kaufmann
  • Patrick Hurban
  • Kathleen F Kerr
  • Valerie S Palmer
  • Blair U Bradford
  • Helmut Zarbl
  • Michael R Lasarev
  • Peter S Spencer
  • Michael L Cunningham
  • Edward K Lobenhofer
  • Richard S Paules
  • Stella O Sieber
  • Jennifer L Robbins-Manke
  • Tae Woo Kim
  • Theodore Bammler
  • Joan Kelly
  • Steven R Tannenbaum
  • R Scott Obach
  • Walker Inman
  • Keith Hoffmaster
  • Samantha Sevidal
  • Lisa A McConnachie
  • J Peter Svensson
  • Alex B Cranson
  • William Suk
  • Mark Ambrose
  • Raymond J Tennant
  • Robert J Kayton
  • Thomas J Begley
  • Portia A Vliet
  • Courtney G Woods
  • Peter T So
  • Christine L Powell
  • Oksana Kosyk
  • Donna B Stolz
  • Gregory M Higgins
  • Russel Wolfinger
  • Pamela K Ross
  • Theo K Bammler
  • Elwood Linney
  • Joanna Klapacz
  • Lisiane B Meira
  • Anand Sivaraman
  • John S Wishnok
  • Lisa Smeester
  • Sean Milton
  • Li Xuan Qin
  • Fredrico M Farin
  • Jean P O'Malley
  • Renae L Malek
  • Signe A Todd
  • Patrick Pattee
  • Charles M Perou
  • Jung Lim Shin
  • Ken Phillips
  • Gary A Boorman
  • Roger E Bumgarner
  • Yan Shi
  • Yang Qiu
  • Shibing Deng
  • Catherine L Drennan
  • Dongseok Choi
  • Li Jing
  • William A Suk
  • Angel Harper
  • Bennett Van Houten
  • Kabir Chaturvedi
  • Cintyu Wong
  • Eric T Kool
  • Xinfang Lu
  • Pierre R Bushel
  • Martin Marinus
  • Michael C Humble

Detail Information

Publications18

  1. pmc A rapid survival assay to measure drug-induced cytotoxicity and cell cycle effects
    Chandni Valiathan
    Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, USA
    DNA Repair (Amst) 11:92-8. 2012
    ..untreated cells. Finally, this assay can be used in high-throughput format to simultaneously screen multiple cell lines and drugs for accurate measurements of cell survival and cell cycle effects after drug treatment...
  2. pmc The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner
    Glen E Kisby
    Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 6:e20911. 2011
    ..Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease...
  3. pmc Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Mol Biosyst 6:1195-206. 2010
    ..Our findings highlight the critical role of kinase signaling in drug/cytokine hepatic cytotoxicity synergies and reveal that hepatic cytotoxicity responses are governed by multi-pathway signaling network balance...
  4. pmc A multipathway phosphoproteomic signaling network model of idiosyncratic drug- and inflammatory cytokine-induced toxicity in human hepatocytes
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
    Conf Proc IEEE Eng Med Biol Soc 2009:5452-5. 2009
    ....
  5. pmc Liver tissue engineering in the evaluation of drug safety
    Ajit Dash
    Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Expert Opin Drug Metab Toxicol 5:1159-74. 2009
    ....
  6. pmc Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Toxicol Appl Pharmacol 237:317-30. 2009
    ..Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity...
  7. pmc Genomic predictors of interindividual differences in response to DNA damaging agents
    Rebecca C Fry
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Genes Dev 22:2621-6. 2008
    ..Many proteins encoded by these genes are interconnected in cellular networks related to human cancer and tumorigenesis...
  8. ncbi An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha
    Benjamin D Cosgrove
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Hepatology 48:276-88. 2008
    ..Exogenous TGF-alpha can either enhance or diminish apoptosis in adenoviral vector-treated and TNF-treated hepatocytes, in a biphasic relationship also mediated by autocrine IL-1alpha/beta feedback...
  9. pmc Transcriptional networks in S. cerevisiae linked to an accumulation of base excision repair intermediates
    Ivan Rusyn
    Center for Environmental Health Sciences and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
    PLoS ONE 2:e1252. 2007
    ..Taken together, these results suggest that a branch point exists in the current model for DNA damage-signaled transcription in S. cerevisiae...
  10. pmc Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothers
    Rebecca C Fry
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
    PLoS Genet 3:e207. 2007
    ..These studies clearly demonstrate the robust impact of a mother's arsenic consumption on fetal gene expression as evidenced by transcript levels in newborn cord blood...
  11. ncbi Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses
    Richard P Beyer
    University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington 98195, USA
    Toxicol Sci 99:326-37. 2007
    ..We show that phenotypic anchoring of gene expression data is required for biologically meaningful analysis of toxicogenomic experiments...
  12. ncbi Rat liver sinusoidal endothelial cells survive without exogenous VEGF in 3D perfused co-cultures with hepatocytes
    Albert J Hwa
    Department of Mechanical Engineering, MIT, 77 Mass Ave, Cambridge, MA 02139, USA
    FASEB J 21:2564-79. 2007
    ..Global transcriptional profiling did not reveal profound changes between 2D and 3D cultures in expression of most canonical angiogenic factors but suggested changes in several pathways related to endothelial cell function...
  13. pmc The DNA-damage signature in Saccharomyces cerevisiae is associated with single-strand breaks in DNA
    Rebecca C Fry
    Department of Biological Engineering, Massachusetts Institute of Technology, NE47 277, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
    BMC Genomics 7:313. 2006
    ..The genome-wide responses were compared to those induced by the non-selective oxidant gamma-radiation...
  14. pmc Probing the active site tightness of DNA polymerase in subangstrom increments
    Tae Woo Kim
    Department of Chemistry, Stanford University, Stanford, CA 94305 5080, USA
    Proc Natl Acad Sci U S A 102:15803-8. 2005
    ..In addition, the results suggest that even high-fidelity replicative enzymes have more steric room than necessary, possibly to allow for an evolutionarily advantageous mutation rate...
  15. ncbi AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo
    James C Delaney
    Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Nat Struct Mol Biol 12:855-60. 2005
    ..These reactions show a previously unrecognized chemical versatility of AlkB. In mammals, the corresponding AlkB homologs may defend against aging, cancer and oxidative stress...
  16. pmc Analysis of global gene expression and double-strand-break formation in DNA adenine methyltransferase- and mismatch repair-deficient Escherichia coli
    Jennifer L Robbins-Manke
    Biological Engineering Division, Massachusetts Institute of Technology, 77 Massachusetts Ave, 56 670, Cambridge, MA 02139, USA
    J Bacteriol 187:7027-37. 2005
    ..We propose that the up-regulation of recombinational repair in dam mutants allows for the efficient repair of double-strand breaks whose formation is dependent on functional mismatch repair...
  17. ncbi Genome-wide responses to DNA-damaging agents
    Rebecca C Fry
    Biological Engineering Division and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Annu Rev Microbiol 59:357-77. 2005
    ..This review highlights many of the studies that detail genome-wide responses to DNA-damaging agents and examines how these datasets have been used to build a systems view of cellular responses to damage...
  18. ncbi Standardizing global gene expression analysis between laboratories and across platforms
    Theodore Bammler
    Nat Methods 2:351-6. 2005
    ..These findings indicate that microarray results can be comparable across multiple laboratories, especially when a common platform and set of procedures are used...