Genomes and Genes
Global Responses to Aflatoxin B1 & Alkylating Agents
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
- A rapid survival assay to measure drug-induced cytotoxicity and cell cycle effectsChandni 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...
- The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked mannerGlen 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...
- Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulationBenjamin 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...
- A multipathway phosphoproteomic signaling network model of idiosyncratic drug- and inflammatory cytokine-induced toxicity in human hepatocytesBenjamin 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....
- Liver tissue engineering in the evaluation of drug safetyAjit Dash
Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Expert Opin Drug Metab Toxicol 5:1159-74. 2009....
- Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicityBenjamin 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...
- Genomic predictors of interindividual differences in response to DNA damaging agentsRebecca 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...
- An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alphaBenjamin 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...
- Transcriptional networks in S. cerevisiae linked to an accumulation of base excision repair intermediatesIvan 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...
- Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothersRebecca 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...
- Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analysesRichard 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...
- Rat liver sinusoidal endothelial cells survive without exogenous VEGF in 3D perfused co-cultures with hepatocytesAlbert 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...
- The DNA-damage signature in Saccharomyces cerevisiae is associated with single-strand breaks in DNARebecca 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...
- Probing the active site tightness of DNA polymerase in subangstrom incrementsTae 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...
- AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivoJames 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...
- Analysis of global gene expression and double-strand-break formation in DNA adenine methyltransferase- and mismatch repair-deficient Escherichia coliJennifer 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...
- Genome-wide responses to DNA-damaging agentsRebecca 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...
- Standardizing global gene expression analysis between laboratories and across platformsTheodore 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...