Biography
Michael L. Cunningham, Ph.D.
University of Arizona, Pharmacology and Toxicology, 1981.
Chemical Toxicology Group
National Institutes of Health
National Institute of Environmental Health Science
Research Triangle Park, North Carolina
USA
Recent advances in genomic, metabonomic and proteomic research, coupled with the availability of novel tools and methods to analyze the products of altered gene expression, have provided new insights into mechanisms of toxicity evoked by xenobiotics. While these advances promise to revolutionize our ability to characterize hazard, the challenge in the near future is to establish a body of available knowledge to serve as a foundation for applying the data generated by these new methods to risk assessment. Toxicogenomics is a powerful tool for improving human risk assessment because it will measure specific changes in gene expression in humans and other species that are exposed to drugs or other agents and to profile the process of disease progression. Careful data analysis could identify similar patterns in different species, leading to a "signature" for a given pathway of toxicity or disease state in humans. Once signatures are identified using large scale, global microarray analysis, it will then be possible to develop smaller, multi-chemical and multi-pathway arrays that can be used to assess the potential toxicity of chemicals in a rapid, prospective manner. This would result in better interspecies extrapolation, greater confidence in animal models, reduction in the number of animals needed for testing, faster testing, and most importantly, insights into pathways of toxicity and disease processes and their mechanisms heretofore unattainable using less developed technologies. The mission of the Toxicology/Pathology Workgroup is to provide fundamental toxicology and pathology expertise in the design and conduct of NCT sponsored studies in-house and extramurally in order to assure genomic and proteomic data can be interpreted in the correct phenotypic context. The Tox/Path Workgroup efforts within the NCT consists of four components; 1) an intramural program; 2) liaison activities with the National Toxicology Program; 3) collaboration with the International Life Sciences Institute; and 4) liaison with the extramural Toxicogenomic Research Consortium. The close association of the Tox/Path Workgroup with the Microarray Center, NTP, ILSI and the TRC provides an opportunity to integrate fundamental toxicology with the new genomic, proteomic, and metabonomic technologies.
Intramural Toxicology/Pathology Program: Conduct of a typical study in-house comprises collaboration with other staff members at NIEHS and Toxicogenomics Research Consortium during the design phase of NCT studies; performance of a comprehensive literature review; selection of the disease model to study (hepatic necrosis, renal tubular necrosis, apoptosis, etc.); selection of agent(s) known to induce the disease process and structural analogs that do not elicit the disease; design the study (dose ranges to produce toxic and nontoxic responses or pharmacological responses, duration of exposure/recovery); protocol preparation (both animal and chemical protocols); procurement of chemical and animals; acquisition of in-life data; dose formulation; administration of chemical; monitor study animals to assess toxicity; collection of tissues (blood, liver, kidney, urine) and data at termination; processing of tissues in an appropriate manner for analysis (blood for hematology, serum for clinical chemistry proteomics, tissues into liquid nitrogen, urine at ¿80¿C, tissues into neutral buffered formalin and/or fixative for ultrastructural studies); monitor histopathology and ultrastructure preparation and clinical chemistry and hematology analyses; provide pathology evaluation and review; provide oversight of entry of clinical chemistry and pathology data into TDMS; archive data from clinical chemistry measurements; and analysis of all data (clinical chemistry, histopathology, ultrastructure) for complete toxicological characterization prior to genomic, metabonomic and/or proteomic analyses. Support for the pathology aspects of the studies are also provided by the Laboratory of Experimental Pathology.
Collaboration with the National Toxicology Program: The Tox/Path Workgroup also is the liaison between the NCT and the National Toxicology Program. We interact with both groups to maximize the communication between these two programs in order to optimize the utilization of resources. Our goal is the incorporation of the latest technologies into NTP toxicity assessments by bringing genomics experience of the NCT to the NTP. We provide animals on test by the NTP to the NCT in order to utilize the animals in their toxicity testing and reduce repetitive testing. Our current efforts on this behalf include participation in the design of the toxicogenomic portion of two NTP studies- the effect of circadian rhythm on gene expression and the toxicity of the algal toxin microcystin). He is Project Officer for the contract 'Chemical Disposition in Mammals' at the University of Arizona; Project Leader for the Peroxisome Proliferation Initiative which is evaluating WY-14,643, gemfibrozil, 2,4-dichlorophenoxyacetic acid, and dibutyl phthalate; and Project Leader for the class study for toxicological evaluation of alpha, beta-unsaturated ketones (methyl vinyl ketone, ethyl vinyl ketone, cyclohexene-1-one and methyl styryl ketone), and Study Director for the toxicological assessment of various chemicals. In 1999, Dr. Cunningham was detailed to the newly formed National Center for Toxicogenomics, headquartered at NIEHS. He coordinates the activities of the Toxicology/Pathology Group with responsibility for overseeing comprehensive toxicological evaluation of in-life studies conducted in support of the Microarray, Proteomics, and Gene Expression Groups.
Collaboration with the International Life Sciences Institute: The Tox/Path Workgroup is the NCT leader for collaboration with the International Life Sciences Institute Initiative for Genomics and Proteomics Nephrotoxicity Workgroup. We interact with scientists from many private and governmental institutes to design, conduct and interpret toxicity studies on 3 nephrotoxicants: cisplatin, gentamycin and puromycin and the cardiotoxins doxorubicin and Etoposide. Primary responsibility has focused on the conduct of a subchronic puromycin study in rats. We also serve as the repository for samples and data for that study. We also collaborate in the data analysis from all three studies and provide data and samples to others from the puromycin study. This interaction includes monthly conference calls and bimonthly meetings as well as laboratory analyses.
Collaboration with the Toxicogenomics Research Consortium: The Tox/Path Workgroup is also providing the universal control RNA samples to be used by all members of the Toxicogenomics Research Consortium (TRC) Steering Committee and Cooperative Research Project (CRP) members. We were chosen to plan and conduct the in-life portion of the collaboration to provide RNA that will be used by all Consortium members as control RNA for future experiments in C57 black male mice. The RNA pool is composed of RNA from liver, kidney, lung, brain and spleen and Arabodopsis mRNA.
Recent Publications
Rusyn, I., Asakura, S., Pachkowski, B., Bradford, B.U., Denissenko, M.F., Peters, J.M., Holland, S.M., Reddy, J.K., Cunningham, M.L. and Swenberg, J.A.: Expression of base excision DNA repair genes is a sensitive biomarker for in vivo detection of chemical-induced chronic oxidative stress: Identification of the molecular source of radicals responsible for DNA damage by peroxisome proliferators. Cancer Research, 64, 1050-1057, 2004.
Irwin, R.D., Boorman, G.A., Cunningham, M.L., Heinloth, A.N., Malarkey, D.E., and Paules R.S.: Application of toxigenomics to toxicology: Basic concepts in the analysis of microarray data, Toxicologic Pathology 32(suppl. 1) 72-83, 2004.
Wang, C., Youssef, J., Cunningham, M.L. and Badr, M.: Correlation Between Animal Thyroid Hormone Status and Hepatic Hyperplasia and Hypertrophy Caused By the Peroxisome Proliferator-Activated Receptor alpha Agonist Wy-14,643. Journal of Carcinogenesis, 3:9-31, 2004.
Youssef, J., Warren, B., Elbi, C., Yourtee, D., Nagarur, R., Molteni, A.,
Cunningham, M.L. and Badr, M.: Glucocorticoid-like effects of the antihepatocarcinogen rotenone are mediated via enhanced serum corticosterone levels: Molecular fitting and receptor activation studies, Journal of Carcinogenesis 3:9-14, 2004.
Amin, R.P., Vickers, A.E., Sistare, F., Thompson, K.L., Roman, R.J., Lawton, M., Kramer, J., Hamadeh, H.K., Collins, J., Grissom, S., Bennett, L., Tucker, C.J., Wild, S., Kind, C., Oreffo, V., Davis, J.W., Curtiss, S., Naciff, J.M., Cunningham, M.L., Tennant, R., Stevens, J., Car, B., Bertram, T.A., and Afshari, C.A.: Identification of putative gene based markers of renal toxicity, Environmental Health Perspectives-Toxicogenomics, 112: 464-479, 2004.
Thompson, K.L., Afshari, C.A., Amin, R.P., Bertram, T.A., Car, B., Cunningham, M.L., Kind, C., Kramer, J.A., Lawton, M., Mirsky, M., Naciff, J.M., Oreffo, V., Pine, P.S. and Sistare, F.D.: Identification of platform-independent gene expression markers of cisplatin nephrotoxicity, Environmental Health Perspectives-Toxicogenomics 112: 488-494, 2004.
Kramer, J.A., Pettit, S.D., Amin, R.P., Bertram, T.A., Car, B., Cunningham, M.L., Curtiss, S.W., Davis, J.W., Kind, C., Lawton, M., Naciff, J.M., Oreffo, V., Roman, R.J., Sistare, F.D., Thompson, K., Vickers, A.E., Wild, S. and Afshari, C.A.: Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment, Environmental Health Perspectives-Toxicogenomics 112: 460-464, 2004.
Schecter, A., Lucier, G.W., Cunningham, M.L., Abdo, K.M., Blumenthal, G., Silver, A., Melnick, R., Portier, C., Barr, D.B., Barr, J.B., Ashley, D.L., Patterson, D., Needham, L.L., Sampson, E.J., Stopford, W., Masten, S. and Mignogna, J.: Methyleugenol metabolism in humans, Environmental Health Perspectives, 112, 678-680, 2004.
Qin, L.-X., Kerr, K.F., Boyles, A., Dressman, H.K., Freedman, J.H., Li, Y.-J., Malek, R.L., Schwartz, D.A., Slifer, S., Speer, M.C., Yang, I., Zarbl, H., Shin, J.-L., Jing, L., Sullivan, R.C., Fry, R., Samson, L., Tucker, C.J., Fannin, R.D., Sieber, S.O., Li, J., Bushel, P.R., Paules, R.S., Boorman, G.A., Cunningham, M.L., Weis, B.K., Choi, D., Lapidus, J., Lasarev, M., Lu, X., O¿Malley, J., Pattee, P., Nagalla, S., Todd, S., Rodland, M., Spencer, P., Kaufmann, W., Perou, C., Rusyn, I., Swenberg, J. and Bradford, B. : Empirical evaluation of data transformations and ranking statistics for microarray analysis, Nucleic Acids Research, 32: 5471-5479, 2004.
Heinloth, A.N., Irwin, R.D., Boorman, G.A., Nettesheim, P., Fannin, R.D., Sieber, S.O., Snell, M.L., Tucker, C.J., Li, L., Travlos, G.S., Vansant, G., Monforte, J., Blackshear, P.E., Tennant, R.W., Cunningham, M.L. and Paules, R.S.: Gene expression profiling of rat liver predicts potential adverse effects. Toxicological Sciences, 80, 193-202, 2004.
Cunningham, M.L. and Lehman-Mckeeman, L.: Toxicological Highlight: Applying toxicogenomics in mechanistic and predictive toxicology, Toxicological Sciences, 83, 205-206, 2005.
Bammler, T., Beyer, R.P., Bhattacharya, S., Boorman, G., Boyles, A., Bradford, B., R., Bumgarner, Bushel, P.R., Chaturvedi, K., Choi, D., Cunningham, M.L., Deng, S., Dressman, H., Fannin, R.D., Farin, F.M., Freedman, J.H., Fry, R.C., Harper, A., Humble, M., Hurban, P., Kavanagh, T., Kaufmann, W.K., Kerr, K.F., Jing, L., Lapidus, J.A., Milton, S., Nagalla, S., O¿Malley, J., P., Palmer, V. S., Pattee, P., Paules, R.S., Perou, C.M., Phillips, K., Quin, L.-X., Qui, Y., Quigley, S.D., Rodland, M., Rusyn, I., Samson,L., Schwartz, D.A., Shi, Y., Shin, J.-L., Sieber, S.O., Slifer, S., Speer, M.C., Spencer, P., Sproles, D.I., Swenberg, J.A., Suk, W.A., Sullivan, R.C., Tian, R., Tennant, R.W., Todd, S.A., Tucker, C.J., van Houten, B., Weis, B.K., Xuan, S. and Zarbl, H.:Standardizing global gene expression analysis between laboratories and across platforms, Nature Methods, 2, 351-356, 2005.
Iida, M., Anna, C.H., Holliday, W.W., Collins, J.B., Cunningham, M.L., Sills, R.C. and Devereux, T.R. : Unique patterns of gene expression changes in liver after treatment of mice for 2 weeks with different known carcinogens and non-carcinogens, Carcinogenesis 26, 689-699, 2005.
Tyrrell, S., Shane, B.S. and Cunningham, M.L.: The food additive, methyleugenol, is mutagenic in vivo in Big Blue® female transgenic rats, Mutation Research, in press, 2006.
Fostel, J.M., Choi, D., Zwickl, C., Morrison,N., Bao,W., Richard, A., Yang, C., Bruno, M.E., Heinloth, A.N., Madenspacher,J.H., Merrick,B.A., Paules, R.S., Tomer,K.B., Wetmore, B.A., Tennant, R., Cunningham, M.L., Boorman, G.A., Irwin, R., Garcia,A., Papoian, T., Brown, R., Stevens, J. and Waters, M.D.:
Chemical Effects in Biological Systems ¿ Data Dictionary (CEBS-DD) for capture and integration of biological study design description, conventional phenotypes and `omics data, Toxicological Sciences, 88, 585-601, 2005.
Sanders, J.M., Burka, L.T., Smith, C.S., Black, W., James, R. and Cunningham, M.L.: Differential expression of CYP1A, 2B and 3A genes in the F344 rat following exposure to a polybrominated diphenyl ether mixture or individual components, Toxicological Sciences, 88, 127-133, 2005.
Dunnick, J., Blackshear, P., Kissling, G., Cunningham, M.L., Parker, J., Nyska, A.: Critical pathways in heart function: Bis(2-chloroethoxy)methane-induced heart gene change in F344 rats. Toxicologic Pathology, 2006, in press.
Rusyn, I., Peters, J.M. and Cunningham, M.L.: Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Critical Reviews in Toxicology, 2006, in press.
Powell, C.L., Kosyk, O., Ross, P.K., Schoonhoven, R., Boysen, G., Swenberg, J.A., Heinloth, A.N., Boorman, G.A., Cunningham, M.L., Paules, R.S. and Rusyn, I. (2006) Phenotypic achoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver. Toxicological Sciences, in press.
Coecke, S., Ahr, H., Blaauboer, B.J., Bremer, S., Casati, S., Castell, J., Combes, R., Corvi, R., Crespi, C.L., Cunningham, M.L., Elaut, G., Eletti, B., Freidig, A., Gennari, A., Ghersi-Egea, J.-F., Guillouzo, A., Hartung, T., Hoet, P., Ingelman-Sundberg, M., Munn, S., Janssens, W., Ladstetter, B., Leahy, D., Long, A., Meneguz, A., Monshouwer, M., Morath, S., Nagelkerke, F., Pelkonen, O., Ponti, J. Prieto, P., Richert, L., Sabbioni, E., Schaack, B., Steiling, W., Testai, E., Vericat, J.-A. and Worth, A. Metabolism: a Bottleneck in In Vitro Toxicological Test Development: Alternatives to Laboratory Animals, 34, 49-54, 2006.
Wyde, M.E., Cunningham, M.L. et al.: NTP technical report on the toxicology and carcinogenesis studies of alpha-methylstyrene (CAS No. 98-83-9) in F344/N rats and B6C3F1 mice (inhalation studies), NTP Toxicity Report Series Number 543, 2006.
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