University of Wisconsin School of Medicine and Public Health McArdle Lab home

Christopher A. Bradfield, Ph.D.

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C. Bradfield photo Professor of Oncology

B.Sc., 1982, Environmental Toxicology, University of California at Davis
Ph.D., 1986, Toxicology/Nutrition, University of California at Berkeley
Postdoctoral research: McArdle Laboratory, University of Wisconsin-Madison

Office: 213A McArdle Laboratory
Telephone: Office - (608) 262-2024; Lab (608) 262-1209
Email: bradfield@oncology.wisc.edu

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Research Interests: Molecular biology of the PAS family of proteins

Research Description: Our laboratory is interested in a family of transcriptional regulators known as PAS proteins. Members of this emerging family of proteins control a number of processes, including xenobiotic metabolism (Ah-receptor and Arnt), circadian rhythms (Per), angiogenesis (HIF1a and Arnt), and neurogenesis (Sim). The model system that is currently emphasized is the signal transduction pathway mediated by Ah-receptor/Arnt heterodimeric complex. These helix-loop-helix-PAS proteins regulate the induction of a number of xenobiotic metabolizing enzymes that occur in response to exposure to a variety of polycyclic aromatic environmental pollutants. In addition, the Ah-receptor mediates a second battery of genes responsible for a number of "toxic effects" of dioxins, such as epithelial hyperplasia, immunosuppression, teratogenesis, and tumor promotion.

To understand these proteins and their signal transduction pathways, we are focusing on the characterization of the Ah-receptor/Arnt pathway in genetically manipulable organisms such as mice and yeast. We use yeast genetics as a method to identify genes that are required for signaling. In addition, the yeast system is proving valuable in modifier screens to identify novel components of the dioxin signaling pathway. Experiments in the murine system help us to understand the physiological function of these proteins, as well as to identify new members of the PAS family. Current areas of interest include the use of gene-targeting to generate informative bHLH-PAS loci and the use of more classical transgenic approaches to construct murine models that will help us characterize the mechanisms that underlie the toxicological and developmental effects of halogenated aromatics like dioxin.

Selected recent publications

Bunger, M. K., Glover, E., Moran, S. M., Walisser, J. A., Lahvis, G. P., Hsu, E. L., and Bradfield, C. A.  Abnormal Liver Development and Resistance to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity in Mice Carrying a Mutation in the DNA Binding Domain of the Aryl Hydrocarbon Receptor.  Toxicol. Sci., in press, 2008 [Epub ahead of print Jul 27 2008].

Kunieda, T., Minamino, T., Miura, K., Katsuno, T., Tateno, K., Miyauchi, H., Kaneko, S., Bradfield, C. A., FitzGerald, G. A., and Komuro, I.  Reduced Nitric Oxide Causes Age-Associated Impairment of Circadian Rhythmicity.  Circ. Res., 102: 607-614, 2008.

Lin, B. C., Nguyen, L. P., Walisser, J. A., and Bradfield, C. A.  A Hypomorphic Allele of Aryl-hydrocarbon Receptor-associated-protein-9 Produces a Phenocopy of the Ahr Null.  Mol. Pharmacol., in press, 2008 [Epub ahead of print Jul 31 2008].

Nguyen, L. P., and Bradfield, C. A.  The Search for Endogenous Activators of the Aryl Hydrocarbon Receptor.  Chem. Res. Toxicol., 21:  102-116, 2008.

Smith, A. A., Vollrath, A., Bradfield, C. A., and Craven, M.  Similarity Queries for Temporal Toxicogenomic Expression Profiles.  PLoS Comput. Biol., 4(7):e1000116, 2008.

Stevens, E. A., and Bradfield, C. A.  T Cells Hang in the Balance.  Nature, 453:  46-47, 2008.

Westgate, E. J., Cheng, Y., Reilly, D. F., Price, T. S., Walisser, J. A., Bradfield, C. A., and FitzGerald, G. A.  Genetic Components of the Circadian Clock Regulate Thrombogenesis In Vivo.  Circulation, 117:  2087-2095, 2008.

Hayes, K. R., Zastrow, G. M., Nukaya, M., Pande, K., Glover, E., Maufort, J. P., Liss, A. L., Liu, Y., Moran, S. M., Vollrath, A. L., and Bradfield, C. A.  Hepatic Transcriptional Networks Induced by Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin.  Chem. Res. Toxicol., 20:  1573-1581, 2007.

Lin, B. C., Sullivan, R., Lee, Y., Moran, S., Glover, E., and Bradfield, C. A.  Deletion of the Aryl Hydrocarbon Receptor-associated Protein 9 Leads to Cardiac Malformation and Embryonic Lethality.  J. Biol. Chem., 282:  35924-35932, 2007.

McMillan, B. J., and Bradfield, C. A.  The Aryl Hydrocarbon Receptor Is Activated by Modified Low-density Lipoprotein.  Proc. Natl. Acad. Sci. USA, 104:  1412-1417, 2007.

McMillan, B. J., and Bradfield, C. A.  The Aryl Hydrocarbon Receptor sans Xenobiotics:  Endogenous Function in Genetic Model Systems.  Mol. Pharmacol., 72:  487-498, 2007.

McMillan, B. J., McMillan, S. N., Glover, E., and Bradfield, C. A.  2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Premature Activation of the KLF2 Regulon during Thymocyte Development.  J. Biol. Chem., 282:  12590-12597, 2007.

Dunham, E. E., Stevens, E. A., Glover, E., and Bradfield, C. A.  The Aryl Hydrocarbon Receptor Signaling Pathway Is Modified through Interactions with a Kelch Protein.  Mol. Pharmacol., 70:  8-15, 2006.

Harstad, E. B., Guite, C. A., Thomae, T. L., and Bradfield, C. A. Liver Deformation in Ahr-Null Mice: Evidence for Aberrant Hepatic Perfusion in Early Development. Mol. Pharmacol., 69: 1534-1541, 2006.

McDearmon, E. L., Patel, K. N., Ko, C. H., Walisser, J. A., Schook, A. C., Chong, J. L., Wilsbacher, L. D., Song, E. J., Hong, H.-K., Bradfield, C. A., and Takahashi, J. S.  Dissecting the Functions of the Mammalian Clock Protein BMAL1 by Tissue-Specific Rescue in Mice.  Science, 314:  1304-1308, 2006.

Thomae, T. L., Stevens, E. A., Liss, A. L., Drinkwater, N. R., and Bradfield, C. A. The Teratogenic Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Is Modified by a Locus on Mouse Chromosome 3. Mol. Pharmacol., 69: 770-775, 2006.

Walisser, J. A., and Bradfield, C. A.  A Time to Divide:  Does the Circadian Clock Control Cell Cycle?  Dev. Cell, 10:  539-548, 2006.

Bunger, M. K., Walisser, J. A., Sullivan, R., Manley, P. A., Moran, S. M., Kalscheur, V. L., Colman, R. J., and Bradfield, C. A. Progressive Arthropathy in Mice with a Targeted Disruption of the Mop3/Bmal-1 Locus. Genesis, 41: 122-132, 2005.

Hayes, K. R., and Bradfield, C. A.  Advances in Toxicogenomics.  Chem. Res. Toxicol., 18: 403-414, 2005.

Hayes, K. R., Vollrath, A. L., Zastrow, G. M., McMillan, B. J., Craven, M., Jovanovich, S., Rank, D. R., Penn, S., Walisser, J. A., Reddy, J. K., Thomas, R. S., and Bradfield, C. A. EDGE: A Centralized Resource for the Comparison, Analysis, and Distribution of Toxicogenomic Information. Mol. Pharmacol., 67: 1360-1368, 2005.

Lahvis, G. P., Pyzalski, R. W., Glover, E., Pitot, H. C., McElwee, M. K., and Bradfield, C. A. The Aryl Hydrocarbon Receptor Is Required for Developmental Closure of the Ductus Venosus in the Neonatal Mouse. Mol. Pharmacol., 67: 714-720, 2005.

Laposky, A., Easton, A., Dugovic, C., Walisser, J., Bradfield, C., and Turek, F. Deletion of the Mammalian Circadian Clock Gene BMAL1/Mop3 Alters Baseline Sleep Architecture and the Response to Sleep Deprivation. Sleep, 28: 395-409, 2005.

Pande, K., Moran, S. M., and Bradfield, C. A. Aspects of Dioxin Toxicity Are Mediated by Interleukin 1-Like Cytokines. Mol. Pharmacol., 67: 1393-1398, 2005.

Rankin, E. B., Higgins, D. F., Walisser, J. A., Johnson, R. S., Bradfield, C. A., and Haase, V. H. Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice. Mol. Cell. Biol., 25: 3163-3172, 2005.

Thomae, T. L., Stevens, E. A., and Bradfield, C. A. Transforming Growth Factor-b3 Restores Fusion in Palatal Shelves Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin. J. Biol. Chem., 280: 12742-12746, 2005.

Walisser, J. A., Glover, E., Pande, K., Liss, A. L., and Bradfield, C. A. Aryl Hydrocarbon Receptor-dependent Liver Development and Hepatotoxicity Are Mediated by Different Cell Types. Proc. Natl. Acad. Sci. USA, 102: 17858-17863, 2005.

Bradfield, C. Genomics and Proteomics. Chem. Res. Toxicol., 17: 2, 2004.

Guengerich, F. P., Martin, M. V., McCormick, W. A., Nguyen, L. P., Glover, E., and Bradfield, C. A. Aryl Hydrocarbon Receptor Response to Indigoids in Vitro and in Vivo. Arch. Biochem. Biophys., 423: 309-316, 2004.

Thomae, T. L., Glover, E., and Bradfield, C. A. A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis. J. Biol. Chem., 279: 30189-30194, 2004.

Walisser, J. A., Bunger, M. K., Glover, E., and Bradfield, C. A. Gestational Exposure of Ahr and Arnt Hypomorphs to Dioxin Rescues Vascular Development. Proc. Natl. Acad. Sci. USA, 101: 16677-16682, 2004.

Walisser, J. A., Bunger, M. K., Glover, E., Harstad, E. B., and Bradfield, C. A. Patent Ductus Venosus and Dioxin Resistance in Mice Harboring a Hypomorphic Arnt Allele. J. Biol. Chem., 279: 16326-16331, 2004.

Williams, S. N., Dunham, E., and Bradfield, C. A. Induction of Cytochrome P450 Enzymes. In: P. R. Ortiz de Montellano (Ed.), Cytochrome P450: Structure, Mechanism, and Biochemistry, pp. 1-24. New York, NY: Kluwer Academic Publishers, 2004.

Yao, G., Craven, M., Drinkwater, N., and Bradfield, C. A. Interaction Networks in Yeast Define and Enumerate the Signaling Steps of the Vertebrate Aryl Hydrocarbon Receptor. PLoS Biol., 2: E65, 2004.

Bittinger, M. A., Nguyen, L. P., and Bradfield, C. A. Aspartate Aminotransferase Generates Proagonists of the Aryl Hydrocarbon Receptor. Mol. Pharmacol., 64: 550-556, 2003.

Bradfield, C. A. Gene Targeting. Introduction. In: M. D. Maines, L. G. Costa, E. Hodgson, D. J. Reed, and I. G. Sipes (Eds.), Current Protocols in Toxicology, Chap. 15, pp. 15.0.1-15.0.2. John Wiley & Sons, Inc., 2003. Print Publication Date: November 2001; Online Posting Date: February 2002; Copyright Date 2003.

Bunger, M. K., Moran, S. M., Glover, E., Thomae, T. L., Lahvis, G. P., Lin, B. C., and Bradfield, C. A. Resistance to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity and Abnormal Liver Development in Mice Carrying a Mutation in the Nuclear Localization Sequence of the Aryl Hydrocarbon Receptor. J. Biol. Chem., 278: 17767-17774, 2003.

Yao, G., Harstad, E. B., and Bradfield, C. A. The Ah Receptor. In: S. T. Crews (Ed.), PAS Proteins: Regulators and Sensors of Development and Physiology, Chapter 7, pp. 149-182. Boston: Kluwer Academic Publishers, 2003.

Thomas, R. S., Hayes, K. R., Zastrow, G. M., Tran, K., Penn, S. G., Rank, D. R., and Bradfield, C. A. Application of DNA Microarrays for Predicting Toxicity and Evaluating Cross-Species Extrapolation. In: T. Inoue and W. D. Pennie (Eds.), Toxicogenomics, pp. 31-38. Tokyo: Springer-Verlag, 2002.

Thomas, R. S., Penn, S. G., Holden, K., Bradfield, C. A., and Rank, D. R. Sequence Variation and Phylogenetic History of the Mouse Ahr Gene. Pharmacogenetics, 12: 151-163, 2002.

Thomas, R. S., Rank, D. R., Penn, S. G., Craven, M. W., Drinkwater, N. R., and Bradfield, C. A. Developing Toxicologically Predictive Gene Sets Using cDNA Microarrays and Bayesian Classification. Methods Enzymol., 357: 198-205, 2002.

Thomas, R. S., Rank, D. R., Penn, S. G., Zastrow, G. M., Hayes, K. R., Hu, T., Pande, K., Lewis, M., Jovanovich, S. B., and Bradfield, C. A. Application of Genomics to Toxicology Research. Environ. Health Perspect., 110(Suppl.6): 919-923, 2002.

Walisser, J. A., and Bradfield, C. A. The PAS Protein Superfamily. In: J. P. Vanden Heuvel, G. H. Perdew, W. B. Mattes, and W. F. Greenlee (Eds.), Comprehensive Toxicology, Vol. 14: Cellular and Molecular Toxicology, pp. 107-117. Elsevier Science BV, 2002.

Walisser, J. A., and Bradfield, C. A. The Aryl Hydrocarbon Receptor: A Model of Gene-Environment Interactions. In: J. P. Vanden Heuvel, G. H. Perdew, W. B. Mattes, and W. F. Greenlee (Eds.), Comprehensive Toxicology, Vol. 14, Cellular and Molecular Toxicology, pp. 119-132. Elsevier Science BV, 2002.

Walker, M. K., Bradfield, C. A., and Walisser, J. A. Hypoxia Regulation of Gene Expression through HIF1 Signaling. In: J. P. Vanden Heuvel, G. H. Perdew, W. B. Mattes, and W. F. Greenlee, (Eds.), Comprehensive Toxicology, Vol. 14: Molecular and Cellular Toxicology, pp. 389-407. Elsevier Science BV, 2002.

Bittinger, M. A., and Bradfield, C. A. The Ah Receptor. Encyclopedia of Molecular Medicine, Vol. 1, pp. 265-266. New York: John Wiley & Sons, Inc., 2001.

Cherkaoui-Malki, M., Meyer, K., Cao, W.-Q., Latruffe, N., Yeldandi, A. V., Rao, M. S., Bradfield, C. A., and Reddy, J. K. Identification of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Target Genes in Mouse Liver Using cDNA Microarray Analysis. Gene Expr., 9: 291-304, 2001.

Thomas, R. S., Rank, D. R., Penn, S. G., Zastrow, G. M., Hayes, K. R., Pande, K., Glover, E., Silander, T., Craven, M. W., Reddy, J. K., Jovanovich, S. B., and Bradfield, C. A. Identification of Toxicologically Predictive Gene Sets using cDNA Microarrays. Mol. Pharmacol., 60: 1189-1194, 2001.

Bunger, M. K., Wilsbacher, L. D., Moran, S. M., Clendenin, C., Radcliffe, L. A., Hogenesch, J. B., Simon, M. C., Takahashi, J. S., and Bradfield, C. A.  Mop3 Is an Essential Component of the Master Circadian Pacemaker in Mammals. Cell, 103: 1009-1017, 2000.

Gu, Y.-Z., Hogenesch, J. B., and Bradfield, C. A. The PAS Superfamily: Sensors of Environmental and Developmental Signals. Annu. Rev. Pharmacol. Toxicol., 40: 519-561, 2000.

Hogenesch, J. B., Gu, Y.-Z., Moran, S. M., Shimomura, K., Radcliffe, L. A., Takahashi, J. S., and Bradfield, C. A. The Basic Helix-Loop-Helix-PAS Protein MOP9 Is a Brain-Specific Heterodimeric Partner of Circadian and Hypoxia Factors. J. Neurosci., 20: RC83, 5 pp, 2000.

Lahvis, G. P., Lindell, S. L., Thomas, R. S., McCuskey, R. S., Murphy, C., Glover, E., Bentz, M., Southard, J., and Bradfield, C. A. Portosystemic Shunting and Persistent Fetal Vascular Structures in Aryl Hydrocarbon Receptor-deficient Mice. Proc. Natl. Acad. Sci. USA, 97: 10442-10447, 2000.

LaPres, J. J., Glover, E., Dunham, E. E., Bunger, M. K., and Bradfield, C. A. ARA9 Modifies Agonist Signaling through an Increase in Cytosolic Aryl Hydrocarbon Receptor. J. Biol. Chem., 275: 6153-6159, 2000.

Chan, W. K., Yao, G., Gu, Y.-Z., and Bradfield, C. A. Cross-talk between the Aryl Hydrocarbon Receptor and Hypoxia Inducible Factor Signaling Pathways. Demonstration of Competition and Compensation. J. Biol. Chem., 274: 12115-12123, 1999.

Bunger, M. K., and Bradfield, C. A. Generation of Allelic Series in Mice by Gene Targeting. In: I. R. Phillips and E. A. Shephard (Eds.), Methods in Molecular Biology, Vol. 107: Cytochrome P450 Protocols, Chapter 44, pp. 439-468. Totowa, NJ: Humana Press, Inc., 1998.

Carver, L. A., and Bradfield, C. A. Simple Models of Dioxin Action. In: A. Puga and K. Wallace (Eds.), Molecular Biology in Toxicology, pp. 355-375. Washington, D.C.: Taylor & Francis, 1998.

Carver, L. A., LaPres, J. J., Jain, S., Dunham, E. E., and Bradfield, C. A. Characterization of the Ah Receptor-associated Protein, ARA9. J. Biol. Chem., 273: 33580-33587, 1998.

Gu, Y.-Z., Moran, S. M., Hogenesch, J. B., Wartman, L., and Bradfield, C. A. Molecular Characterization and Chromosomal Localization of a Third α-Class Hypoxia Inducible Factor Subunit, HIF3α. Gene Expr., 7: 205-213, 1998.

Hogenesch, J. B., Gu, Y.-Z., Jain, S., and Bradfield, C. A. The Basic-Helix-Loop-Helix-PAS Orphan MOP3 Forms Transcriptionally Active Complexes with Circadian and Hypoxia Factors. Proc. Natl. Acad. Sci. USA, 95: 5474-5479, 1998.

Jain, S., Maltepe, E., Lu, M. M., Simon, C., and Bradfield, C. A. Expression of ARNT, ARNT2, HIF1α, HIF2α and Ah Receptor mRNAs in the Developing Mouse. Mech. Dev., 73: 117-123, 1998.

Lahvis, G. P., and Bradfield, C. A. Ahr Null Alleles: Distinctive or Different? Biochem. Pharmacol., 56: 781-787, 1998.

Powell-Coffman, J., Bradfield, C. A., and Wood, W. B. Caenorhabditis elegans Orthologs of the Aryl Hydrocarbon Receptor and Its Heterodimerization Partner the Aryl Hydrocarbon Receptor Nuclear Translocator. Proc. Natl. Acad. Sci. USA, 95: 2844-2849, 1998.

Carver, L. A., and Bradfield, C. A. Ligand-dependent Interaction of the Aryl Hydrocarbon Receptor with a Novel Immunophilin Homologue in Vivo. J. Biol. Chem., 272: 11452-11456, 1997.

Hogenesch, J. B., Chan, W. K., Jackiw, V. H., Brown, R. C., Gu, Y.-Z., Pray-Grant, M., Perdew, G. H., and Bradfield, C. A. Characterization of a Subset of the Basic-Helix-Loop-Helix-PAS Superfamily That Interacts with Components of the Dioxin Signaling Pathway. J. Biol. Chem., 272: 8581-8593, 1997.

Maltepe, E., Schmidt, J. V., Baunoch, D., Bradfield, C. A., and Simon, M. C. Abnormal Angiogenesis and Responses to Glucose and Oxygen Deprivation in Mice Lacking the Protein ARNT. Nature, 386: 403-407, 1997.

Schmidt, J. V., Su, G. H.-T., Reddy, J. K., Simon, M. C., and Bradfield, C. A. Characterization of a Murine Ahr Null Allele: Involvement of the Ah Receptor in Hepatic Growth and Development. Proc. Natl. Acad. Sci. USA, 93: 6731-6736, 1996.