Christopher A. Bradfield, Ph.D.

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

Lab Home Page

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

Lee, J. S., Cella, M., McDonald, K. G., Garlanda, C., Kennedy, G. D., Nukaya, M., Mantovani, A., Kopan, R., Bradfield, C. A., Newberry, R. D., and Colonna, M.  AHR Drives the Development of Gut ILC22 Cells and Postnatal Lymphoid Tissues via Pathways Dependent On and Independent of Notch.  Nat. Immunol., 13:  144-151, 2012.

Chernoff, N., Rogers, E. H., Zehr, R. D., Gage, M. I., Malarkey, D. E., Bradfield, C. A., Liu, Y., Schmid, J. E., Jaskot, R. H., Richards, J. H., Wood, C. R., and Rosen, M. B.  Toxicity and Recovery in the Pregnant Mouse After Gestational Exposure to the Cyanobacterial Toxin, Cylindrospermopsin.  J. Appl. Toxicol., 31: 242-254, 2011.

Marcheva, B., Moynihan Ramsey, K., Buhr, E. D., Kobayashi, Y., Su, H., Ko, C. H., Ivanova, G., Omura, C., Mo, S., Vitaterna, M. H., Lopez, J. P., Philipson, L. H., Bradfield, C. A., Crosby, S. D., JeBailey, L., Wang, X., Takahashi, J. S., and Bass, J.  Disruption of the Clock Components CLOCK and BMAL1 Leads to Hypoinsulinaemia and Diabetes.  Nature, 466:  627-631, 2010.

McIntosh, B. E., Hogenesch, J. B., and Bradfield, C. A.  Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation.  Annu. Rev. Physiol., 72:  625-645, 2010.

Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., and Bradfield, C. A.  An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells.  J. Immunol., 185: 3190-3198, 2010.

Nukaya, M., Lin, B. C., Glover, E., Moran, S. M., Kennedy, G. D., and Bradfield, C. A.  The Aryl Hydrocarbon Receptor-Interacting Protein (AIP) Is Required for Dioxin-Induced Hepatotoxicity but Not for the Induction of the Cyp1a1 and Cyp1a2 Genes.  J. Biol. Chem., 285:  35599-35605, 2010.

Nukaya, M., Walisser, J. A., Moran, S. M., Kennedy, G. D., and Bradfield, C. A.  Aryl Hydrocarbon Receptor Nuclear Translocator in Hepatocytes Is Required for Aryl Hydrocarbon Receptor-Mediated Adaptive and Toxic Responses in Liver.  Toxicol. Sci., 118:  554-563, 2010. 

Shen, A. L., O’Leary, K. A., Dubielzig, R. R., Drinkwater, N., Murphy, C. J., Kasper, C. B., and Bradfield, C. A. The PPCD1 Mouse: Characterization of a Mouse Model for Posterior Polymorphous Corneal Dystrophy and Identification of a Candidate Gene.  PLoS ONE, 5(8):e12213, 2010.

Chowdhury, G., Dostalek, M., Hsu, E. L., Nguyen, L. P., Stec, D. F., Bradfield, C. A., and Guengerich, F. P.  Structural Identification of Diindole Agonists of the Aryl Hydrocarbon Receptor Derived from Degradation of Indole-3-pyruvic Acid.  Chem. Res. Toxicol., 22:  1905-1912, 2009.

Nguyen, L. P., Hsu, E. L., Chowdhury, G., Dostalek, M., Guengerich, F. P., and Bradfield, C. A.  D-Amino Acid Oxidase Generates Agonists of the Aryl Hydrocarbon Receptor from D-Tryptophan.  Chem. Res. Toxicol., 22:  1897-1904, 2009.

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