Gary H. Perdew, PhD
- H. Thomas and Dorothy Willits Hallowell Chair in Agricultural Sciences
University Park, PA 16802
- Email ghp2@psu.edu
- Office 814-865-0400
Areas of Expertise
- microbiome
- aryl hydrocarbon receptor
- dioxin
- drug metabolism
- toxicology
- transcriptional regulation
Education
- PhD, Food Toxicology, Oregon State University
- MS, Food Science, University of Maryland
- BS, Food Science, University of Maryland
Graduate Programs
- Molecular Cellular Integrative Biosciences (MCIBS)
Research
Molecular mechanism(s) of toxicity, dioxin-mediated signal transduction, regulation of cellular homeostasis by the Ah receptor, Ah receptor-mediated control of gene expression; biochemistry of heat shock protein complexes
Ah receptor-mediated toxicity
We are interested in the long-term health effects of persistent exposure to industrial pollutants. Dioxin and other halogenated polycyclic aromatic hydrocarbons (HPAHs) are produced during the combustion of organic matter and as a result of bleaching paper. The Ah receptor plays a central role in the biological response to dioxin, which is both carcinogenic and toxic. The Ah receptor is a member of a family of helix-loop- helix/basic region transcriptional factors. Upon binding a HPAH, the Ah receptor translocates to the nucleus and heterodimerizes with Arnt, another helix-loop-helix/basic region protein. This heterodimer is subsequently able to bind to a specific enhancer core sequence in the nucleus, leading to alter transcription of a set of genes. This sequence of events is believed to result in the high level of toxicity observed with many HPAHs and perhaps the tumor-promoting properties of dioxins. We are examining a number of biochemical properties of the Ah receptor, including the level of receptor heterogeneity, composition of the inactive form of the receptor, proteolytic turnover of liganded receptor, and its ability to interact with other transcription factors. We are testing whether structurally diverse Ah receptor ligands can illicit differing gene expression patterns. Ligand-independent function of the Ah receptor in normal cellular processes is also being explored, using a variety of molecular techniques. The critical target genes regulated by the Ah receptor that lead to toxicity are being identified through DNA microarray analysis. Through this series of studies, we hope to gain an understanding of the multiple points of regulation of the Ah receptor and its role in dioxin-mediated toxicity and normal cell biology. Yet another issue that we are addressing is whether the human Ah receptor can mediate toxicity of dioxin in a transgenic mouse model.
Role of the Ah receptor in physiology
The Ah receptor plays an important role in normal cellular physiology; this is best exemplified by the phenotype in mice where the Ah receptor gene has been disrupted. Ah receptor null mice exhibit a number of defects, such as; low productive success, abnormal vasculature in the liver, small liver size and altered immune system. We are interested in how the activity of the Ah receptor is regulated under normal physiologic conditions; this is being explored by screening certain endogenous chemicals for their ability to activate the Ah receptor. A number of nuclear receptors (e.g. estrogen receptor) have been shown to modulate transcriptional activity through tethering to other transcription factors at the promoter region of genes. We have developed a point mutant of the Ah receptor that fails to bind to DNA, yet stills binds ligand and heterodimerizes with ARNT. A transgenic mouse has been developed that expresses this mutant receptor and the transgene has been crossed onto an Ah receptor null background. DNA microarray studies have been performed to determine whether the Ah receptor can regulate gene expression through protein-protein interactions. A number of biochemical pathways important in human health are attenuated by activation of the Ah receptor. Ah receptor ligands that can selectively elicit a transrepression response, and not a DNA binding response (e.g. induction of CYP1A1), are currently being designed and screened. Studies are being designed to examine whether the Ah receptor will be an important drug target.
Lab members:
Chris Chairo- Genetics Graduate program
Luis Morales- Biochemistry Graduate program
Brett DiNatale- Molecular Medicine Graduate program
Colin Flaveny- Toxicology Graduate program
Rushang Patel- Molecular Medicine Graduate program
Ann Kusnadi- Research Associate
Iain Murray - Postdoctoral Fellow
Jennifer Schroeder- Postdoctoral Fellow
Kelly Wagner- Technician
Lab Alumni (partial list):
Hollie Swanson- Associate Professor- University of Kentucky
Murray Whitelaw- Associate Professor- University of Adelaide
Norman Nord- Associate Professor- Michigan State University
Steve Levine- Scientist- Monstanto
David Carlson- FDA, drug approval division
Brian Meyer- Scientist- Merck Laboratories
Mohan Kumar - Scientist- RheoGene, Inc.
Peter Long- Patent Attorney
John Petrulis- Scientist- Schering-Plough
Preeti Ramadoss - Post-doctoral fellow Harvard
Brett Hollingshead - Post-doctoral fellow- National Cancer Institute
Publications
Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran.
Metabolites, Nichols, Renea, Zhang, Jian, Cai, Jingjing, Murray, Iain, Koo, I, Smith, Philip, Perdew, Gary, Patterson, Andrew, 2019
Selective Ah receptor ligands mediate enhanced SREBP1 proteolysis to restrict lipogenesis in sebocytes.
Toxicological sciences : an official journal of the Society of Toxicology, Muku, G, Blazanin, N, Dong, F, Smith, Philip, Thiboutot, Diane, Gowdahalli, Krishnegowda, Amin, Shantu, Murray, Iain, Perdew, Gary, 2019
Isolation and identification of aryl hydrocarbon receptor modulators in white button mushrooms (Agaricus bisporus)
Journal of agricultural and food chemistry, Tian, Yuan, Gui, Wei, Smith, Philip B., Koo, Imhoi, Murray, Iain A., Cantorna, Margherita T., Perdew, Gary H., Patterson, Andrew D., 2019
PCB126 blocks the thermogenic beiging response of adipocytes
Environmental Science and Pollution Research, Gourronc, Francoise A., Perdew, Gary H., Robertson, Larry W., Klingelhutz, Aloysius J., 2019
Selective Ah receptor modulators attenuate NPC1L1-mediated cholesterol uptake through repression of SREBP-2 transcriptional activity
Laboratory Investigation, Muku, Gulsum E., Kusnadi, Ann, Kuzu, Guray, Tanos, Rachel, Murray, Iain Alexander, Gowda, Krishne, Amin, Shantu, Perdew, Gary H., 2019
Metabolomics reveals aryl hydrocarbon receptor activation induces liver and mammary gland metabolic dysfunction in lactating mice
Journal of Proteome Research, Belton, Kerry R., Tian, Yuan, Zhang, Limin, Anitha, Mallappa, Smith, Philip B., Perdew, Gary H., Patterson, Andrew David, 2018
Allelic variants of the aryl hydrocarbon receptor differentially influence UVB-mediated skin inflammatory responses in SKH1 mice
Toxicology, Smith, Kayla J., Murray, Iain Alexander, Boyer, Jacob A., Perdew, Gary H., 2018
Assessment of Ah receptor transcriptional activity mediated by halogenated dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) in human and mouse cell systems
Journal of Environmental Science and Health - Part A Toxic/Hazardous Substances and Environmental Engineering, Organtini, Kari L., Hubbard, Troy D., Perdew, Gary H., Dorman, Frank L., 2017
Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses
Laboratory Investigation, Muku, Gulsum E., Lahoti, Tejas S., Murray, Iain A., Podolsky, Michael A., Smith, Kayla J., Hubbard, Troy D., Kuzu, Guray, Gowda, Krishne, Amin, Shantu G., Perdew, Gary H., 2017
Dietary broccoli impacts microbial community structure and attenuates chemically induced colitis in mice in an Ah receptor dependent manner
Journal of Functional Foods, Hubbard, Troy D., Murray, Iain Alexander, Nichols, Robert G., Cassel, Kaitlyn, Podolsky, Michael, Kuzu, Guray, Tian, Yuan, Smith, Philip B., Kennett, Mary J., Patterson, Andrew David, Perdew, Gary H., 2017
Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor
Toxicology and Applied Pharmacology, Moyer, Benjamin J., Rojas, Itzel Y., Murray, Iain A., Lee, Seokwon, Hazlett, Haley F., Perdew, Gary H., Tomlinson, Craig R., 2017
Regulation of cytochrome P450 2B10 (CYP2B10) expression in liver by peroxisome proliferator-activated receptor-β/δ modulation of SP1 promoter occupancy
Journal of Biological Chemistry, Koga, Takayuki, Yao, Pei Li, Goudarzi, Maryam, Murray, Iain A., Balandaram, Gayathri, Gonzalez, Frank J., Perdew, Gary H., Fornace, Albert J., Peters, Jeffrey M., 2016
Divergent Ah Receptor Ligand Selectivity during Hominin Evolution
Molecular Biology and Evolution, Hubbard, Troy D., Murray, Iain Alexander, Bisson, William H., Sullivan, Alexis P., Sebastian, Aswathy, Perry, George H., Jablonski, Nina G., Perdew, Gary H., 2016
Expression of the aryl hydrocarbon receptor contributes to the establishment of intestinal microbial community structure in mice
Scientific reports, Murray, Iain A., Nichols, Robert G., Zhang, Limin, Patterson, Andrew D., Perdew, Gary H., 2016
A novel AhR ligand, 2AI, protects the retina from environmental stress
Scientific reports, Gutierrez, Mark A., Davis, Sonnet S., Rosko, Andrew, Nguyen, Steven M., Mitchell, Kylie P., Mateen, Samiha, Neves, Joana, Garcia, Thelma Y., Mooney, Shaun, Perdew, Gary H., Hubbard, Troy D., Lamba, Deepak A., Ramanathan, Arvind, 2016
Selective programming of CCR10+ innate lymphoid cells in skin-draining lymph nodes for cutaneous homeostatic regulation
Nature Immunology, Yang, Jie, Hu, Shaomin, Zhao, Luming, Kaplan, Daniel H., Perdew, Gary H., Xiong, Na, 2016
Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
Scientific reports, Hubbard, Troy D., Murray, Iain A., Bisson, William H., Lahoti, Tejas S., Gowda, Krishne, Amin, Shantu G., Patterson, Andrew D., Perdew, Gary H., 2015
Metabolomics Reveals that Aryl Hydrocarbon Receptor Activation by Environmental Chemicals Induces Systemic Metabolic Dysfunction in Mice
Environmental Science and Technology, Zhang, Limin, Hatzakis, Emmanuel, Nichols, Robert G., Hao, Ruixin, Correll, Jared, Smith, Philip B., Chiaro, Christopher R., Perdew, Gary H., Patterson, Andrew D., 2015
Differential regulation of Th17 and T regulatory cell differentiation by aryl hydrocarbon receptor dependent xenobiotic response element dependent and independent pathways
Toxicological Sciences, Mohinta, Sonia, Kannan, Arun K., Gowda, Krishne, Amin, Shantu, Perdew, Gary H., August, Avery, 2015
Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation
Journal of Investigative Dermatology, Van Den Bogaard, Ellen H., Podolsky, Michael A., Smits, Jos P., Cui, Xiao, John, Christian, Gowda, Krishne, Desai, Dhimant, Amin, Shantu G., Schalkwijk, Joost, Perdew, Gary H., Glick, Adam B., 2015
A Structural Switch Between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain
Biology, Perkins, Arden, Phillips, Jessica L., Kerkvliet, Nancy I., Tanguay, Robert L., Perdew, Gary H., Kolluri, Siva K., Bisson, William H., 2014
In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract
British Journal of Pharmacology, Fang, Zhong Ze, Krausz, Kristopher W., Nagaoka, Kenjiro, Tanaka, Naoki, Gowda, Krishne, Amin, Shantu G., Perdew, Gary H., Gonzalez, Frank J., 2014
Role of the Ah receptor in homeostatic control of fatty acid synthesis in the liver
Toxicological Sciences, Tanos, Rachel, Murray, Iain A., Smith, Philip B., Patterson, Andrew, Perdew, Gary H., 2012
Ah receptor antagonism represses head and neck tumor cell aggressive phenotype
Molecular Cancer Research, DiNatale, Brett C., Smith, Kayla, John, Kaarthik, Krishnegowda, Gowdahalli, Amin, Shantu G., Perdew, Gary H., 2012
Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure
Journal of Pharmacology and Experimental Therapeutics, Narayanan, Gitanjali A., Murray, Iain A., Krishnegowda, Gowdahalli, Amin, Shantu, Perdew, Gary H., 2012
Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element-independent manner
Hepatology, Tanos, Rachel, Patel, Rushang D., Murray, Iain Alexander, Smith, Philip B., Patterson, Andrew David, Perdew, Gary H., 2012
Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3′,4′-dimethoxy- α-naphthoflavone
Molecular pharmacology, Murray, Iain Alexander, Flaveny, Colin A., Chiaro, Christopher R., Sharma, Arun, Tanos, Rachel S., Schroeder, Jennifer C., Amin, Shantu, Bisson, William H., Kolluri, Siva K., Perdew, Gary H., 2011
Estrogen receptor expression is required for low-dose resveratrol-mediated repression of aryl hydrocarbon receptor activity
Journal of Pharmacology and Experimental Therapeutics, Perdew, Gary H., Hollingshead, Brett D., DiNatale, Brett C., Morales, J. Luis, Labrecque, Mark P., Takhar, Mandeep K., Tam, Kevin J., Beischlag, Timothy V., 2010
Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells
Science, Boitano, Anthony E., Wang, Jian, Romeo, Russell, Bouchez, Laure C., Parker, Albert E., Sutton, Sue E., Walker, John R., Flaveny, Colin A., Perdew, Gary H., Denison, Michael S., Schultz, Peter G., Cooke, Michael P., 2010
Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties
Chemical research in toxicology, Murray, Iain A., Krishnegowda, Gowdahalli, Dinatale, Brett C., Flaveny, Colin, Chiaro, Chris, Lin, Jyh Ming, Sharma, Arun K., Amin, Shantu, Perdew, Gary H., 2010
Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling
Toxicological Sciences, DiNatale, Brett C., Murray, Iain A., Schroeder, Jennifer C., Flaveny, Colin A., Lahoti, Tejas S., Laurenzana, Elizabeth M., Omiecinski, Curtis J., Perdew, Gary H., 2010
Protein function analysis
Cytotechnology, DiNatale, Brett C., Perdew, Gary H., 2010
Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity
Molecular pharmacology, Murray, Iain A., Morales, Jose L., Flaveny, Colin A., DiNatale, Brett C., Chiaro, Chris, Gowdahalli, Krishnegowda, Amin, Shantu, Perdew, Gary H., 2010
The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor
Biochemistry, Schroeder, Jennifer C., DiNatale, Brett C., Murray, Iain A., Flaveny, Colin A., Liu, Qiang, Laurenzana, Elizabeth M., Lin, Jyh Ming, Strom, Stephen C., Omiecinski, Curtis J., Amin, Shantu, Perdew, Gary H., 2010
Antagonism of aryl hydrocarbon receptor signaling by 6,2′,4′- trimethoxyflavone
Journal of Pharmacology and Experimental Therapeutics, Murray, Iain A., Flaveny, Colin A., DiNatale, Brett C., Chairo, Chris R., Schroeder, Jennifer C., Kusnadi, Ann, Perdew, Gary H., 2010
