This laboratory focuses on the molecular mechanisms whereby the halogenated heterocyclic aromatics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), produce toxicity in mammals. These compounds are environmental contaminants and extremely potent toxic chemicals. The recognition that they act via a gene regulatory protein, the Ah receptor (AhR), to modulate gene expression and alter cell proliferation and differentiation, has also stimulated their use as probes to understand gene regulation. All mammalian species, including humans, possess the AhR. This suggests the conservation of some, as yet unknown, function of this protein in basic cell regulatory processes.

       Much of the research is centered on understanding the properties of the AhR, its interactions with DNA, and the mechanisms whereby it modulates gene expression in a cell-specific manner. Part of this is directed at determining the molecular mechanisms for the ability of chemicals to bind to the AhR and act as agonists or antagonists. In addition, more recent studies have focused on identifying the target cells and genes that are affected in developing animals as this period appears to be extremely sensitive to these chemicals.

       Immunosuppression is one of the most consistent biological responses that is observed in mammals following exposure to TCDD. Specific alterations in immune function are observed in animals at doses as low as 0.01 µg/kg body weight. This laboratory is also defining the molecular and cellular events, mediated by the AhR, that lead to TCDD-elicited suppression of immune function. We have found that TCDD affects bone marrow stem cells by modulating their ability to proliferate and/or differentiate into more mature cells. Further studies are examining the effects of TCDD on discrete developmental stages of lymphocyte ontogeny and the role of the AhR in mediating these changes.

Garrett RW, Gasiewicz TA. 2006. The aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin alters the circadian rhythms, quiescence, and expression of clock genes in murine hematopoietic stem and progenitor cells. Mol Pharmacol. Jun;69(6):2076-2083

Henry EC, Bemis JC, Henry O, Kende AS, Gasiewicz TA. 2006. A potential endogenous ligand for the aryl hydrocarbon receptor has potent agonist activity in vitro and in vivo. Arch Biochem Biophys. Jun 1;450(1):67-77.

Kim SH, Henry EC, Kim DK, Kim YH, Shin KJ, Han MS, Lee TG, Kang JK, Gasiewicz TA, Ryu SH, Suh PG. 2006. Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol. Jun;69(6):1871-8.

Bemis JC, Nazarenko DA, Gasiewicz TA. 2005. Coplanar polychlorinated biphenyls activate the aryl hydrocarbon receptor in developing tissues of two TCDD-responsive lacZ mouse lines. Toxicol Sci. Oct;87(2):529-536.

Martey CA, Baglole CJ, Gasiewicz TA, Sime PJ, Phipps RP. 2005. The aryl hydrocarbon receptor is a regulator of cigarette smoke induction of the cyclooxygenase and prostaglandin pathways in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. Sep;289(3):L391-399

Palermo CM, Westlake CA, Gasiewicz TA. 2005. Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein. Biochemistry. Apr 5;44(13):5041-5052.

Williamson MA, Gasiewicz TA, and Opanashuk LA. 2005. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity. Toxicol Sci. Feb;83(2):340-348.

Filbrandt CR, Wu Z, Zlokovic B, Opanashuk L, and Gasiewicz TA. 2004. Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes. Neurotoxicology. 2004 Jun;25(4):605-616.

Minsavage GD, Park SK, and Gasiewicz TA. 2004. The aryl hydrocarbon receptor (AhR) tyrosine 9, a residue that is essential for AhR DNA binding activity, is not a phosphoresidue but augments AhR phosphorylation. J Biol Chem. May 14;279(20):20582-20593.

Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, and Reiners JJ Jr. 2003. The Jun N-terminal kinase inhibitor sp600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos. Nov;31(11):1279-1282.

Laiosa MD, Wyman A, Murante FG, Fiore NC, Staples JE, Gasiewicz TA, and Silverstone AE. 2003. Cell proliferation arrest within intrathymic lymphocyte progenitor cells causes thymic atrophy mediated by the aryl hydrocarbon receptor. J Immunol. Nov 1;171(9):4582-4591.

Palermo CM, Hernando JI, Dertinger SD, Kende AS, and Gasiewicz TA. 2003. Identification of potential aryl hydrocarbon receptor antagonists in green tea. Chem Res Toxicol. Jul;16(7):865-872.

Zhou J, and Gasiewicz TA. 2003 3'-methoxy-4'-nitroflavone, a reported aryl hydrocarbon receptor antagonist, enhances Cyp1a1 transcription by a dioxin responsive element-dependent mechanism. Arch Biochem Biophys. Aug 1;416(1):68-80.

Minsavage GD, Vorojeikina DP, and Gasiewicz TA. 2003. Mutational analysis of the mouse aryl hydrocarbon receptor tyrosine residues necessary for recognition of dioxin response elements. Arch Biochem Biophys. Apr 1;412(1):95-105.

Zhou JG, Henry EC, Palermo CM, Dertinger SD, and Gasiewicz TA. 2003. Species-specific transcriptional activity of synthetic flavonoids in guinea pig and mouse cells as a result of differential activation of the aryl hydrocarbon receptor to interact with dioxin-responsive elements. Mol Pharmacol. Apr;63(4):915-924.

Henry EC, and Gasiewicz TA." 2003. Agonist but not antagonist ligands induce conformational change in the mouse aryl hydrocarbon receptor as detected by partial proteolysis. Mol Pharmacol. Feb;63(2):392-400.