|University of Rochester|
School of Medicine & Dentistry
|Molecular Toxicology & Environmental Medicine Cluster|
|Ph.D. Program in Toxicology|
|Thomas A. Gasiewicz|
Professor and Chair, Department of Environmental Medicine
B.S. 1972 (Canisius College)
Ph.D. 1977 (University of Rochester)
Receptor-mediated Modulation of Gene Expression
and Association with Biological and Toxic Responses
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.
Yin Z, Henry EC, Gasiewicz TA. (-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. Biochemistry. 2009 Jan 20;48(2):336-345.
Singh KP, Casado FL, Opanashuk LA, Gasiewicz TA. The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol. 2009 Feb 15;77(4):577-587.
Singh KP, Wyman A, Casado FL, Garrett RW, Gasiewicz TA. Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis. 2009 Jan;30(1):11-19.
Vezina CM, Allgeier SH, Moore RW, Lin TM, Bemis JC, Hardin HA, Gasiewicz TA, Peterson RE. Dioxin causes ventral prostate agenesis by disrupting dorsoventral patterning in developing mouse prostate. Toxicol Sci. 2008 Dec;106(2):488-496.
Baglole CJ, Maggirwar SB, Gasiewicz TA, Thatcher TH, Phipps RP, Sime PJ. The aryl hydrocarbon receptor attenuates tobacco smoke-induced cyclooxygenase-2 and prostaglandin production in lung fibroblasts through regulation of the NF-kappaB family member RelB. J Biol Chem. 2008 Oct 24;283(43):28944-28957.
Henry EC, Gasiewicz TA. Molecular determinants of species-specific agonist and antagonist activity of a substituted flavone towards the aryl hydrocarbon receptor. Arch Biochem Biophys. 2008 Apr 15;472(2):77-88.
Collins LL, Williamson MA, Thompson BD, Dever DP, Gasiewicz TA, Opanashuk LA. 2,3,7,8-Tetracholorodibenzo-p-dioxin exposure disrupts granule neuron precursor maturation in the developing mouse cerebellum. Toxicol Sci. 2008 May;103(1):125-136
Ryan EP, Holz JD, Mulcahey M, Sheu TJ, Gasiewicz TA, Puzas JE. Environmental toxicants may modulate osteoblast differentiation by a mechanism involving the aryl hydrocarbon receptor. J Bone Miner Res. 2007 Oct;22(10):1571-1580.
Thatcher TH, Maggirwar SB, Baglole CJ, Lakatos HF, Gasiewicz TA, Phipps RP, Sime PJ. Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB. Am J Pathol. 2007 Mar;170(3):855-864.
Bemis JC, Alejandro NF, Nazarenko DA, Brooks AI, Baggs RB, Gasiewicz TA. TCDD-induced alterations in gene expression profiles of the developing mouse paw do not influence morphological differentiation of this potential target tissue. Toxicol Sci. 2007 Jan;95(1):240-248.
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):1871-1878.
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Revised June 15 2009(vgl)