Environmental toxicology: The role of environmental and chemical toxicants on gene expression
University of Iowa
University of Minnesota
Exposure to environmental toxicants such as air born combustion products, industrial waste that contaminates water supplies or continuous contact with chemical agents through job related exposure have the potential to impact on human health. In most instances, the body is capable of handling chemical exposure by forcing the compounds to undergo metabolism, an event which leads to excretion and elimination. However, in many instances, direct chemical contact leads to alterations in the genetic composition of the cell by introducing randomized mutations or enhancement of programmed gene transcription. The latter facilitates a toxic episode. Our laboratory is interested in the cellular and molecular events that lead to cell toxicity.
There are several cellular events that are initiated as the result of exposure to a toxicant. In most instances, the chemical agent undergoes oxidative metabolism and detoxification through highly specific conjugation reactions. These events lead to changes in the water: lipid partition coefficient and forces the metabolite more towards the water compartments of the cell. Alternatively, oxidative metabolism alters the biological activity of the metabolite to a more toxic agent, which in turn facilitates changes in the transcriptional machinery of the cell. These transcriptional changes are recruited by the cell to manufacture protein in an effort to fight against potential cellular damage. Two very significant alterations occur. First, activation of signal transduction mechanisms leading to oxidative stress are initiated. The end result is enhanced transcriptional alterations. Second, these acute changes reprogram how the cell handles these metabolites by assuring adequate changes in the machinery that facilitates cellular detoxification.
Our laboratory focuses its efforts on 1) understanding the cellular and molecular events that lead to activation of nuclear transcription factors, such as the family of nuclear xenobiotic receptors and 2) the genetic mechanisms that underlie the contribution of oxidative metabolism and cellular defense as a result of insult to environmental exposure.
Primary Research Area
- Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. With W. Xie, M.F. Yeuh, A. Radominska-Pandya, S.P. Saini, Y. Negishi, B.S. Bottroff, G.Y. Cabrera, and R.M. Evans. Proc Natl Acad Sci U S A. 100, 4150-4155 (2003).
- Involvement of the Xenobiotic Response Element (XRE) in Ah Receptor-mediated Induction of Human UDP-glucuronosyltransferase 1A1*. With M.F. Yueh, Y.H. Huang, A. Hiller, S. Chen, and N. Nguyen. J. Biol. Chem. 278, 15001-15006 (2003).
- The role of the Ah-receptor and p38 in benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide induced apoptosis. With S.Chen, N. Nguyen, K. Tamura, and M. Karin. J. Biol. Chem. 278, 19526-19533 (2003).
- Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. With Y.H. Huang, A. Galijatovic, N. Nguyen,D. Geske, D. Beaton, J. Green, M. Green, and W.H. Peters. Pharmacogenetics. 12: 287-97, (2002).